Skip to main content

Nanoscale Drug Delivery Systems in Glioblastoma

Abstract

Glioblastoma is the most aggressive cerebral tumor in adults. However, the current pharmaceuticals in GBM treatment are mainly restricted to few chemotherapeutic drugs and have limited efficacy. Therefore, various nanoscale biomaterials that possess distinct structure and unique property were constructed as vehicles to precisely deliver molecules with potential therapeutic effect. In this review, nanoparticle drug delivery systems including CNTs, GBNs, C-dots, MOFs, Liposomes, MSNs, GNPs, PMs, Dendrimers and Nanogel were exemplified. The advantages and disadvantages of these nanoparticles in GBM treatment were illustrated.

Introduction

Glioblastoma, also called glioblastoma multiforme (GBM), is considered as the most aggressive cerebral tumor in adults. The standard therapy for GBM is maximal safe resection followed by adjuvant radiation and oral temolozomide (TMZ), which extends patients’ life expectancy only by 16 to 18 months [1]. Due to the aggressive and invasive characteristics of GBM, resecting all tumor tissues in surgery is acknowledged to be impractical. Additionally, extensive resistance can be easily induced after long-term radiotherapy and chemotherapy treatments. The high phenotypic and genotypic heterogeneity of GBM result in multidrug resistance and limited specificity for drug delivery. The bioavailability and efficacies of delivered therapeutic drugs are mainly impaired by factors including tumor microenvironment, stem cell, immune escape, and the most importantly, Blood–Brain Barrier (BBB).

Nanotechnology is an interdisciplinary science to develop and investigate materials at nanometer scale. Disciplines such as physics, chemistry, engineering and biomedical are involved in, hence nanotechnology has become an emerging field in recent years. Although the sensu stricto description of nanotechnology is defined as the manipulation of matters from 1 to 100 nm (by National Nanotechnology Initiative), researchers prefer to recognize it with the broad range to hundreds of nanometers (in submicron scale), especially in the biomedical field. With the remarkable advancements in nanotechnology, nanomaterials were translated into the biomedical area and numerous nanoparticles (NPs) have been developed as drug delivery systems (DDS) for diagnostic and therapeutic application. Based on their different action modes, nanoscale DDS can be classified as passive targeting or active targeting systems. The passive targeting DDS exploit the signatures of tumoral angiogenesis, in which the new blood vessels have enhanced permeability, and the poor lymphatic drainage can passively cause NPs retention (EPR effect). However, due to the existence of intact Blood–Brain Barrier, passive targeting DDS that lack selectivity are unable to penetrate into brain effectively and are unsuited to the GBM treatment. Therefore, active targeting DDS modified with vectors including peptide, protein, aptamer, small molecule and hybrid membrane are utilized in GBM therapy to improve the effectiveness of delivered drugs [2].

Active targeting nanoscale drug delivery systems are able to overcome the limitations of conventional medication therapy. Blood–Brain Barrier is established between cerebral capillaries and neuroglia cells. The tight junctions between endothelial cells selectively restrict the paracellular diffusion of more than 98% particular small molecules including chemotherapy drugs and other therapeutic molecules [3]. The insufficient drug concentration in GBM local will lead to inferior therapeutic efficacy, yet several strategies for NPs bio-modification were employed to enhance the infiltration ability of drug platform. By utilizing Receptor-mediated Endocytosis (RME) process, drug-encapsulated NPs that conjugated to the paired ligands on brain endothelial cells could obtain significantly enhanced BBB permeability [4, 5]. Cationic-joint [6] and lipophilic [7, 8] NPs could effectively transport drugs into the brain through Adsorptive-mediated Endocytosis (AME) and transcellular lipophilic pathway, respectively. Besides, Carrier-mediated Endocytosis (CME) involving nutrient transporters [9] was utilized for effective delivery of nanoscale DDS. Hybrid cell membrane-coated NPs [10] could cross the intact BBB via Cell-mediated transport. Comparing to conventional drug administration routine, modified NPs delivery have the advantages of superior pharmacokinetic performance and high specificity. Prolonged half-time, reduced uptake by reticulo-endothelial system and sustained drug release in tumor sites could reduce the delivery dosage and minimize side effects. Smart biomaterials were also employed to achieve specific bio-mechanical application and controlled drug release, in which environmental stimulants such as pH [11], temperature [12] and near-infrared (NIR) light [13] were exploited. Co-delivery of dual/multiple therapeutic molecules by NPs could be utilized to overcome multidrug resistance and the shortcomings of monotherapy. In addition, nanoscale DDS could be applied in surgical implantation [14], transdermal delivery [15], intranasal delivery [16] and ocular delivery [17].Several NPs including Gliadel®, Doxil®, Lupron Depot®, Marqibo® were approved by Food and Drug Administration (FDA) in clinic applications for various diseases.

In this review, we focused on the nanoscale drug delivery systems that have been proposed for the diagnostics and therapeutics of glioblastoma. The synthesis, functionalization and application of NPs were discussed. The advantages and limitation of each nanoparticle were elaborated thoroughly. Finally, the prospect of future GBM nanoscale DDS therapy was discussed.

Carbon Allotropes

Carbon Nanotubes

Carbon nanotubes (CNTs) were recognized as the seamless cylindrical-shape materials with high aspect ratio and satisfactory penetration capacity [18]. CNT has emerged as an influential material in the mechanical and electrical area. They are classified into two structural types: single-walled CNTs (SWCNTs) and multi-walled CNTs (MWCNTs) (Fig. 1). SWCNTs are composed of a single cylindrical graphene sheet with diameter ranging from 0.4 to 2 nm [19]. MWCNTs are multilayer coaxial graphene sheets that encircle an inner cylinder. The outer diameter of MWCNTs ranges from 2 to 100 nm [20]. Although CNTs possess extraordinary properties such as high drug loading efficacy and photoluminescence, limitations including low solubility in aqueous solvent and short half-life impede their applications in life system. Researches [21, 22] indicated that the original CNTs showed inherently toxicity to organism irrespective of the preparation. Functionalization is acknowledged to be an effective approach to improve the dispersion and biocompatibility of CNTs. For instance, by involving hydrophilic groups/polymers, the poor solubility and bio-distribution of CNTs can be significantly improved. The major functionalization of CNTs includes oxidation, acylation, cycloaddition and noncovalent associations, in which the toxicity could be reduced [20]. Consequently, CNTs were exploited as an ideal vehicle for drug delivery in recent years due to the facilely modified features and stability. The advantages and disadvantages of CNTs as drug delivery system were listed in Table 1.

Fig. 1
figure 1

Conceptual diagrams of single-walled carbon nanotubes (SWCNT) (a) and multi-walled carbon nanotubes (MWCNT) (b). Referred from [23], OA

Table 1 The advantages and disadvantages of various nanoparticle systems

By modified with functionalized groups and polymers on surface, CNTs garnered superior properties such as hydrophilicity, biocompatibility and specificity. Samuel et al. [24] designed chemical functionalized nitrogen-doped MWCNT by acid treatment. The products N-MWCNT-ox specifically eliminated RG2 cells through DNA damage and oxidative stress without inducing reactive inflammation or systemic toxicity. In addition, the combination of N-MWCNT with TMZ exhibited additive tumor-suppressive effects on GBM. Although immunostimulatory oligonucleotide CpG was considered to activate TLR9 as well as initiate immune system to counteract GBM, its efficiency was proved disappointed in vivo. Darya et al. [25] integrated CpG with SWCNT non-covalently, which assisted the delivery of CpG without affecting its therapeutic properties. They demonstrated that SWCNT/CpG inhibited the migration of GBM cells by inducing TLR9/ NF-κB pathway of macrophages. In another efforts, chemotherapeutics including Carmustine [26], Oxaliplatin [27], Lucanthone [28] and Dasatinib [29] were encapsulated into the functionalized CNTs for GBM treatment. Evidences suggested that N-CNTs/Carmustine [26] exhibited continuous kinetic release for 72 h, contributing to the increased intratumoral drug concentration and limited systemic toxicity when comparing with conventional administration route. Besides, TAT-PEI-B-MWCNT-COOH-Oxaliplatin [27] and f-MWNT-ANG [30] showed significantly enhanced BBB penetration and GBM targeting properties in animal model. Therefore, in order to effectively utilize CNTs as drug carriers, the surface modification is an indispensable part.

Graphene-Based Nanoparticles (GBNs)

Graphene is recognized as the two-dimensional sp2 hybridized carbon material that assembles tightly in a honeycomb-like lattice structure. It has been widely employed in electronic devices (sensor, battery and transistor), aerospace and composite materials. Technically, graphene is recognized as the basic building blocks of other carbon materials such as CNTs and quantum dot [31]. Graphene materials possess excellent optical, electrical as well as mechanical properties and they have emerged as the revolutionary materials in nanoscale processing, biomedicine and drug delivery area. In respect of the physical features, graphene is well known for its exceptional stability, well diathermancy, high mechanical strength and great electrical conductivity. The common derivatives of GBNs are graphene oxides (GO) and reduced graphene oxides (rGO) (Fig. 2). They possess superior biocompatibility and straightforward bio-functionalization capacity [32] when comparing to carbon allotrope CNTs. Additionally, the unique photothermic property of GBNs can be utilized in the stimuli-responsive drug release [33].

Fig. 2
figure 2

a Two main routes to prepare GBNs: “Top-down” splitting approach and “Bottom-up” synthesis approach. b Classifications of graphenes based on lateral size. The GQDs represent graphene quantum dots. Referred from [34] with permission

The planar structure of GBNs provide large surface for the chemical conjugation of drugs or molecules [35]. Cationic glycoprotein Lactoferrin (Lf) belongs to the transferrin family which can be associated with the Lf receptor overexpressed on BBB endothelia cells. Therefore, the Lf-modified drug delivery systems were commonly utilized to across BBB through receptor-mediated endocytosis [36]. Song et al. [37] decorated GO with Lactoferrin and Fe3O4 to construct superparamagnetic drug-loaded nanocomposite Lf@GO@Fe3O4@DOX (Doxorubicin). The NPs performed admirable DOX delivery efficiency as well as exceptional anti-tumor capacity. Similarly, peptide angiopep (ANG)-2 is a specific ligand for the low-density lipoprotein receptor-related protein-1 (LRP-1) expressed on BBB endothelia cells. ANG@GO@DOX designed by Zhao et al. [38] displayed enhanced intracellular uptake and cytotoxicity due to the specific endocytosis capacity. In addition, functionalized GO such as PF127@GO@DOX [39], FA@GO@TMZ [40], PLGA@GO@IUdR [41] and mAb@GO@PPa [42] showed promising therapeutic efficacies, indicating functionalization could significantly improve the BBB transport and GBM specificity.

Carbon dots (C-dots)

Carbon dots, which is also recognized as carbon quantum dots (CQDs), are composed of dispersed spherical carbon particles (graphite-like core and amorphous oxygen-containing shell) with small size below 10 mm [43]. The synthetic materials of CQDs were readily available, and the synthesis methods of CQDs are multifarious, which are generally based on “top-down” or “bottom-up” approaches [44]. Carbon dots possess unique photoluminescence (PL) properties, hence they are promising nanoparticles for imaging, photocatalysis and photovoltaics applications [45]. In addition, owing to the plentiful functional groups for branching and decorating, C-dots became one of the prominent drug delivery systems in GBM therapy.

The single chemotherapeutic drug administration may easily induce resistance and relapse of GBM after long-term employment. Researches [46, 47] focused on dual drug delivery were conducted to surmount the single drug delivery dilemma, however, the overall particle sizes of NPs are too large to across BBB. Sajini et al. [48] developed a triple conjugated system of C-dots with an average particle size of 3.5 nm, in which transferrin, epirubicin and temozolomide were associated. The triple conjugated system exerted intense cytotoxicity to GBM cells and displayed synergistic effects owing to the dual-drug combination. Wang et al. [49] designed the polymer-coated CODs with DOX and I6P7 (IL-6 fragment peptide for targeting). Based on the photoluminescence property of special CODs, fluorescence resonance energy transfer (FRET) effect were able to be induced by specific wavelength for DOX release real-time monitoring. In acidic solutions, the drug-encapsulated CODs exhibited increased DOX release similarly with other carbon allotropes. This pH-sensitive releasing performance attributed to the acid-induced protonation of NH2 group in DOX and consequent dissociation of π-π interaction [50]. Piumi et al. [51] conjugated Gemcitabine and transferrin protein with CODs for pediatric GBM treatment, in which the outstanding BBB penetration, selective targeting as well as anti-GBM efficacy were observed.

Apart from CNTs, GBNs and CODs, other carbon nanostructures like fullerene and nanodiamond (ND) were also exploited for GBM drug delivery. The DDS based on carbon allotropes including CF@LYS@TEG@MMF [52], ND@DOX [53] (via convection-enhanced delivery) and Polyglycerol@ND@DOX [54] were reported in corresponding anti-GBM investigations. With respect to these carbon allotropic NPs, their biocompatibility and toxicity are greatly depended on the layer number, lateral size, hydrophilicity, and the most importantly, surface chemistry [31]. Hence, proper comprehending of how carbon NPs interact with cells is of significance to improve the biocompatibility and specificity through functionalization,

Metal–Organic Frameworks (MOFs)

Metal–organic frameworks, the synthetic nanomaterials with mesoporous structure and prominent surface area (1000 ~ 14,000 m2/g), are consisted of metal core and coordinated organic ligands [55]. The history of two-dimensional MOFs went back to 1897, when Hofmann [56] fabricated the first hybrid networks of nickel-organic crystal. MOFs were concerned to have pH-sensitive properties and tunable structures (pore size), therefore plenty of them were prepared as ideal drug delivery system. However, the non-biodegradable metal ions including iron, copper, cobalt, cadmium and nickel in MOFs could show potential toxicity to organism [57]. Materials of Institute Lavoisier (MILs) [58], Zeolitic Imidazolate Frameworks (ZIFs) [59], pDBI [60], Hong Kong University of Science and Technology (HKUST-1) [61], University of Oslo (UiOs) [62] and Isoreticular Metal Organic Frameworks (IRMOFs) [63] (Fig. 3) were widely applied in cancer drug delivery, among which ZIF-8 were the most eximious one in GBM investigation.

Fig. 3
figure 3

a Crystal structures of different MOFs. b High resolution TEM image of Uio-66. Referred from [64, 65] with permission

ZIF-8 is composed of central tetrahedral zinc and coordinated 2-methylimidazole at an angle of 145° [66]. The self-assemble lamellar structure of ZIF-8 was maintained by π–π stacking interaction and hydrogen bonds [66], resulting in the mesoporous cavity and large surface area of ZIF-8. With respect to biocompatibility, zinc represents the second most abundant metal in human, exerting nearly no potential metal cytotoxicity on human cells. Abhijeet et al. [67] developed LND-HA@ZIF-8@Lf@5-FU nanoparticles, in which hyaluronic acid (HA) targeted the CD44 receptors overexpressed on GBM cells, and Lf endowed NPs with BBB penetrating ability. In addition, chemotherapeutics Lenalidomide (LND) and 5-Fluorouracil (5-FU) exerted anti-GBM function in a synergetic manner. Pan et al. [68] produced bimetallic Mn-ZIF-8 aiming to deliver 5-FU. Due to the excessive glycolysis of Warburg effect, pH-sensitive Mn2+ and 5-FU were easily released in the relatively acidic GBM microenvironment. Meanwhile, the accumulation of Mn2+ in GBM provided available T1-weighted MR signals for in vivo imaging, enabling NPs to exert diagnostic and therapeutic effects simultaneously. Zhang et al. [14] constructed modified ZIF-8 system (THINR) wrapped with glioma-associated macrophage membrane (GAMM). Chemokines CXCL10 and GAMM camouflaged with α4β1 integrin provided ZIF-8 NPs with GBM-tropistic property. Chemotherapeutic Mitoxantrone (MIT) and siRNA that targeted endogenous immunosuppressive mediator IDO1 (siIDO1) were co-delivered in ZIF-8 system via intratumor nanogel implantation. The THINR-CXCL10-nanogel restrained relapse of GBM and prolonged overall survival (OS) in tumor-resected animal models.

Liposomes

Liposomes are the closed bilayer systems fabricated from self-assembly phospholipids. Depending on the numbers of bilayers as well as method of preparation, the particle size of liposomes ranges from nanometers to micrometers [69] (Fig. 4). Liposomes have attracted substantial attentions in DDS due to their prominent biocompatibility, high loading efficacy, extremely low cytotoxicity and low immunogenicity. The phospholipids are consisted of polar phosphate and hydrophobic lipid tails, which endows liposomes with the ability to encapsulate drug regardless of its physiochemical properties [70]. Drugs can be incorporated into the lipid bilayers [71], sequestered in the hydrophilic core [72] or conjugated on the surface of liposomes [73]. Despite that, the instability and rapid clearance of liposomes in circulation lead to attenuated efficiency, hence invading reticulo-endothelial system is essential for liposomes DDS.

Fig. 4
figure 4

The structure, vesicle size (a) and lamellarity classification (b) of liposome drug delivery systems. c, d The cryo-electron tomography liposomes Doxil structure with the liposome density shown in purple and doxorubicin density shown in pink. Referred from [74, 75] with permission

Wei et al. [76] investigated the efficacies of functionalized liposome that loaded with DOX. They synthesized stable peptide DCDX and c(RGDyK) against enzymatic microenvironments through cyclization, partial D-amino acid substitution and retro-inverso isomerization while the GBM-targeting and BBB penetration function remained. Polyethylene glycol (PEG) moiety was adopted as sheath, contributing to the camouflage and prolonged circulation. Butylidenephthalide (BP) was considered to be a promising anti-GBM compound while limited by its hydrophobicity and low bioavailability [77]. Thus, Lin et al. [78] prepared BP-embraced LP@cyclodextrin (a truncated cone shape drug delivery system) complex for expanded loading efficacy and controlled release. In order to evade BBB, the liposomal formulations were administrated through intranasal path. Taken together, the uniqueness of liposomes structure that allows intercalating all kinds of therapeutic molecules highlighted their use in drug delivery.

Apart from liposomes, analogous nanoparticles such as extracellular vesicles (EV), niosomes, solid lipid nanoparticles (SLP), exosomes and microparticles were also acknowledged to be promising vehicles for drug delivery. See in Table 2.

Table 2 Liposome particle (LP) based anti-GBM drug delivery system

Inorganic Nanoparticles

Mesoporous Silica

Based on the porous structure and well biocompatibility, mesoporous silica nanoparticles (MSNs) are widely applied in biomedicine and drug delivery field. According to International Union of Pure and Applied Chemistry (IUPAC), MSNs are considered to be the ordered silicon oxide structures with pore size ranging from 2 to 50 nm. MSNs possess satisfactory cell bioavailability and show inappreciable cytotoxicity in low dose (< 50 μg/mL) [85]. The synthesis of MSNs is mainly based on silica precursors and surfactants in a template-directed method, which play an indispensable role in determining the pore size and orientation of MSNs products [86, 87]. In order to obtain GBM-tropistic function, modifications including homing ligand and magnetic molecules were introduced to MSNs. Various magnetic-MSNs were designed and the most common magnetic MSNs were composed of metal core and silica shell in an embedded core–shell manner [88, 89]. Apart from that, sandwich-structured [90], hollow-type [91] and rattle-type [92] magnetic MSNs were developed for multidisciplinary applications [93] while seldom were employed in drug delivery.

Zhu et al. [94] developed angiopep-2 modified and lipid coated mesoporous silica (ANG@LP@MSN) to delivery paclitaxel (PTX). The ang-2 and lipid layer contributed to the brain penetrating capacity and effective surface functionalization respectively. In general, MSNs exhibited burst drug release while lipid coating decreased the trend from 46 to 25% in initial 2 h. The T1/2 (half life time) and AUCblood (Area under curve of the blood concentration) were increased to 4.5 and 2.5 times respectively comparing with MSNs without lipid layer. The MSN system exerted anti-tumor efficacy (proliferation and migration) both in vitro and in vivo, inducing the cell cycle arrest of GBM cells. Nanoplatform Fe3O4@mSiO2(DOX)@HSA(Ce6) was constructed by Tang et al. [95]. Due to the employment of metal molecule, magnetic guidance ability was achieved by Fe3O4 core surrounded with silica shell (mSiO2). Consequently, aggregation and retention of the whole delivery system in GBM site were observed during magnetic triggering, exhibiting targeting capacity and long-lasting superiority of magnetic nanoparticles. In addition, the combination of photodynamic therapy and chemotherapy (by chlorin e6 and DOX) displayed synergistic antitumor efficacy against GBM. Additional mesoporous silica nanoparticles for GBM therapy were listed in Table 3.

Table 3 Mesoporous silica (MSN) based anti-GBM drug delivery system

Gold Nanoparticles (GNPs)

Gold nanoparticles, also recognized as AuNPs or colloidal gold, have attracted tremendous attentions on the diagnosis and drug delivery applications of GBM. GNPs have been recommended for antimicrobial applications and showed low toxicity to [102]. Synthetic GNPs have distinct conformations such as spherical [103], cylindrical [104], cage-like [105] and hollow [106] shapes with core sizes ranging from 1 to 150 nm [107] (Fig. 5). Tunable conformations and sizes endow GNPs with unique optical and electrical properties. Surface plasmon resonance (SPR) is the optical phenomenon when GNPs form dipole oscillation in response of incoming light [108]. It has been explored in local induction heating, imaging, biosensor analysis and drug release [107]. The synthesis of GNPs is mainly based on colloidal synthesis method, in which the metal precursor, reductant and stabilizer were applied sequentially [109]. It was elaborated that the size of GNPs profoundly affected the bio-distribution in circulation. Investigation [110] revealed that GNPs with different sizes (10, 50, 100, 250 nm) exhibited distinct distribution patterns after intravenous administration. The depositions of gold were detected through inductively coupled plasma mass spectrometry (ICP-MS) and only the 10 nm GNPs were found accumulated in organs such as testis, thymus, heart and brain. The functionalizations on GNPs including peptides, antibodies and drugs, which are feasible due to the negative charge on surface [111].

Fig. 5
figure 5

The TEM images of gold nanoparticles with cage-like (a), cylindrical (b), triangular (c) and hexagonal (d) morphologies. Referred from [112,113,114] with permission

Researchers [115] investigated the efficacies of functionalized GNPs that were co-loaded with DOX and HCQ (hydroxychloroquine). Programmed death 1 (PD-1) is a critical immunosuppressive receptor located on T cells, and the overexpression of which indicates the T cell depletions and immune escape in various diseases including GBM. Evidence [116] suggested that impeding PD-1/PD-L1 pathway contributed to the potential antitumor immunity. PD-L1 antibody was associated with GNP drug delivery system [115], which was consisted of peptide (Ala-Ala-Asn-Cys-Lys) conjugated polyethylene glycol-thiol (PEG-SH) and 2-cyano-6-amino-benzothiazole (CABT) conjugated PEG-SH. The modifications of peptide and CABT on GNPs significantly reduced the protein corona effects caused by intravenous administration. The stable physicochemical properties of GNPs contributed to the controlled release of DOX and HCQ in GBM local. In addition, HCQ was reported to resensitize GBM by inhibiting DOX-induced autophagy, which exerted excellent anti-GBM capacity in combine with PD-1/PD-L1 pathway blocking. Gallic acid (3,4,5‐trihydroxybenzoic acid, GA) is a well‐established antioxidant that shows potential anti-tumor capacity against GBM in vitro, however, the limited delivery method and poor drug availability restrict its further application. Through physical agitation adsorption, Zhou et al. [117] constructed the GA@GNPs characterized with an average diameter of 23 ± 0.34 nm. The GA@GNPs system exhibited cytotoxic effect on GBM cells and sensitized the radiation‐mediated S and G2/M cell cycle arrest.

Inorganic nanoparticles such as calcium phosphate nanoparticles (CPNs) [118], layered double hydroxides (LDHs) [119] and halloysite clay nanotubes (HNTs) [120] showed therapeutic benefits in pre-clinical GBM settings. In addition, other metal nanoparticles were designed for GBM therapy such as sliver nanoparticles (AgNPs, especially for enhancing radiosensitivity), copper oxide nanoparticles (CuONPs), zinc oxide nanoparticles (ZnONPs), iron oxide nanoparticles (IONPs), gadolinium-based nanoparticles (GdNPs, for enhancing radiosensitization) and manganese oxide nanoparticles (MnO2NPs). The metal NPs based drug delivery systems were listed in Table 4.

Table 4 Metal nanoparticle based anti-GBM drug delivery system

Polymeric Micelles (PMs)

Polymeric micelles are the sphere-like colloidal particles consistently ranging from 10 to 100 nm [126]. PMs are composed of self-assembly copolymers, which typically possess the analogous conformations similar to phospholipids and surfactants: a hydrophilic domain and a hydrophobic domain. Apart from the most common amphiphilic copolymers (di-block) micelles, PMs that consist of tri-block copolymers (hydrophilic-hydrophobic-hydrophilic) [127, 128] and graft copolymers [129, 130] were developed for the availability of additional functionalization. Comparing to other types of DDS, PMs could act as solubilizing agents for the replacement of toxic solvents [131]. PMs with different morphologies (spherical [132], cylindrical [133], lamellar [134]) garner distinctive biological and pharmacokinetic properties, among which the spherical assembly micelles were extensively elaborated (Fig. 6).

Fig. 6
figure 6

a Schematic illustration of the core–shell structure of a polymer micelle. b Cryogenic transmission electron microscopy (cryo-TEM), tomography (cryo-ET) and computational 3D reconstruction of multicompartment micelles. Referred from [135, 136] respectively with permission

The inward-facing hydrophobic segments of copolymers serve as core in spherical PMs. In order to associate with the interior drugs, hydrophobic segments that possess various functional groups are commonly constructed by polyesters such as PLA [137], PGA [138] and PCL [139]. In addition, the camouflage outer layers of PMs play a pivotal role in stability and targeting. Numerous evidences [140, 141] have indicated the particular functions of polyethylene glycol (PEG) on drug sustained release and surface modification. The external modification of biomaterials with PEG could reduce the immunogenicity of NPs, provide grafting sites and improve the surface absorption.

The micellization of amphiphilic copolymers in aqueous media is mainly dependent on hydrophobic interactions (attractive force) and occurs automatically when concentration reaches the critical micelle concentration (CMC). The CMC of each individual PMs (ranging from 10–7 to 10–6 M) is mainly affected by environmental temperature, copolymer structure and relative molecular weight [142]. Copolymers start to disassociate when concentration remains below CMC, which results in off-target effects and rapid clearance of formulation by circulation. Dispersity (D) or polydispersity index (PDI), is measured as a crucial parameter for micellization performance assessment. Evidence [73] suggested that copolymers with low dispersity (D < 1.2) were suitable for controlled drug delivery system. Therefore, determining CMC and PDI are indispensable for the development and application of PMs.

Owing to the minimal size and unique micellar structure, PMs delivery system plays an essential role in smart releasing and local accumulation comparing to conventional drug administration method. Typically, water-insoluble drugs were encapsulated in PMs to gain augmented loading capacity. It was acknowledged that cyclic peptide Arg-Gly-Asp (cRGD) could specifically bind to the αvβ3 and αvβ5 integrins overexpressed on GBM cells. The cRGD installed epirubicin (EPI)-loaded polymeric (Acetal-PEG-b-PBLA) micelles were constructed by Quader et al. [143] for GBM treatment. Specifically, the hydrazide functional groups were involved in copolymers and the constituent hydrazine-bond would contribute to the pH-sensitive property. siRNA has been recognized as promising therapeutic agent to induce target gene silencing, however, it was limited by instability and low bioavailability in vivo. Peng et al. [144] focused on the cationic polymers Poly(ethylenimine) (PEI) which was reported to facilitate lysosomal escape of siRNA through proton sponge effect [145]. Tri-block polymeric micelle TMZ-FaPEC (Fa-PEG-PEI-PCL)@siRNA were designed to silence antiapoptotic BCL-2 gene, in which the folic acid (FA) moiety could specifically bind to the folate receptors on GBM cells. Consequently, the intracranial injection of micelle DDS exhibited significant GBM inhibition and survival benefit. The additional polymeric micelles for GBM therapeutic drug delivery employments were listed in Table 5.

Table 5 Polymeric micelle (PM) based anti-GBM drug delivery system

Dendrimers

Since polypropylenimine (PPI) and polyamidoamine (PAMAM) were firstly developed by Buhleier [150] and Donald [151] respectively, the synthetic dendrimers have emerged as profound drug delivery vehicles for their varied applicability. Dendrimers are well known for the dendritic architecture consisting of internal core and repeated external branching units [152]. The layers of repeated polymers are also recognized as generations (G) [153]. It was reported that the increase of one generation led to practically double molecular mass of dendrimers [154]. In general, the toxicity of dendrimers depends on generations, surface group and terminal moieties [155]. Introducing chemical modifications could decrease the cytotoxicity while maintaining advantageous properties [155]. The peripheral branching framework of dendrimers provides adequate graft sites for functional groups and bioactive drugs (Fig. 7), which are typically achieved by covalent conjugation, hydrogen bonding or electrostatic adsorption [156]. Additionally, segmented cavities between polymer blocks allow drug entrapment. Dendrimers can be synthesized through divergent and convergent methods, in which the conformations are constructed in the procedures of core-to-shell and shell-to-core manners respectively [157]. Depending on various compositions and generations, dendrimers and the derivatives possess engineerable sizes ranging from 1 to 15 nm [156]. In recent years. a variety of dendrimers are developed for drug delivery, including PAMAM [158], PPI [159], PLL (Poly-l-lysine) [160], PHH (phosphorus) [161], carbosilane [162] and janus [163] dendrimers. The small sizes and flexible surface modifications provide practicable BBB penetrating and GBM targeting ability for dendrimers.

Fig. 7
figure 7

Schematic representation of pharmaceutical applications of dendrimers. Referred from [164] with permission

Tumor-associated macrophages (TAMs) were recognized as an oncogenic factor in GBM. It was demonstrated that the infiltrating and resident macrophages/microglia could be reprogrammed by GBM cells, and the numbers of which were positively correlated with GBM grades [165]. Sharma et al. [166] focused on TAMs and designed PAMAM-OH dendrimer-based rapamycin (Rapa) conjugate. The PAMAM dendrimers with four generations were developed based on ethylenediamine core. Rapa is considered to be a promising anti-GBM reagent towards mTOR pathway and the inhibition of mTOR pathway in TAMs can induce GBM regression. Since Rapa possesses low bioavailability and extremely low aqueous solubility, PAMAM vehicle provided alternative delivery approach across BBB for Rapa administration. The DDS exhibited profound anti-tumor effects by targeting TAMs and GBM cells in vivo. Zhao et al. [167] modified PAMAM with peptide CREKA, which is characterized as tumor-homing ligand towards peritumoral fibrin deposition [168]. The G5 PAMAM was prepared with PEG-CREKA and the average of nanoparticles size was 7.52 ± 0.35 nm. In vivo imaging spectrum (IVIS) results revealed that PAMAM-PEG-CREKA had enhanced retention effect in GBM area, therefore CREKA coated PAMAM was expected to be a potential delivery system for GBM treatment. The additional researches for GBM dendrimers DDS were listed in Table 6.

Table 6 Dendrimer based anti-GBM drug delivery system

Nanogel

As an emerging class of synthetic and multifunctional polymers, nanogel have garnered immense attentions in tissue engineering and pharmaceutical fields. Nanogel represents the combination of “hydrogel” and “nanoparticles”. It is composed by cross-linked hydrophilic polymers networks and characterized as tunable sizes (50–500 nm) and admirable elasticity [174] (Fig. 8). The construction of nanogel is based on physical crosslinks (van der Waals, electrostatic interactions and hydrogen bonding) and/or chemical covalent bonds, endowing nanogel with the conformational changeability property against environmental stimuli [175]. Nanogel particles can be synthesized in an initiated [176] or self-assembly [177] manner, through which initiator/gelator is required or not respectively. Unlike micelle, the amphiphilic associations between nanogel polymers exhibited superior stability, which is attributed to the plentiful cross-link points in nanogel instead of di-/tri-blocks structure in micelles. Numerous hydrophilic groups (such as -OH、-COOH、-CONH2 and -SO3H) and porous cavity were possessed by nanogel [178], which contributed to the swelling (water absorption) instead of dissolution of the polymeric conformation in aqueous condition. The imperative consideration on toxicity is of significance for nanogel. Consequently, natural polymers such as alginate [179], amylopectin [180], hyaluronic acid [181] and chitosan [182] have been utilized as building blocks for nanogel drug delivery system.

Fig. 8
figure 8

Schematic representation of the network construction of hydrogels, micelles, nanogels and microgels. Referred from [175] with permission

The release of encapsulated drugs is mainly based on passive diffusion. The swelling of nanogel enlarges the interior mesh size and allows the entrapped drugs release. Therefore, micro-molecules are prone to release in a burst manner while macro-molecules (protein, peptides) in nanogel exhibit sustained release [174]. Additionally, the degradation of physical/chemical bonds between polymeric chains results in hydrolysis of whole delivery system and drug release. In this regard, factors that can trigger the swelling or degradation of polymeric networks enable nanogel to perform stimulus–response property [183]. Environmental factors such as temperature, pH, ionic change, redox and light are exploited as stimuli for the responsive controlled drug release. As described before, the microenvironment of tumor possesses lower pH level due to excessive apoptosis and Warburg effect when comparing to blood and normal tissue (pH 7.4). The methacrylated hyaluronic acid (MAHA) nanogel [184] was designed for pH-sensitive drug release against GBM. Cross-linking gelator MA-OE-MA forms ortho ester linkages with MAHA via aqueous dispersion polymerization. The acid-labile ortho ester bond was effectively sensitive to mildly acid condition [185]. Therefore, the hydrolysis of chemical bonds between polymers and gelators lead to the release of embedded DOX, achieving anti-GBM capacity and tumor targeting. Thermos-responsive nanogel with negative sensitivity is characterized by lower critical solution temperature (LCST). At the temperature lower than LCST, the polymers form hydrogen bonds with water and exhibit in a swollen state. When the temperature reach LCST, the hydrophobic interaction between polymers dominate and the conformation of nanogel appear to shrink and collapse [183, 186]. Lu et al. [187] integrated GO into chitosan nanogel to transport irinotecan, cetuximab and SLP2 shRNA against GBM. The nanogel system exhibited thermo-sensitive characteristic with phase transition temperature/LCST at 32 °C. At room temperature, GO that loaded with drugs and shRNA were embedded into the liquid phase nanogel. The injection of chitosan nanogel into GBM area (> 32 °C) enabled the dehydration and solidification of nanogel, contributing to the subsequent sustained release of anti-tumor agents in situ. The additional nanogel DDS for GBM therapeutic employments were listed in Table 7.

Table 7 Nanogel based anti-GBM drug delivery system

Discussion

In 1986, Matsumura [193] proposed a phenomenon where nanoparticles with specific sizes displayed tumor accumulation properties. This tumoritropic performance was then recognized as enhanced permeability and retention (EPR) effect and played an indispensable role in nanoscale drug delivery therapy field (Fig. 9). With respect to tumorous tissues, the augmented angiogenesis is prone to accompany with wide inter-endothelial gap, poor vessel structural integrity and lymphatic reflux deficiency. These vascular alterations enable micromolecular substances (100 nm to 200 nm) to selectively permeate and retain in tumor surroundings [194]. The EPR effect endows drug delivery systems with passive targeting ability and contributes to increased therapeutic efficiency as well as reduced systemic side effects. However, controversy exists since the EPR effect tremendously varies intratumorally and intertumorally due to distinct tumor microenvironments and vascular densities [195, 196]. Warrenet al. [197] demonstrated that rare nanoparticles could passively penetrate into the tumor vessels of ovarian cancer, breast cancer and GBM. Based on mouse models, human tumorous tissues and mathematical models, conclusion was made that 97% of nanoparticles were transported through active process instead of passive diffusion [197]. Ding et al. [198] held opposite opinion that 87% renal cancer exhibited significant EPR effect, despite considerable heterogeneity was also observed in tumors with different size and gender (male samples showed intensified EPR) [198]. The EPR effect may eventually depend on the specific tumor pathophysiology, because differences were observed in the variety of tumor types. Although numerous EPR effect studies based on animal models achieved significant efficacy, the majority of which were failed to be translated into clinic [199]. Therefore, more intensive investigations should be conducted to fully illustrate the EPR effect behind nanoparticle drug delivery platforms.

Fig. 9
figure 9

a Schematic representation of the conceptual passive targeting (EPR effect) of nanomedicine. b Active targeting of nanomedicine grafted with peptide or antibody able to bind specific receptors overexpressed by (1) cancer cells or (2) endothelial cells. Referred from [199] with permission

Conventional anti-GBM drug delivery is invariably accompanied by unsatisfactory bio-distribution and systemic side effects. Since plenty of therapeutic agents against GBM cells fail to reach the action site and function in vivo, novel nanoscale biomaterials have been developed as vehicle to escort them. For one thing, nanoparticle delivery systems play an indispensable role in drug camouflage. The association between therapeutic agents and biomaterials can significantly improve the stability, solubility and bioavailability of drugs, which contributes to excellent pharmacokinetic performances (increased blood-drug concentration, prolonged half-life, etc.) of nanodrugs [2]. It is widely acknowledged that the most critical obstacle on GBM medication is BBB. Hydrophobic nanoparticles (liposomes, polymeric micelles) as well as modifications (transferrin/lactoferrin conjugation) were developed to increase the permeability of BBB. For another, actively GBM-specific property can be managed by nano-biomaterials. Several ligands such as FA, oligopeptide cRGD, Ang-2 and A7R [200] were associated with NPs to enhance their selectivity. The GBM-homing characteristic plays a pivotal role in decreased drug delivery frequency and reduced off-target effects.

The novel anti-GBM therapeutic agents range from chemotherapeutic drugs to chemokine, oligonucleotide, siRNA/shRNA, protein and etc. Therefore, diverse nanoparticle systems were utilized based on their unique characteristics and the associations with drugs. Sjoerd et al. [201] developed terminally functionalized PEG-b-PS and PEG-b-PDLLA libraries with 32 variants. The different amine groups on the terminal of PEG polymers allowed the chemical conjugations with specific drugs as well as the subsequent modifications through click chemistry reactions. Additionally, based on the physical characteristics such as size, charge, magnetism, hydrophobicity and photoexcitability, varied nanoparticles are selected to transport the drugs with diverse properties. Small interfering RNA (siRNA) is able to inhibit the expression of specific mRNA and is employed for cancer therapy. However, the vulnerable siRNA can be easily degraded by widely-existing RNase, repelled by cell membranes with the same negatively charge [202]. Cationic nanoparticles such as dendrimers, polymers and liposomes were used to carry siRNA via electrostatically association and protect it from rapid renal/phagocytic clearance [203].

Nanoscale DDS are also applied in diagnostic imaging, hyperthermia therapy and photodynamic therapy against GBM [204, 205]. Near-infrared (NIR) dye has been used as a noninvasive, real-time, in situ fluorescence imaging tool [206]. The cooperation of phtosensitizers and NPs could provide tumor targeting property [207], in which the active-targeting NIR exhibited profound potential on precise phototheranostics [9, 208]. In recent, more and more investigations focused on multimodal theranostic regimens. For example, superparamagnetic Fe3O4 nanoparticles was applied for magnetic fluid hyperthermia (MFH) and could be combined with chemotherapy drugs [209] as well as NIR hyperthermia [210]. Specifically, the administration routes of GBM delivery systems expanded to intravenous injection, nasal inhalation, and in situ implantation, which provided available strategies for appropriate treatment of GBM.

It was widely acknowledged that the significance of nanoscale biomaterials in drug delivery had been profoundly improved in the past few years due to their unique structures and properties. The prodigious progresses that have been made in biomedical field contributed to the diagnostic and therapeutic applications of anti-GBM nanoparticles. However, the majority of GBM nanoparticles investigations ended up at animal models and rare of these could enter preclinical stages. GBM is characterized by remarkably intra and inter-tumoral heterogeneity, therefore the inbred strain models lack complexity and diversity to reproduce human GBM. Except from BBB, biological or pathological barriers such as mononuclear phagocyte system, renal clearance, opsonization and blood tumor barrier (BTB) also have significant impacts on insufficient nanoparticles accumulation [211]. Additionally, limitations still exist on the safety issue. Although most nanoparticles exhibit excellent biocompatibility and biodegradability, fundamental investigations on the potential toxicity, immunogenicity, genotoxicity and bio-pharmacokinetics (absorption, distribution, metabolism, excretion) of each biomaterial must be scrupulously assessed in vivo. The bio-implants may trigger foreign body reactions (FBR) [212, 213], and hence the underlying influences of activated immune system on biomaterials, local homeostasis and even prognosis should be cautiously concerned. Despite the emergence of numerous nanoscale DDS for GBM treatment, explorations on effective dosage and bioavailability should also be scrupulously considered to minimize the side effects.

Currently, a great many of studies in drug delivery field still focused on pre-existing nanoparticles/biomaterials. The innovations of those DDS were mainly confined to superficial modifications and/or simply nanohybrid formation of multiple nanoparticles. Consequently, the development of novel biomaterials with superior vehicle capability is urgently needed for GBM therapy. Besides, despite most studies have described the material characterization of NPs thoroughly, investigations on the specific biological pathways behind DDS were comparatively inadequate.

In the future, more and more molecular targets behind GBM will be discovered. Therefore, the interdisciplinary nanoscale DDS that are able to precisely deliver the associated therapeutics will play a more significant role in GBM therapy.

Conclusion

In this review, the major types of drug delivery systems in GBM were clarified, and each of them were systematically interpreted and exemplified. The advantages and limitations of drug delivery systems were discussed, mainly covering safety, design, synthesis, bio-distribution, functionalization and efficiency. In the discussion, challenges and opportunities for GBM nanodrug therapy were proposed.

Availability of Data and Materials

Not applicable.

Abbreviations

GBM:

Glioblastoma multiforme

NPs:

Nanoparticles

DDS:

Drug delivery system

BBB:

Blood–brain-barrier

BTB:

Blood tumor barrier

RME:

Receptor-mediated endocytosis

AME:

Absoptive-mediated endocytosis

CNTs:

Carbon nanotubues

GBNs:

Graphene-based nanoparticles

CQDs:

Carbon quantum dots

MOFs:

Metal–organic frameworks

LPs:

Liposome particles

MSNs:

Mesoporous slica nanoparticles

GNPs:

Gold nanoparticles

PMs:

Polymeric micelles

EPR:

Enhanced permeability and retention

NIR:

Near-infrared

DOX:

Doxorubicin

TMZ:

Temozolomide

CPT:

Camptothecin

RAPA:

Rapamycin

CXB:

Celecoxib

PTX:

Paclitaxel

MFH:

Magnetic fluid hyperthermia

CMC:

Critical micelle concentration

SPR:

Surface plasmon resonance

References

  1. Wen PY, Weller M, Lee EQ, Alexander BM, Barnholtz-Sloan JS, Barthel FP et al (2020) Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol 22(8):1073–1113

    Article  CAS  Google Scholar 

  2. Li J, Zhao J, Tan T, Liu M, Zeng Z, Zeng Y et al (2020) Nanoparticle drug delivery system for glioma and its efficacy improvement strategies: a comprehensive review. Int J Nanomedicine 15:2563–2582

    Article  CAS  Google Scholar 

  3. Pardridge WM (2005) The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2(1):3–14

    Article  Google Scholar 

  4. Liu HM, Liu XF, Yao JL, Wang CL, Yu Y, Wang R (2006) Utilization of combined chemical modifications to enhance the blood-brain barrier permeability and pharmacological activity of endomorphin-1. J Pharmacol Exp Ther 319(1):308–316

    Article  CAS  Google Scholar 

  5. Dollinger S, Lober S, Klingenstein R, Korth C, Gmeiner P (2006) A chimeric ligand approach leading to potent antiprion active acridine derivatives: design, synthesis, and biological investigations. J Med Chem 49(22):6591–6595

    Article  CAS  Google Scholar 

  6. Lu W, Sun Q, Wan J, She Z, Jiang XG (2006) Cationic albumin-conjugated pegylated nanoparticles allow gene delivery into brain tumors via intravenous administration. Cancer Res 66(24):11878–11887

    Article  CAS  Google Scholar 

  7. Xue J, Zhao Z, Zhang L, Xue L, Shen S, Wen Y et al (2017) Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Nat Nanotechnol 12(7):692–700

    Article  CAS  Google Scholar 

  8. Xu HL, Yang JJ, ZhuGe DL, Lin MT, Zhu QY, Jin BH et al (2018) Glioma-targeted delivery of a theranostic liposome integrated with quantum dots, superparamagnetic iron oxide, and cilengitide for dual-imaging guiding cancer surgery. Adv Healthc Mater 7(9):e1701130

    Article  Google Scholar 

  9. Geng X, Gao D, Hu D, Liu Q, Liu C, Yuan Z et al (2020) Active-targeting NIR-II phototheranostics in multiple tumor models using platelet-camouflaged nanoprobes. ACS Appl Mater Interfaces 12(50):55624–55637

    Article  CAS  Google Scholar 

  10. Han Y, Gao C, Wang H, Sun J, Liang M, Feng Y et al (2021) Macrophage membrane-coated nanocarriers co-modified by RVG29 and TPP improve brain neuronal mitochondria-targeting and therapeutic efficacy in Alzheimer’s disease mice. Bioact Mater 6(2):529–542

    Article  CAS  Google Scholar 

  11. Tiwari AP, Hwang TI, Oh JM, Maharjan B, Chun S, Kim BS et al (2018) pH/NIR-responsive polypyrrole-functionalized fibrous localized drug-delivery platform for synergistic cancer therapy. ACS Appl Mater Interfaces 10(24):20256–20270

    Article  CAS  Google Scholar 

  12. Choi Y, Kim J, Yu S, Hong S (2020) pH- and temperature-responsive radially porous silica nanoparticles with high-capacity drug loading for controlled drug delivery. Nanotechnology 31(33):335103

    Article  Google Scholar 

  13. Sun P, Huang T, Wang X, Wang G, Liu Z, Chen G et al (2020) Dynamic-covalent hydrogel with NIR-triggered drug delivery for localized chemo-photothermal combination therapy. Biomacromol 21(2):556–565

    Article  CAS  Google Scholar 

  14. Zhang J, Chen C, Li A, Jing W, Sun P, Huang X et al (2021) Immunostimulant hydrogel for the inhibition of malignant glioma relapse post-resection. Nat Nanotechnol 16(5):538–548

    Article  CAS  Google Scholar 

  15. Luo Z, Sun W, Fang J, Lee K, Li S, Gu Z et al (2019) Biodegradable gelatin methacryloyl microneedles for transdermal drug delivery. Adv Healthc Mater 8(3):e1801054

    Article  Google Scholar 

  16. Zhang Q, Zhu W, Xu F, Dai X, Shi L, Cai W et al (2019) The interleukin-4/PPARgamma signaling axis promotes oligodendrocyte differentiation and remyelination after brain injury. PLoS Biol 17(6):e3000330

    Article  Google Scholar 

  17. Zambrano-Andazol I, Vazquez N, Chacon M, Sanchez-Avila RM, Persinal M, Blanco C et al (2020) Reduced graphene oxide membranes in ocular regenerative medicine. Mater Sci Eng C Mater Biol Appl 114:111075

    Article  CAS  Google Scholar 

  18. Henna TK, Raphey VR, Sankar R, Ameena Shirin VK, Gangadharappa HV, Pramod K (2020) Carbon nanostructures: the drug and the delivery system for brain disorders. Int J Pharm 587:119701

    Article  CAS  Google Scholar 

  19. Mehra NK, Palakurthi S (2016) Interactions between carbon nanotubes and bioactives: a drug delivery perspective. Drug Discov Today 21(4):585–597

    Article  CAS  Google Scholar 

  20. Sajid MI, Jamshaid U, Jamshaid T, Zafar N, Fessi H, Elaissari A (2016) Carbon nanotubes from synthesis to in vivo biomedical applications. Int J Pharm 501(1–2):278–299

    Article  CAS  Google Scholar 

  21. Yan H, Xue Z, Xie J, Dong Y, Ma Z, Sun X et al (2019) Toxicity of carbon nanotubes as anti-tumor drug carriers. Int J Nanomedicine 14:10179–10194

    Article  CAS  Google Scholar 

  22. Francis AP, Devasena T (2018) Toxicity of carbon nanotubes: a review. Toxicol Ind Health 34(3):200–210

    Article  CAS  Google Scholar 

  23. He H, Pham-Huy LA, Dramou P, Xiao D, Zuo P, Pham-Huy C (2013) Carbon nanotubes: applications in pharmacy and medicine. Biomed Res Int 2013:578290

    Article  Google Scholar 

  24. Romano-Feinholz S, Salazar-Ramiro A, Munoz-Sandoval E, Magana-Maldonado R, Hernandez Pedro N, Rangel Lopez E et al (2017) Cytotoxicity induced by carbon nanotubes in experimental malignant glioma. Int J Nanomedicine 12:6005–6026

    Article  CAS  Google Scholar 

  25. Alizadeh D, White EE, Sanchez TC, Liu S, Zhang L, Badie B et al (2018) Immunostimulatory CpG on carbon nanotubes selectively inhibits migration of brain tumor cells. Bioconjug Chem 29(5):1659–1668

    Article  CAS  Google Scholar 

  26. Salazar A, Pérez-de la Cruz V, Muñoz-Sandoval E, Chavarria V, García Morales ML, Espinosa-Bonilla A et al (2021) Potential use of nitrogen-doped carbon nanotube sponges as payload carriers against malignant glioma. Nanomaterials (Basel) 11(5)

  27. You Y, Wang N, He L, Shi C, Zhang D, Liu Y et al (2019) Designing dual-functionalized carbon nanotubes with high blood-brain-barrier permeability for precise orthotopic glioma therapy. Dalton Trans (Cambridge, England: 2003) 48(5):1569–1573

  28. Chowdhury SM, Surhland C, Sanchez Z, Chaudhary P, Suresh Kumar MA, Lee S et al (2015) Graphene nanoribbons as a drug delivery agent for lucanthone mediated therapy of glioblastoma multiforme. Nanomedicine 11(1):109–118

    Article  CAS  Google Scholar 

  29. Moore TL, Grimes SW, Lewis RL, Alexis F (2014) Multilayered polymer-coated carbon nanotubes to deliver dasatinib. Mol Pharm 11(1):276–282

    Article  CAS  Google Scholar 

  30. Kafa H, Wang JT, Rubio N, Klippstein R, Costa PM, Hassan HA et al (2016) Translocation of LRP1 targeted carbon nanotubes of different diameters across the blood-brain barrier in vitro and in vivo. J Control Release 225:217–229

    Article  CAS  Google Scholar 

  31. Liao C, Li Y, Tjong SC (2018) Graphene nanomaterials: synthesis, biocompatibility, and cytotoxicity. Int J Mol Sci 19(11)

  32. Hoseini-Ghahfarokhi M, Mirkiani S, Mozaffari N, Abdolahi Sadatlu MA, Ghasemi A, Abbaspour S et al (2020) Applications of graphene and graphene oxide in smart drug/gene delivery: is the world still flat? Int J Nanomedicine 15:9469–9496

    Article  CAS  Google Scholar 

  33. Patil TV, Patel DK, Dutta SD, Ganguly K, Lim KT (2021) Graphene oxide-based stimuli-responsive platforms for biomedical applications. Molecules 26(9)

  34. XiaoYe Wang AN (2018) Klaus Müllen Precision synthesis versus bulk-scale fabrication of graphenes. Nat Rev Chem 2:0100

    Article  Google Scholar 

  35. Lakshmanan R, Maulik N (2018) Graphene-based drug delivery systems in tissue engineering and nanomedicine. Can J Physiol Pharmacol 96(9):869–878

    Article  CAS  Google Scholar 

  36. Agrawal M, Tripathi DK, Saraf S, Saraf S, Antimisiaris SG et al (2017) Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer’s disease. J Control Release 260:61–77

    Article  CAS  Google Scholar 

  37. Song MM, Xu HL, Liang JX, Xiang HH, Liu R, Shen YX (2017) Lactoferrin modified graphene oxide iron oxide nanocomposite for glioma-targeted drug delivery. Mater Sci Eng C Mater Biol Appl 77:904–911

    Article  CAS  Google Scholar 

  38. Zhao Y, Yin H, Zhang X (2020) Modification of graphene oxide by angiopep-2 enhances anti-glioma efficiency of the nanoscaled delivery system for doxorubicin. Aging (Albany NY) 12(11):10506–10516

    Article  CAS  Google Scholar 

  39. Wang P, Wang X, Tang Q, Chen H, Zhang Q, Jiang H et al (2020) Functionalized graphene oxide against U251 glioma cells and its molecular mechanism. Mater Sci Eng C Mater Biol Appl 116:111187

    Article  CAS  Google Scholar 

  40. Wang LH, Liu JY, Sui L, Zhao PH, Ma HD, Wei Z et al (2020) Folate-modified graphene oxide as the drug delivery system to load temozolomide. Curr Pharm Biotechnol 21(11):1088–1098

    Article  CAS  Google Scholar 

  41. Shirvalilou S, Khoei S, Khoee S, Raoufi NJ, Karimi MR, Shakeri-Zadeh A (2018) Development of a magnetic nano-graphene oxide carrier for improved glioma-targeted drug delivery and imaging: In vitro and in vivo evaluations. Chem Biol Interact 295:97–108

    Article  CAS  Google Scholar 

  42. Wei Y, Zhou F, Zhang D, Chen Q, Xing D (2016) A graphene oxide based smart drug delivery system for tumor mitochondria-targeting photodynamic therapy. Nanoscale 8(6):3530–3538

    Article  CAS  Google Scholar 

  43. Tian XT, Yin XB (2019) Carbon dots, unconventional preparation strategies, and applications beyond photoluminescence. Small 15(48):e1901803

    Article  Google Scholar 

  44. Pardo J, Peng Z, Leblanc RM (2018) Cancer targeting and drug delivery using carbon-based quantum dots and nanotubes. Molecules 23(2)

  45. Kang Z, Lee ST (2019) Carbon dots: advances in nanocarbon applications. Nanoscale 11(41):19214–19224

    Article  CAS  Google Scholar 

  46. Shen JM, Gao FY, Yin T, Zhang HX, Ma M, Yang YJ et al (2013) cRGD-functionalized polymeric magnetic nanoparticles as a dual-drug delivery system for safe targeted cancer therapy. Pharmacol Res 70(1):102–115

    Article  CAS  Google Scholar 

  47. Song B, Wu C, Chang J (2012) Dual drug release from electrospun poly(lactic-co-glycolic acid)/mesoporous silica nanoparticles composite mats with distinct release profiles. Acta Biomater 8(5):1901–1907

    Article  CAS  Google Scholar 

  48. Hettiarachchi SD, Graham RM, Mintz KJ, Zhou Y, Vanni S, Peng Z et al (2019) Triple conjugated carbon dots as a nano-drug delivery model for glioblastoma brain tumors. Nanoscale 11(13):6192–6205

    Article  CAS  Google Scholar 

  49. Wang S, Li C, Qian M, Jiang H, Shi W, Chen J et al (2017) Augmented glioma-targeted theranostics using multifunctional polymer-coated carbon nanodots. Biomaterials 141:29–39

    Article  CAS  Google Scholar 

  50. Mura S, Nicolas J, Couvreur P (2013) Stimuli-responsive nanocarriers for drug delivery. Nat Mater 12(11):991–1003

    Article  CAS  Google Scholar 

  51. Liyanage PY, Zhou Y, Al-Youbi AO, Bashammakh AS, El-Shahawi MS, Vanni S et al (2020) Pediatric glioblastoma target-specific efficient delivery of gemcitabine across the blood-brain barrier via carbon nitride dots. Nanoscale 12(14):7927–7938

    Article  CAS  Google Scholar 

  52. Kumar M, Sharma G, Kumar R, Singh B, Katare OP, Raza K (2018) Lysine-based C60-fullerene nanoconjugates for monomethyl fumarate delivery: a novel nanomedicine for brain cancer cells. ACS Biomater Sci Eng 4(6):2134–2142

    Article  CAS  Google Scholar 

  53. Xi G, Robinson E, Mania-Farnell B, Vanin EF, Shim KW, Takao T et al (2014) Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment. Nanomedicine 10(2):381–391

    Article  CAS  Google Scholar 

  54. Li TF, Xu YH, Li K, Wang C, Liu X, Yue Y et al (2019) Doxorubicin-polyglycerol-nanodiamond composites stimulate glioblastoma cell immunogenicity through activation of autophagy. Acta Biomater 86:381–394

    Article  CAS  Google Scholar 

  55. Fang Y, Yang Z, Li H, Liu X (2020) MIL-100(Fe) and its derivatives: from synthesis to application for wastewater decontamination. Environ Sci Pollut Res Int 27(5):4703–4724

    Article  CAS  Google Scholar 

  56. Doonan C, Riccò R, Liang K, Bradshaw D, Falcaro P (2017) Metal-organic frameworks at the biointerface: synthetic strategies and applications. Acc Chem Res 50(6):1423–1432

    Article  CAS  Google Scholar 

  57. Kumar P, Anand B, Tsang YF, Kim KH, Khullar S, Wang B (2019) Regeneration, degradation, and toxicity effect of MOFs: opportunities and challenges. Environ Res 176:108488

    Article  CAS  Google Scholar 

  58. Simon MA, Anggraeni E, Soetaredjo FE, Santoso SP, Irawaty W, Thanh TC et al (2019) Hydrothermal synthesize of HF-free MIL-100(Fe) for isoniazid-drug delivery. Sci Rep 9(1):16907

    Article  Google Scholar 

  59. de Moura Ferraz LR, Tabosa A, da Silva Nascimento DDS, Ferreira AS, de Albuquerque Wanderley Sales V, Silva JYR et al (2020) ZIF-8 as a promising drug delivery system for benznidazole: development, characterization, in vitro dialysis release and cytotoxicity. Sci Rep 10(1):16815

  60. Kundu T, Mitra S, Patra P, Goswami A, Diaz Diaz D, Banerjee R (2014) Mechanical downsizing of a gadolinium(III)-based metal-organic framework for anticancer drug delivery. Chemistry 20(33):10514–10518

    Article  CAS  Google Scholar 

  61. Li Y, Li X, Guan Q, Zhang C, Xu T, Dong Y et al (2017) Strategy for chemotherapeutic delivery using a nanosized porous metal-organic framework with a central composite design. Int J Nanomed 12:1465–1474

    Article  CAS  Google Scholar 

  62. Abanades Lazaro I, Wells CJR, Forgan RS (2020) Multivariate modulation of the Zr MOF UiO-66 for defect-controlled combination anticancer drug delivery. Angew Chem Int Ed Engl 59(13):5211–5217

    Article  CAS  Google Scholar 

  63. Kotzabasaki M, Galdadas I, Tylianakis E, Klontzas E, Cournia Z, Froudakis GE (2017) Multiscale simulations reveal IRMOF-74-III as a potent drug carrier for gemcitabine delivery. J Mater Chem B 5(18):3277–3282

    Article  CAS  Google Scholar 

  64. Gong X, Gnanasekaran K, Chen Z, Robison L, Wasson MC, Bentz KC et al (2020) Insights into the structure and dynamics of metal-organic frameworks via transmission electron microscopy. J Am Chem Soc 142(41):17224–17235

    Article  CAS  Google Scholar 

  65. Liu L, Chen Z, Wang J, Zhang D, Zhu Y, Ling S et al (2019) Imaging defects and their evolution in a metal–organic framework at sub-unit-cell resolution. Nat Chem 11(7):622–628

    Article  CAS  Google Scholar 

  66. Karagiaridi O, Lalonde MB, Bury W, Sarjeant AA, Farha OK, Hupp JT (2012) Opening ZIF-8: a catalytically active zeolitic imidazolate framework of sodalite topology with unsubstituted linkers. J Am Chem Soc 134(45):18790–18796

    Article  CAS  Google Scholar 

  67. Pandey A, Kulkarni S, Vincent AP, Nannuri SH, George SD, Mutalik S (2020) Hyaluronic acid-drug conjugate modified core-shell MOFs as pH responsive nanoplatform for multimodal therapy of glioblastoma. Int J Pharm 588:119735

    Article  CAS  Google Scholar 

  68. Pan YB, Wang S, He X, Tang W, Wang J, Shao A et al (2019) A combination of glioma in vivo imaging and in vivo drug delivery by metal-organic framework based composite nanoparticles. J Mater Chem B 7(48):7683–7689

    Article  CAS  Google Scholar 

  69. Jain AK, Thareja S (2019) In vitro and in vivo characterization of pharmaceutical nanocarriers used for drug delivery. Artif Cells Nanomed Biotechnol 47(1):524–539

    Article  CAS  Google Scholar 

  70. Almeida B, Nag OK, Rogers KE, Delehanty JB (2020) Recent progress in bioconjugation strategies for liposome-mediated drug delivery. Molecules 25(23)

  71. Chen J, Lu WL, Gu W, Lu SS, Chen ZP, Cai BC et al (2014) Drug-in-cyclodextrin-in-liposomes: a promising delivery system for hydrophobic drugs. Expert Opin Drug Deliv 11(4):565–577

    Article  CAS  Google Scholar 

  72. Ahmed S, Corvis Y, Gahoual R, Euan A, Lai-Kuen R, Couillaud BM et al (2019) Conception of nanosized hybrid liposome/poloxamer particles to thicken the interior core of liposomes and delay hydrophilic drug delivery. Int J Pharm 567:118488

    Article  CAS  Google Scholar 

  73. Sakurai Y, Kato A, Hida Y, Hamada J, Maishi N, Hida K et al (2019) Synergistic enhancement of cellular uptake with CD44-expressing malignant pleural mesothelioma by combining cationic liposome and hyaluronic acid-lipid conjugate. J Pharm Sci 108(10):3218–3224

    Article  CAS  Google Scholar 

  74. Zununi Vahed S, Salehi R, Davaran S, Sharifi S (2017) Liposome-based drug co-delivery systems in cancer cells. Mater Sci Eng C Mater Biol Appl 71:1327–1341

    Article  CAS  Google Scholar 

  75. Lengyel JS, Milne JL, Subramaniam S (2008) Electron tomography in nanoparticle imaging and analysis. Nanomedicine (Lond) 3(1):125–131

    Article  CAS  Google Scholar 

  76. Wei X, Gao J, Zhan C, Xie C, Chai Z, Ran D et al (2015) Liposome-based glioma targeted drug delivery enabled by stable peptide ligands. J Control Release 218:13–21

    Article  CAS  Google Scholar 

  77. Lin PC, Lin SZ, Chen YL, Chang JS, Ho LI, Liu PY et al (2011) Butylidenephthalide suppresses human telomerase reverse transcriptase (TERT) in human glioblastomas. Ann Surg Oncol 18(12):3514–3527

    Article  Google Scholar 

  78. Lin EY, Chen YS, Li YS, Chen SR, Lee CH, Huang MH et al (2020) Liposome consolidated with cyclodextrin provides prolonged drug retention resulting in increased drug bioavailability in brain. Int J Mol Sci 21(12)

  79. Zhang Y, Zhang L, Hu Y, Jiang K, Li Z, Lin YZ et al (2018) Cell-permeable NF-kappaB inhibitor-conjugated liposomes for treatment of glioma. J Control Release 289:102–113

    Article  CAS  Google Scholar 

  80. Zhu Y, Liang J, Gao C, Wang A, Xia J, Hong C et al (2021) Multifunctional ginsenoside Rg3-based liposomes for glioma targeting therapy. J Control Release 330:641–657

    Article  CAS  Google Scholar 

  81. Wang X, Meng N, Wang S, Zhang Y, Lu L, Wang R et al (2019) Non-immunogenic, low-toxicity and effective glioma targeting MTI-31 liposomes. J Control Release 316:381–392

    Article  CAS  Google Scholar 

  82. Kang S, Duan W, Zhang S, Chen D, Feng J, Qi N (2020) Muscone/RI7217 co-modified upward messenger DTX liposomes enhanced permeability of blood-brain barrier and targeting glioma. Theranostics 10(10):4308–4322

    Article  CAS  Google Scholar 

  83. Shi D, Mi G, Shen Y, Webster TJ (2019) Glioma-targeted dual functionalized thermosensitive Ferri-liposomes for drug delivery through an in vitro blood-brain barrier. Nanoscale 11(32):15057–15071

    Article  CAS  Google Scholar 

  84. Sun X, Chen Y, Zhao H, Qiao G, Liu M, Zhang C et al (2018) Dual-modified cationic liposomes loaded with paclitaxel and survivin siRNA for targeted imaging and therapy of cancer stem cells in brain glioma. Drug Deliv 25(1):1718–1727

    Article  CAS  Google Scholar 

  85. Li Z, Zhang Y, Feng N (2019) Mesoporous silica nanoparticles: synthesis, classification, drug loading, pharmacokinetics, biocompatibility, and application in drug delivery. Expert Opin Drug Deliv 16(3):219–237

    Article  CAS  Google Scholar 

  86. Wang Y, Zhao Q, Han N, Bai L, Li J, Liu J et al (2015) Mesoporous silica nanoparticles in drug delivery and biomedical applications. Nanomedicine 11(2):313–327

    Article  CAS  Google Scholar 

  87. Tang F, Li L, Chen D (2012) Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Adv Mater 24(12):1504–1534

    Article  CAS  Google Scholar 

  88. Zhang T, Huang B, Elzatahry AA, Alghamdi A, Yue Q, Deng Y (2020) Synthesis of podlike magnetic mesoporous silica nanochains for use as enzyme support and nanostirrer in biocatalysis. ACS Appl Mater Interfaces 12(15):17901–17908

    Article  CAS  Google Scholar 

  89. Shi M, Zhang J, Li J, Fan Y, Wang J, Sun W et al (2019) Polydopamine-coated magnetic mesoporous silica nanoparticles for multimodal cancer theranostics. J Mater Chem B 7(3):368–372

    Article  CAS  Google Scholar 

  90. Zhao W, Gu J, Zhang L, Chen H, Shi J (2005) Fabrication of uniform magnetic nanocomposite spheres with a magnetic core/mesoporous silica shell structure. J Am Chem Soc 127(25):8916–8917

    Article  CAS  Google Scholar 

  91. Chen Y, Chen H, Guo L, He Q, Chen F, Zhou J et al (2010) Hollow/rattle-type mesoporous nanostructures by a structural difference-based selective etching strategy. ACS Nano 4(1):529–539

    Article  CAS  Google Scholar 

  92. Ding S, Chen JS, Qi G, Duan X, Wang Z, Giannelis EP et al (2011) Formation of SnO2 hollow nanospheres inside mesoporous silica nanoreactors. J Am Chem Soc 133(1):21–23

    Article  CAS  Google Scholar 

  93. Zuo B, Li W, Wu X, Wang S, Deng Q, Huang M (2020) Recent advances in the synthesis, surface modifications and applications of core-shell magnetic mesoporous silica nanospheres. Chem Asian J 15(8):1248–1265

    Article  CAS  Google Scholar 

  94. Zhu J, Zhang Y, Chen X, Zhang Y, Zhang K, Zheng H et al (2021) Angiopep-2 modified lipid-coated mesoporous silica nanoparticles for glioma targeting therapy overcoming BBB. Biochem Biophys Res Commun 534:902–907

    Article  CAS  Google Scholar 

  95. Tang XL, Jing F, Lin BL, Cui S, Yu RT, Shen XD et al (2018) pH-responsive magnetic mesoporous silica-based nanoplatform for synergistic photodynamic therapy/chemotherapy. ACS Appl Mater Interfaces 10(17):15001–15011

    Article  CAS  Google Scholar 

  96. Shahein SA, Aboul-Enein AM, Higazy IM, Abou-Elella F, Lojkowski W, Ahmed ER et al (2019) Targeted anticancer potential against glioma cells of thymoquinone delivered by mesoporous silica core-shell nanoformulations with pH-dependent release. Int J Nanomed 14:5503–5526

    Article  CAS  Google Scholar 

  97. Zhang P, Tang M, Huang Q, Zhao G, Huang N, Zhang X et al (2019) Combination of 3-methyladenine therapy and Asn-Gly-Arg (NGR)-modified mesoporous silica nanoparticles loaded with temozolomide for glioma therapy in vitro. Biochem Biophys Res Commun 509(2):549–556

    Article  CAS  Google Scholar 

  98. Turan O, Bielecki P, Perera V, Lorkowski M, Covarrubias G, Tong K et al (2019) Delivery of drugs into brain tumors using multicomponent silica nanoparticles. Nanoscale 11(24):11910–11921

    Article  CAS  Google Scholar 

  99. Bertucci A, Prasetyanto EA, Septiadi D, Manicardi A, Brognara E, Gambari R et al (2015) Combined delivery of temozolomide and anti-miR221 PNA using mesoporous silica nanoparticles induces apoptosis in resistant glioma cells. Small 11(42):5687–5695

    Article  CAS  Google Scholar 

  100. You Y, Yang L, He L, Chen T (2016) Tailored mesoporous silica nanosystem with enhanced permeability of the blood-brain barrier to antagonize glioblastoma. J Mater Chem B 4(36):5980–5990

    Article  CAS  Google Scholar 

  101. Tao J, Fei W, Tang H, Li C, Mu C, Zheng H et al (2019) Angiopep-2-conjugated “core-shell” hybrid nanovehicles for targeted and pH-triggered delivery of arsenic trioxide into glioma. Mol Pharm 16(2):786–797

    Article  CAS  Google Scholar 

  102. Boisselier E, Astruc D (2009) Gold nanoparticles in nanomedicine: preparations, imaging, diagnostics, therapies and toxicity. Chem Soc Rev 38(6):1759–1782

    Article  CAS  Google Scholar 

  103. Lee YJ, Cha SH, Kim H, Choi SE, Cho S, Park Y (2020) Diallyl disulphide-loaded spherical gold nanoparticles and acorn-like silver nanoparticles synthesised using onion extract: catalytic activity and cytotoxicity. Artif Cells Nanomed Biotechnol 48(1):948–960

    Article  CAS  Google Scholar 

  104. Kim DS, Kang ES, Baek S, Choo SS, Chung YH, Lee D et al (2018) Electrochemical detection of dopamine using periodic cylindrical gold nanoelectrode arrays. Sci Rep 8(1):14049

    Article  Google Scholar 

  105. Mondal B, Mukherjee PS (2018) Cage encapsulated gold nanoparticles as heterogeneous photocatalyst for facile and selective reduction of nitroarenes to azo compounds. J Am Chem Soc 140(39):12592–12601

    Article  CAS  Google Scholar 

  106. Imanparast A, Bakhshizadeh M, Salek R, Sazgarnia A (2018) Pegylated hollow gold-mitoxantrone nanoparticles combining photodynamic therapy and chemotherapy of cancer cells. Photodiagnosis Photodyn Ther 23:295–305

    Article  CAS  Google Scholar 

  107. Singh P, Pandit S, Mokkapati V, Garg A, Ravikumar V, Mijakovic I (2018) Gold nanoparticles in diagnostics and therapeutics for human cancer. Int J Mol Sci 19(7)

  108. Capek I (2017) Polymer decorated gold nanoparticles in nanomedicine conjugates. Adv Colloid Interface Sci 249:386–399

    Article  CAS  Google Scholar 

  109. Austin LA, Mackey MA, Dreaden EC, El-Sayed MA (2014) The optical, photothermal, and facile surface chemical properties of gold and silver nanoparticles in biodiagnostics, therapy, and drug delivery. Arch Toxicol 88(7):1391–1417

    Article  CAS  Google Scholar 

  110. De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJ, Geertsma RE (2008) Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 29(12):1912–1919

    Article  Google Scholar 

  111. Mousavi SM, Zarei M, Hashemi SA, Ramakrishna S, Chiang WH, Lai CW et al (2020) Gold nanostars-diagnosis, bioimaging and biomedical applications. Drug Metab Rev 52(2):299–318

    Article  CAS  Google Scholar 

  112. Lee C, Hwang HS, Lee S, Kim B, Kim JO, Oh KT, et al (2017). Rabies virus-inspired silica-coated gold nanorods as a photothermal therapeutic platform for treating brain tumors. Advanced materials (Deerfield Beach, Fla) 29(13)

  113. Zhang X, Xi Z, Machuki JO, Luo J, Yang D, Li J et al (2019) Gold cube-in-cube based oxygen nanogenerator: a theranostic nanoplatform for modulating tumor microenvironment for precise chemo-phototherapy and multimodal imaging. ACS Nano 13(5):5306–5325

    Article  CAS  Google Scholar 

  114. Li X, Zhang Y, Fu M, Tang Y, Yin S, Ma Z et al (2019) Using a graphene-polyelectrolyte complex reducing agent to promote cracking in single-crystalline gold nanoplates. ACS Appl Mater Interfaces 11(44):41602–41610

    Article  CAS  Google Scholar 

  115. Ruan S, Xie R, Qin L, Yu M, Xiao W, Hu C et al (2019) Aggregable nanoparticles-enabled chemotherapy and autophagy inhibition combined with anti-PD-L1 antibody for improved glioma treatment. Nano Lett 19(11):8318–8332

    Article  CAS  Google Scholar 

  116. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567

    Article  CAS  Google Scholar 

  117. Jing Z, Li M, Wang H, Yang Z, Zhou S, Ma J et al (2021) Gallic acid-gold nanoparticles enhance radiation-induced cell death of human glioma U251 cells. IUBMB Life 73(2):398–407

    Article  CAS  Google Scholar 

  118. Huang JL, Jiang G, Song QX, Gu X, Hu M, Wang XL et al (2017) Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis. Nat Commun 8:15144

    Article  Google Scholar 

  119. Wang Z, Liang P, He X, Wu B, Liu Q, Xu Z et al (2018) Etoposide loaded layered double hydroxide nanoparticles reversing chemoresistance and eradicating human glioma stem cells in vitro and in vivo. Nanoscale 10(27):13106–13121

    Article  CAS  Google Scholar 

  120. Sanchez-Fernandez A, Pena-Paras L, Vidaltamayo R, Cue-Sampedro R, Mendoza-Martinez A, Zomosa-Signoret VC et al (2014) Synthesization, characterization, and in vitro evaluation of cytotoxicity of biomaterials based on halloysite nanotubes. Materials (Basel) 7(12):7770–7780

    Article  Google Scholar 

  121. Zhao J, Li D, Ma J, Yang H, Chen W, Cao Y et al (2021) Increasing the accumulation of aptamer AS1411 and verapamil conjugated silver nanoparticles in tumor cells to enhance the radiosensitivity of glioma. Nanotechnology 32(14):145102

    Article  CAS  Google Scholar 

  122. Zhang Y, Fu X, Jia J, Wikerholmen T, Xi K, Kong Y et al (2020) Glioblastoma therapy using codelivery of cisplatin and glutathione peroxidase targeting siRNA from iron oxide nanoparticles. ACS Appl Mater Interfaces 12(39):43408–43421

    Article  CAS  Google Scholar 

  123. Sukumar UK, Bose RJC, Malhotra M, Babikir HA, Afjei R, Robinson E et al (2019) Intranasal delivery of targeted polyfunctional gold-iron oxide nanoparticles loaded with therapeutic microRNAs for combined theranostic multimodality imaging and presensitization of glioblastoma to temozolomide. Biomaterials 218:119342

    Article  CAS  Google Scholar 

  124. Sallem F, Haji R, Vervandier-Fasseur D, Nury T, Maurizi L, Boudon J et al (2019) Elaboration of trans-resveratrol derivative-loaded superparamagnetic iron oxide nanoparticles for glioma treatment. Nanomaterials (Basel) 9(2)

  125. Saalik P, Lingasamy P, Toome K, Mastandrea I, Rousso-Noori L, Tobi A et al (2019) Peptide-guided nanoparticles for glioblastoma targeting. J Control Release 308:109–118

    Article  CAS  Google Scholar 

  126. Jones M, Leroux J (1999) Polymeric micelles - a new generation of colloidal drug carriers. Eur J Pharm Biopharm 48(2):101–111

    Article  CAS  Google Scholar 

  127. Mishra MK, Gupta J, Gupta R (2020) Self-assemble amphiphilic PEO-PPO-PEO tri-block co-polymeric methotrexate nanomicelles to combat against MCF7 cancer cells. Curr Drug Deliv

  128. Song HT, Hoang NH, Yun JM, Park YJ, Song EH, Lee ES et al (2016) Development of a new tri-block copolymer with a functional end and its feasibility for treatment of metastatic breast cancer. Colloids Surf B Biointerfaces 144:73–80

    Article  CAS  Google Scholar 

  129. Shen F, Zhong H, Ge W, Ren J, Wang X (2020) Quercetin/chitosan-graft-alpha lipoic acid micelles: a versatile antioxidant water dispersion with high stability. Carbohydr Polym 234:115927

    Article  CAS  Google Scholar 

  130. Yu N, Li G, Gao Y, Jiang H, Tao Q (2016) Thermo-sensitive complex micelles from sodium alginate-graft-poly(N-isopropylacrylamide) for drug release. Int J Biol Macromol 86:296–301

    Article  CAS  Google Scholar 

  131. Gupta R, Shea J, Scafe C, Shurlygina A, Rapoport N (2015) Polymeric micelles and nanoemulsions as drug carriers: Therapeutic efficacy, toxicity, and drug resistance. J Control Release 212:70–77

    Article  CAS  Google Scholar 

  132. Cheng CC, Sun YT, Lee AW, Huang SY, Fan WL, Chiao YH et al (2020) Self-assembled supramolecular micelles with pH-responsive properties for more effective cancer chemotherapy. ACS Biomater Sci Eng 6(7):4096–4105

    Article  CAS  Google Scholar 

  133. Wu Y, Xiao Y, Huang Y, Xu Y, You D, Lu W et al (2019) Rod-shaped micelles based on PHF- g-(PCL-PEG) with pH-triggered doxorubicin release and enhanced cellular uptake. Biomacromol 20(3):1167–1177

    Article  CAS  Google Scholar 

  134. Authimoolam SP, Lakes AL, Puleo DA, Dziubla TD (2016) Layer-by-layers of polymeric micelles as a biomimetic drug-releasing network. Macromol Biosci 16(2):242–254

    Article  CAS  Google Scholar 

  135. Sutton D, Nasongkla N, Blanco E, Gao J (2007) Functionalized micellar systems for cancer targeted drug delivery. Pharm Res 24(6):1029–1046

    Article  CAS  Google Scholar 

  136. Lobling TI, Haataja JS, Synatschke CV, Schacher FH, Muller M, Hanisch A et al (2014) Hidden structural features of multicompartment micelles revealed by cryogenic transmission electron tomography. ACS Nano 8(11):11330–11340

    Article  Google Scholar 

  137. Sun P, Xiao Y, Di Q, Ma W, Ma X, Wang Q et al (2020) Transferrin receptor-targeted PEG-PLA polymeric micelles for chemotherapy against glioblastoma multiforme. Int J Nanomed 15:6673–6688

    Article  CAS  Google Scholar 

  138. Chen Y, Zhang L, Liu Y, Tan S, Qu R, Wu Z et al (2018) Preparation of PGA-PAE-micelles for enhanced antitumor efficacy of cisplatin. ACS Appl Mater Interfaces 10(30):25006–25016

    Article  CAS  Google Scholar 

  139. Kanazawa T, Taki H, Okada H (2020) Nose-to-brain drug delivery system with ligand/cell-penetrating peptide-modified polymeric nano-micelles for intracerebral gliomas. Eur J Pharm Biopharm 152:85–94

    Article  CAS  Google Scholar 

  140. Hsu HJ, Han Y, Cheong M, Kral P, Hong S (2018) Dendritic PEG outer shells enhance serum stability of polymeric micelles. Nanomedicine 14(6):1879–1889

    Article  CAS  Google Scholar 

  141. Zhang Y, Huang Y, Li S (2014) Polymeric micelles: nanocarriers for cancer-targeted drug delivery. AAPS Pharm Sci Tech 15(4):862–871

    Article  CAS  Google Scholar 

  142. Mandal A, Bisht R, Rupenthal ID, Mitra AK (2017) Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J Control Release 248:96–116

    Article  CAS  Google Scholar 

  143. Quader S, Liu X, Chen Y, Mi P, Chida T, Ishii T et al (2017) cRGD peptide-installed epirubicin-loaded polymeric micelles for effective targeted therapy against brain tumors. J Control Release 258:56–66

    Article  CAS  Google Scholar 

  144. Peng Y, Huang J, Xiao H, Wu T, Shuai X (2018) Codelivery of temozolomide and siRNA with polymeric nanocarrier for effective glioma treatment. Int J Nanomed 13:3467–3480

    Article  CAS  Google Scholar 

  145. Kim JH, Kim YK, Arash MT, Hong SH, Lee JH, Kang BN et al (2012) Galactosylation of chitosan-graft-spermine as a gene carrier for hepatocyte targeting in vitro and in vivo. J Nanosci Nanotechnol 12(7):5178–5184

    Article  CAS  Google Scholar 

  146. Lu L, Zhao X, Fu T, Li K, He Y, Luo Z et al (2020) An iRGD-conjugated prodrug micelle with blood-brain-barrier penetrability for anti-glioma therapy. Biomaterials 230:119666

    Article  CAS  Google Scholar 

  147. Ran D, Mao J, Shen Q, Xie C, Zhan C, Wang R et al (2017) GRP78 enabled micelle-based glioma targeted drug delivery. J Control Release 255:120–131

    Article  CAS  Google Scholar 

  148. Shi H, Sun S, Xu H, Zhao Z, Han Z, Jia J et al (2020) Combined delivery of temozolomide and siPLK1 using targeted nanoparticles to enhance temozolomide sensitivity in glioma. Int J Nanomedicine 15:3347–3362

    Article  CAS  Google Scholar 

  149. Tan X, Kim G, Lee D, Oh J, Kim M, Piao C et al (2018) A curcumin-loaded polymeric micelle as a carrier of a microRNA-21 antisense-oligonucleotide for enhanced anti-tumor effects in a glioblastoma animal model. Biomaterials science 6(2):407–417

    Article  CAS  Google Scholar 

  150. Buhleier E, Vögtle F (1978) “Cascade” and “nonskid-chain-like” syntheses of molecular cavity topologies. Synthesis 2:155–158

    Article  Google Scholar 

  151. Tomalia DBH, Dewald J, Hall M, Kallos G, Martin S, Roeck J, Ryder J, Smith P (1985) A new class of polymers: STARBURST®-dendritic macromolecules. Polym J 17:117–132

    Article  CAS  Google Scholar 

  152. Oliveira JM, Sousa N, Mano JF, Reis RL (2010) Dendrimers and derivatives as a potential therapeutic tool in regenerative medicine strategies - a review. Prog Polym Sci 15:1163–1194

    Article  Google Scholar 

  153. Huang D, Wu D (2018) Biodegradable dendrimers for drug delivery. Mater Sci Eng C Mater Biol Appl 90:713–727

    Article  CAS  Google Scholar 

  154. Hsu HJ, Bugno J, Lee SR, Hong S (2017) Dendrimer-based nanocarriers: a versatile platform for drug delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol 9(1)

  155. Janaszewska A, Lazniewska J, Trzepinski P, Marcinkowska M, Klajnert-Maculewicz B (2019) Cytotoxicity of dendrimers. Biomolecules 9(8)

  156. Chauhan AS (2018) Dendrimers for drug delivery. Molecules 23(4)

  157. Zhu Y, Liu C, Pang Z (2019) Dendrimer-based drug delivery systems for brain targeting. Biomolecules 9(12)

  158. Li J, Liang H, Liu J, Wang Z (2018) Poly (amidoamine) (PAMAM) dendrimer mediated delivery of drug and pDNA/siRNA for cancer therapy. Int J Pharm 546(1–2):215–225

    Article  CAS  Google Scholar 

  159. Kaur A, Jain K, Mehra NK, Jain NK (2017) Development and characterization of surface engineered PPI dendrimers for targeted drug delivery. Artif Cells Nanomed Biotechnol 45(3):414–425

    Article  CAS  Google Scholar 

  160. Zhou Z, Tang J, Sun Q, Murdoch WJ, Shen Y (2015) A multifunctional PEG-PLL drug conjugate forming redox-responsive nanoparticles for intracellular drug delivery. J Mater Chem B 3(38):7594–7603

    Article  CAS  Google Scholar 

  161. Spataro G, Malecaze F, Turrin CO, Soler V, Duhayon C, Elena PP et al (2010) Designing dendrimers for ocular drug delivery. Eur J Med Chem 45(1):326–334

    Article  CAS  Google Scholar 

  162. Apartsin E, Knauer N, Arkhipova V, Pashkina E, Aktanova A, Poletaeva J et al (2020) pH-Sensitive dendrimersomes of hybrid triazine-carbosilane dendritic amphiphiles-smart vehicles for drug delivery. Nanomaterials (Basel) 10(10)

  163. Xing Y, Zhou Y, Zhang Y, Zhang C, Deng X, Dong C et al (2020) Facile fabrication route of janus gold-mesoporous silica nanocarriers with dual-drug delivery for tumor therapy. ACS Biomater Sci Eng 6(3):1573–1581

    Article  CAS  Google Scholar 

  164. Kim Y, Park EJ, Na DH (2018) Recent progress in dendrimer-based nanomedicine development. Arch Pharmacal Res 41(6):571–582

    Article  CAS  Google Scholar 

  165. Lin Y, Xu J, Lan H (2019) Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol 12(1):76

    Article  Google Scholar 

  166. Sharma A, Liaw K, Sharma R, Spriggs T, Appiani La Rosa S, Kannan S et al (2020) Dendrimer-mediated targeted delivery of rapamycin to tumor-associated macrophages improves systemic treatment of glioblastoma. Biomacromolecules 21(12):5148–5161

  167. Zhao J, Zhang B, Shen S, Chen J, Zhang Q, Jiang X et al (2015) CREKA peptide-conjugated dendrimer nanoparticles for glioblastoma multiforme delivery. J Colloid Interface Sci 450:396–403

    Article  CAS  Google Scholar 

  168. Chung EJ, Cheng Y, Morshed R, Nord K, Han Y, Wegscheid ML et al (2014) Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma. Biomaterials 35(4):1249–1256

    Article  CAS  Google Scholar 

  169. Uram L, Markowicz J, Misiorek M, Filipowicz-Rachwal A, Wolowiec S, Walajtys-Rode E (2020) Celecoxib substituted biotinylated poly(amidoamine) G3 dendrimer as potential treatment for temozolomide resistant glioma therapy and anti-nematode agent. Eur J Pharm Sci 152:105439

    Article  CAS  Google Scholar 

  170. Lu Y, Han S, Zheng H, Ma R, Ping Y, Zou J et al (2018) A novel RGDyC/PEG co-modified PAMAM dendrimer-loaded arsenic trioxide of glioma targeting delivery system. Int J Nanomed 13:5937–5952

    Article  CAS  Google Scholar 

  171. Gao S, Li J, Jiang C, Hong B, Hao B (2016) Plasmid pORF-hTRAIL targeting to glioma using transferrin-modified polyamidoamine dendrimer. Drug Des Dev Ther 10:1–11

    Google Scholar 

  172. Liaw K, Sharma R, Sharma A, Salazar S, Appiani La Rosa S, Kannan RM (2021) Systemic dendrimer delivery of triptolide to tumor-associated macrophages improves anti-tumor efficacy and reduces systemic toxicity in glioblastoma. J Control Release 329:434–444

  173. Han S, Zheng H, Lu Y, Sun Y, Huang A, Fei W et al (2018) A novel synergetic targeting strategy for glioma therapy employing borneol combination with angiopep-2-modified, DOX-loaded PAMAM dendrimer. J Drug Target 26(1):86–94

    Article  CAS  Google Scholar 

  174. Zhang H, Zhai Y, Wang J, Zhai G (2016) New progress and prospects: the application of nanogel in drug delivery. Mater Sci Eng C Mater Biol Appl 60:560–568

    Article  CAS  Google Scholar 

  175. Ahmed S, Alhareth K, Mignet N (2020) Advancement in nanogel formulations provides controlled drug release. Int J Pharm 584:119435

    Article  CAS  Google Scholar 

  176. Torres-Martinez A, Angulo-Pachon CA, Galindo F, Miravet JF (2019) Liposome-enveloped molecular nanogels. Langmuir 35(41):13375–13381

    Article  CAS  Google Scholar 

  177. Feng L, Ward JA, Li SK, Tolia G, Hao J, Choo DI (2014) Assessment of PLGA-PEG-PLGA copolymer hydrogel for sustained drug delivery in the ear. Curr Drug Deliv 11(2):279–286

    Article  CAS  Google Scholar 

  178. Hamidi M, Azadi A, Rafiei P (2008) Hydrogel nanoparticles in drug delivery. Adv Drug Deliv Rev 60(15):1638–1649

    Article  CAS  Google Scholar 

  179. El-Feky GS, El-Banna ST, El-Bahy GS, Abdelrazek EM, Kamal M (2017) Alginate coated chitosan nanogel for the controlled topical delivery of Silver sulfadiazine. Carbohydr Polym 177:194–202

    Article  CAS  Google Scholar 

  180. Borah PK, Das AS, Mukhopadhyay R, Sarkar A, Duary RK (2020) Macromolecular design of folic acid functionalized amylopectin-albumin core-shell nanogels for improved physiological stability and colon cancer cell targeted delivery of curcumin. J Colloid Interface Sci 580:561–572

    Article  CAS  Google Scholar 

  181. Pedrosa SS, Pereira P, Correia A, Gama FM (2017) Targetability of hyaluronic acid nanogel to cancer cells: In vitro and in vivo studies. Eur J Pharm Sci 104:102–113

    Article  CAS  Google Scholar 

  182. Algharib SA, Dawood A, Zhou K, Chen D, Li C, Meng K et al (2020) Designing, structural determination and biological effects of rifaximin loaded chitosan- carboxymethyl chitosan nanogel. Carbohydr Polym 248:116782

    Article  CAS  Google Scholar 

  183. Hajebi S, Rabiee N, Bagherzadeh M, Ahmadi S, Rabiee M, Roghani-Mamaqani H et al (2019) Stimulus-responsive polymeric nanogels as smart drug delivery systems. Acta Biomater 92:1–18

    Article  CAS  Google Scholar 

  184. Yang G, Fu S, Yao W, Wang X, Zha Q, Tang R (2017) Hyaluronic acid nanogels prepared via ortho ester linkages show pH-triggered behavior, enhanced penetration and antitumor efficacy in 3-D tumor spheroids. J Colloid Interface Sci 504:25–38

    Article  CAS  Google Scholar 

  185. Tang R, Ji W, Wang C (2011) Synthesis and characterization of new poly(ortho ester amidine) copolymers for nonviral gene delivery. Polymer (Guildf) 52(4):921–932

    Article  CAS  Google Scholar 

  186. Zhang XZ, Zhuo RX, Cui JZ, Zhang JT (2002) A novel thermo-responsive drug delivery system with positive controlled release. Int J Pharm 235(1–2):43–50

    Article  CAS  Google Scholar 

  187. Lu YJ, Lan YH, Chuang CC, Lu WT, Chan LY, Hsu PW et al (2020) Injectable thermo-sensitive chitosan hydrogel containing CPT-11-loaded EGFR-targeted graphene oxide and SLP2 shRNA for localized drug/gene delivery in glioblastoma therapy. Int J Mol Sci 21(19)

  188. Gadhave D, Rasal N, Sonawane R, Sekar M, Kokare C (2021) Nose-to-brain delivery of teriflunomide-loaded lipid-based carbopol-gellan gum nanogel for glioma: Pharmacological and in vitro cytotoxicity studies. Int J Biol Macromol 167:906–920

    Article  CAS  Google Scholar 

  189. Zhang M, Asghar S, Tian C, Hu Z, Ping Q, Chen Z et al (2021) Lactoferrin/phenylboronic acid-functionalized hyaluronic acid nanogels loading doxorubicin hydrochloride for targeting glioma. Carbohydr Polym 253:117194

    Article  CAS  Google Scholar 

  190. Lopalco A, Cutrignelli A, Denora N, Perrone M, Iacobazzi RM, Fanizza E et al (2018) Delivery of proapoptotic agents in glioma cell lines by TSPO ligand-dextran nanogels. Int J Mol Sci 19(4)

  191. Zhao M, Bozzato E, Joudiou N, Ghiassinejad S, Danhier F, Gallez B et al (2019) Codelivery of paclitaxel and temozolomide through a photopolymerizable hydrogel prevents glioblastoma recurrence after surgical resection. J Control Release 309:72–81

    Article  CAS  Google Scholar 

  192. Baklaushev VP, Nukolova NN, Khalansky AS, Gurina OI, Yusubalieva GM, Grinenko NP et al (2015) Treatment of glioma by cisplatin-loaded nanogels conjugated with monoclonal antibodies against Cx43 and BSAT1. Drug Deliv 22(3):276–285

    Article  CAS  Google Scholar 

  193. Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12 Pt 1):6387–6392

    CAS  Google Scholar 

  194. Kalyane D, Raval N, Maheshwari R, Tambe V, Kalia K, Tekade RK (2019) Employment of enhanced permeability and retention effect (EPR): nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer. Mater Sci Eng C Mater Biol Appl 98:1252–1276

    Article  CAS  Google Scholar 

  195. Zhao M, van Straten D, Broekman MLD, Preat V, Schiffelers RM (2020) Nanocarrier-based drug combination therapy for glioblastoma. Theranostics 10(3):1355–1372

    Article  CAS  Google Scholar 

  196. Kang H, Rho S, Stiles WR, Hu S, Baek Y, Hwang DW et al (2020) Size-dependent EPR effect of polymeric nanoparticles on tumor targeting. Adv Healthc Mater 9(1):e1901223

    Article  Google Scholar 

  197. Sindhwani S, Syed AM, Ngai J, Kingston BR, Maiorino L, Rothschild J et al (2020) The entry of nanoparticles into solid tumours. Nat Mater 19(5):566–575

    Article  CAS  Google Scholar 

  198. Ding Y, Yang W, Niu P, Li X, Chen Y, Li Z, Liu Z, An Y, Liu Y, Shen W, Shi L (2020) Investigating the EPR effect of nanomedicines in human renaltumors via ex vivo perfusion strategy. Nano Today 35

  199. Danhier F (2016) To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine? J Control Release 244(Pt A):108–121

    Article  CAS  Google Scholar 

  200. Wang H, Wang X, Xie C, Zhang M, Ruan H, Wang S et al (2018) Nanodisk-based glioma-targeted drug delivery enabled by a stable glycopeptide. J Control Release 284:26–38

    Article  CAS  Google Scholar 

  201. Rijpkema SJ, Langens S, van der Kolk MR, Gavriel K, Toebes BJ, Wilson DA (2020) Modular approach to the functionalization of polymersomes. Biomacromol 21(5):1853–1864

    Article  CAS  Google Scholar 

  202. Wang R, Degirmenci V, Xin H, Li Y, Wang L, Chen J et al (2018) PEI-coated Fe3O4 nanoparticles enable efficient delivery of therapeutic siRNA targeting REST into Glioblastoma cells. Int J Mol Sci 19(8)

  203. Kim HJ, Kim A, Miyata K, Kataoka K (2016) Recent progress in development of siRNA delivery vehicles for cancer therapy. Adv Drug Deliv Rev 104:61–77

    Article  CAS  Google Scholar 

  204. Chen H, Shi Y, Sun L, Ni S (2020) Electrospun composite nanofibers with all-trans retinoic acid and MWCNTs-OH against cancer stem cells. Life Sci 258:118152

    Article  CAS  Google Scholar 

  205. Caverzán MD, Beaugé L, Chesta CA, Palacios RE, Ibarra LE (2020) Photodynamic therapy of Glioblastoma cells using doped conjugated polymer nanoparticles: an in vitro comparative study based on redox status. J Photochem Photobiol B Biol 212:112045

    Article  Google Scholar 

  206. Liu Y, Tan J, Zhang Y, Zhuang J, Ge M, Shi B et al (2018) Visualizing glioma margins by real-time tracking of gamma-glutamyltranspeptidase activity. Biomaterials 173:1–10

    Article  Google Scholar 

  207. Luo S, Zhang E, Su Y, Cheng T, Shi C (2011) A review of NIR dyes in cancer targeting and imaging. Biomaterials 32(29):7127–7138

    Article  CAS  Google Scholar 

  208. Qian W, Qian M, Wang Y, Huang J, Chen J, Ni L et al (2018) Combination glioma therapy mediated by a dual-targeted delivery system constructed using OMCN-PEG-Pep22/DOX. Small 14(42):e1801905

    Article  Google Scholar 

  209. Zhao M, Liang C, Li A, Chang J, Wang H, Yan R et al (2010) Magnetic paclitaxel nanoparticles inhibit glioma growth and improve the survival of rats bearing glioma xenografts. Anticancer Res 30(6):2217–2223

    CAS  Google Scholar 

  210. Lu Q, Dai X, Zhang P, Tan X, Zhong Y, Yao C et al (2018) Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells. Int J Nanomed 13:2491–2505

    Article  CAS  Google Scholar 

  211. Liu D, Yang F, Xiong F, Gu N (2016) The smart drug delivery system and its clinical potential. Theranostics 6(9):1306–1323

    Article  CAS  Google Scholar 

  212. Klopfleisch R (2016) Macrophage reaction against biomaterials in the mouse model—phenotypes, functions and markers. Acta Biomater 43:3–13

    Article  CAS  Google Scholar 

  213. Anderson JM, Rodriguez A, Chang DT (2008) Foreign body reaction to biomaterials. Semin Immunol 20(2):86–100

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Qian Xia and Zixiao Wang for providing advice assistance.

Funding

This work was supported by Natural Science Foundation of China (81471517), Key project of Shandong Provincial Natural Science Foundation (ZR202010300086), Key Research and Development Program of Shandong Province (2019GSF107046).

Author information

Authors and Affiliations

Authors

Contributions

XT and LQ proposed the draft. ZH and XS was the major contributor in writing the manuscript. HD and ZR made the graphic abstract and tables. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Qian Liu or Tao Xin.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, Z., Ji, X., He, D. et al. Nanoscale Drug Delivery Systems in Glioblastoma. Nanoscale Res Lett 17, 27 (2022). https://doi.org/10.1186/s11671-022-03668-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s11671-022-03668-6

Keywords

  • Glioblastoma
  • Nanoparticles
  • Biomaterials
  • Drug delivery systems