Comparative studies of salinomycin-loaded nanoparticles prepared by nanoprecipitation and single emulsion method
© Wang et al.; licensee Springer. 2014
Received: 13 March 2014
Accepted: 14 June 2014
Published: 15 July 2014
To establish a satisfactory delivery system for the delivery of salinomycin (Sal), a novel, selective cancer stem cell inhibitor with prominent toxicity, gelatinase-responsive core-shell nanoparticles (NPs), were prepared by nanoprecipitation method (NR-NPs) and single emulsion method (SE-NPs). The gelatinase-responsive copolymer was prepared by carboxylation and double amination method. We studied the stability of NPs prepared by nanoprecipitation method with different proportions of F68 in aqueous phase to determine the best proportion used in our study. Then, the NPs were prepared by nanoprecipitation method with the best proportion of F68 and single emulsion method, and their physiochemical traits including morphology, particle size, zeta potential, drug loading content, stability, and in vitro release profiles were studied. The SE-NPs showed significant differences in particle size, drug loading content, stability, and in vitro release profiles compared to NR-NPs. The SE-NPs presented higher drug entrapment efficiency and superior stability than the NR-NPs. The drug release rate of SE-NPs was more sustainable than that of the NR-NPs, and in vivo experiment indicated that NPs could prominently reduce the toxicity of Sal. Our study demonstrates that the SE-NPs could be a satisfactory method for the preparation of gelatinase-responsive NPs for intelligent delivery of Sal.
KeywordsSalinomycin Nanoprecipitation method Single emulsion method Gelatinase Drug delivery Nanoparticles
Cancer stem cells (CSCs) represent a small proportion of cancer cells that exist in the cancer cell population, which drives tumor growth and recurrence [1, 2]. And CSCs are found to be resistant to conventional cancer treatments, including chemotherapy and radiotherapy [3–6], which suggests that many cancer therapies, though killing bulks of tumor cells, may ultimately fail because they do not eliminate CSCs, which survive to regenerate new tumors. Alternatively, tumor drug-resistant cells induced by traditional chemotherapeutics also present cancer stem-like characteristics . Therefore, novel therapeutic strategies specifically targeting CSCs are urgently needed.
Salinomycin (Sal) was originally used to kill bacteria, fungi, and parasites . In 2009, Gupta et al. identified Sal by a high-throughput screening that could potentially be used to target breast CSCs, and it killed breast CSCs at least 100 times more effectively than paclitaxel in mice . Since then, large amounts of studies have been conducted and indicated that Sal can effectively kill various types of cancer stem-like cells, for instance, colorectal cancer, pancreatic cancer, prostate cancer, and so on [10–12]. Thus, it is considered to be a potential anticancer drug for cancer therapy. However, for several reasons, Sal has never been established as a drug for human diseases until now. For example, owing to its poor aqueous solubility, it could not be administered by intraperitoneal injection without the aid of ethanol . In particular, several reports and studies published in the last three decades revealed a considerable toxicity of Sal in different kinds of mammals including humans after accidental oral or inhalative intake [14–17]. To solve these problems, significant efforts have been done, and the widely used are nanoparticles (NPs) due to their satisfying traits.
Amphiphilic copolymer NPs consisting of hydrophilic and hydrophobic segments have drawn intensive attention in antitumor drug delivery systems since the 1990s [18–20]. They present unique characteristics as drug carriers including high drug encapsulation efficiency due to optimized drug solubility in the core , preferential accumulation in tumor tissue via enhanced permeation and retention (EPR) effect [22, 23], the ability to prolong drug release  because of the protection of the drug against chemical and enzymatic degradation , and the capacity to reduce the systemic adverse effects and the risks of toxicity [26, 27] with the purpose of minimizing the number of administrations for a better patient compliance . Progress in this field has made it possible for NPs being able to deliver the drugs to the targeted tumor sites [29–31], which can increase the drug concentration in the tumor region and reduce the drug content in the normal region. This characteristic can reduce the side effects of the drugs to a large extent. In the present work, the intelligent gelatinase-stimuli NPs which are modified by inserting the optimal gelatinase-cleavable peptide (PVGLIG) between polyethylene glycol (mPEG) and polycaprolactone (PCL) segment (mPEG-Pep-PCL)  were set up to deliver Sal. Owing to their special structures, the NPs prepared from mPEG-Pep-PCL have their own characteristics, such as prolonged circulating time and accumulation in the tumor site by the EPR effect [33–35]. Since the gelatinases are known to be abundantly present in most tumors, once the NPs accumulate in the tumors, the mPEG-PCL conjugates will be cleaved at the certain site of the peptide which results in the dePEGylated NPs being retained in the tumor regions, effectively interacting with more tumor cells, increasing cellular uptake of NPs into cancer cells, and improving intracellular anticancer drug concentration.
By encapsulating Sal into the PEG-Pep-PCL NPs that are based on biodegradable polymers, its side effects can be reduced because of the EPR effects of copolymeric NPs, sustained release pattern, and gelatinase-triggered drug targeting. NPs can be formulated by using different preparation methods . However, few studies have been done to evaluate the satisfying preparation method for Sal delivery by NPs. Thus, the aims of this work are to emphasize the relationship among the particle elaboration process, the nature of the particles, their size stability, and the encapsulated drug release and to choose the optimized way for Sal delivery. In our study, we confirmed the optimum preparation method for Sal-loaded NP preparation.
Synthesis of PEG-peptide conjugates
Two-hundred milligrams of methoxy-polyethylene glycol-NHS (mPEG-NHS, Jiankai Technology Co., Ltd., Beijing, China) and 26 mg of PVGLIG (HD Biosciences Co., Shanghai, China) were dissolved in 3 mL of dimethyl formamide (DMF) containing 3% triethylamine (Et3N) and stirred for 3 h at room temperature to prepare PEG-peptide conjugates. The unconjugated peptides were removed by dialysis in a 3,500-Da MWCO membrane (Greenbird, Shanghai, China) against deionized water for 24 h.
Synthesis of PCL-COOH copolymers
The dichloromethane (DCM)-dissolved PCL (Mn13800, determined by proton nuclear magnetic resonance (1H NMR)) polymers were added with succinic anhydride, 4-dimethylamiopryidine (DMAP), and pyridine and then stirred at room temperature for 48 h. The resultant mixture was precipitated in ethyl ether and washed three times with methanol and then dried under vacuum to prepare the PCL-COOH.
Synthesis of PCL-NH2 copolymers
The DMF-dissolved PCL-COOH polymers were added with DMAP, 1-ethyl-3-[3-dimethylaminopropyl] carbodimide hydrochloride (EDC), ethylenediamine and N-hydroxysulfosuccinimide sodium salt (NHS), and stirred at 37°C for 18 h. The mixture was precipitated in ethanol and dried under vacuum to prepare the PCL-NH2.
Synthesis of PEG-Pep-PCL and PEG-PCL copolymers
The mixture of PCL-NH2 (0.002 mol), PEG-peptide conjugates (0.002 mol), DMAP (0.003 mol), EDC (0.002 mol), and NHS (0.002 mol) in DMF was stirred for 24 h at 32°C. The crude PEG-peptide-PCL copolymers were purified by dialysis (MWCO 13 kDa) for 24 h, lyophilized to powder, and stored at 4°C for further use.
Nanoprecipitation method with different proportions of poloxamer 188 (F68) in deionized water (aqueous phase)
Different concentrations of surfactants were designed to select the optimal formulation, which could have long-term stability. Briefly, 5 mg of PEG-Pep-PCL copolymers was dissolved in 200 μL acetone, and then, the mixed solution was slowly added to five aqueous solutions (5 mL each) containing 0.125%, 0.25%, 0.5%, and 1.0% (w/w) F68 with quick stirring. The NPs formed and the solution turned to blue immediately. The remaining acetone was removed by rotary vacuum evaporation and the resulting solution was filtered to remove nonincorporated drugs.
Sal NPs and blank NPs prepared by nanoprecipitation method with the best proportion of F68
After the optimal surfactant concentration had been determined, 5 mg of copolymer and 0.5 mg of Sal (China Institute of Veterinary Drug Control, Beijing, China) were dissolved in 200 μL acetone, and the mixture was added into 5 mL deionized water that contains the best proportion of F68 with quick stirring. The NPs formed and the solution turned to blue immediately. The remaining acetone was removed by rotary vacuum evaporation and the resulting solution was filtered to remove nonincorporated drugs. The blank NPs were produced in the same manner without adding Sal.
Single emulsion method
The NPs loaded with Sal were prepared by a modified single emulsion method. Briefly, 20 mg of each copolymer and 2 mg Sal were dissolved in 1 mL of DCM. The mixture was emulsified in 3 mL of aqueous polyvinyl alcohol (PVA) solution at 3% (w/v) by sonication (XL2000, Misonix, Farmingdale, NY, USA) for 60 s (4 W) to obtain an o/w emulsion. This emulsion was then emulsified in 5 mL of aqueous solution containing 0.5% (w/v) PVA by sonication (XL2000, Misonix, USA) for 10 s (2.5 W). The w/o/w emulsion formed was gently stirred at room temperature in a fume hood until the evaporation of the organic solvent was complete. The resulting solution was filtered to remove nonincorporated drugs. Blank NPs were produced in the same manner without adding Sal.
Size and zeta potential analysis of the NPs
Mean diameter and size distribution were measured by photon correlation spectroscopy (DLS) with a Brookhaven BI-9000AT instrument (Brookhaven Instruments Corporation, Holtsville, NY, USA). Zeta potential was measured by the laser Doppler anemometry (Zeta Plus, Zeta Potential Analyzer, Brookhaven Instruments Corporation, USA). All measurements were performed at 25°C. The values were calculated from the measurements performed at least in triplicate.
Morphological examination of the NPs was conducted using a JEM-100S transmission electron microscope (TEM, JEOL Ltd., Akishima-shi, Japan). One drop of NP suspension was placed on a copper grid covered with nitrocellulose membrane and air-dried before observation.
Drug loading content and encapsulation efficiency
To determine the Sal-loaded NPs’ drug loading content, 1 mL of the NPs was dried in the oven. Then, Sal was redissolved in 3 mL 95% ethanol and centrifuged. The supernatant derivatized with vanillin (Accelerating Scientific and Industrial Development thereby Serving Humanity, Shanghai, China) in an acidic medium at 72°C for 40 min. The derivatization mixture was determined by the ultraviolet absorption at the wavelength of 527 nm, a strong absorption band of Sal with reference to a calibration curve on a Shimadzu UV3100 spectrophotometer (Shimadzu, Hadano, Japan).
Sal-loaded NPs and blank NPs were kept at room temperature. Particle sizes were determined by DLS every 2 days for 15 days to evaluate stability.
In vitro release of Sal-loaded NPs
In vitro release of Sal from NPs was investigated by a dialysis method. Briefly, a volume of 1 mL NP solution was sealed in the dialysis bag (molecular weight cutoff 14,000 Da). The dialysis bag was immersed into a 5-mL 0.01 M pH 7.4 PBS solution containing 0.5% Tween 80 at 37°C in a constant temperature shaker. At predetermined time points, aliquots were withdrawn from the beaker and replaced with equal volume of the media. The Sal content in the release medium was determined by pre-HPLC (derivatized with 2,4-dinitrophenol (DNP, Accelerating Scientific and Industrial Development thereby Serving Humanity, Shanghai, China) in an acidic medium at 55°C for 30 min in a C18 column (Agilent Technologies, Ltd., Santa Clara, CA, USA), with the mobile phase consisting of methanol:1.5% aqueous acetic acid = 93:7, the flow rate of 1 mL/min, the column temperature of 25°C, the injection volume of 20 μL, and the detector at a wavelength of 392 nm). All the experiments met the sink condition and were repeated in triplicate.
In vivo safety studies of Sal-loaded SE-NPs
All animal studies were performed in compliance with guidelines set by the Animal Care Committee at Drum Tower Hospital, Nanjing, China. 8BC nudes (18 to 22 g, 4 to 5 weeks, male, Animal Care Committee at Drum Tower Hospital, Nanjing, China) were embedded with 1 × 1-cm tumor pieces subcutaneously on the right axilla. Tumor dimensions were measured with vernier calipers, and the volumes were calculated as follows: Tumor volume (mm3) = Width2 × Length / 2. When the tumors reached 100 mm3 (designated as day 1), the animals were randomized into the following treatment groups: free Sal (4 mg/kg), free Sal (8 mg/kg), and Sal NPs prepared by the single emulsion method (SE-NPs) (8 mg/mL). The number of surviving mice was counted to preliminarily evaluate the safety of Sal SE-NPs in vivo.
Statistical analyses of data were done using Student's t test. The data are listed as mean ± SD, and values of P < 0.05 were accepted as a statistically significant difference.
Results and discussion
Copolymer synthesis and characterization
Determination study of the surfactant concentration
Size and morphology studies of NPs prepared by the two methods
The diameter and polydispersity of NPs prepared by different methods
235.8 ± 1.9
0.160 ± 0.028
224.1 ± 7.5
0.166 ± 0.005
151.1 ± 1.1
0.099 ± 0.041
148.1 ± 2.9
0.11 ± 0.015
Drug loading content and encapsulation efficiency
The drug loading content and encapsulation efficiency of Sal NPs prepared by different methods
Drug loading content (%)
Encapsulation efficiency (%)
89.70 ± 5.7
8.12 ± 5.7
81.51 ± 8.9
7.40 ± 8.9
In vitro release of Sal-loaded NPs
Primary toxicity observation of Sal-loaded SE-NPs
The number of live nude mice after injection with different drugs and dosages
Free sal (8 mg/kg)
Free sal (4 mg/kg)
Sal-loaded SE-NPs (8 mg/kg)
In this paper, we used the PEG-Pep-PCL NPs, which have been proven effective for targeting tumor tissue specifically, to improve drug efficacy and reduce Sal-caused adverse effects. To determine the optimum method for Sal-loaded NP preparation, we made a comparison between NR-NPs prepared with different proportions of F68. Besides, we compared the physiochemical traits of NR-NPs and SE-NPs. Based on the results of our study, we confirmed that 1% is the best proportion of F68 for NR-NP preparation, due to the best stability of NR-NPs prepared with 1% of F68, and the SE-NPs showed superior stability, higher drug loading efficiency, and more sustainable but complete release, which means that the single emulsion method is better for Sal-loaded NP formulation. Preliminary toxicity observation indicated a striking higher survival rate of mice injected with Sal-loaded SE-NPs, which means that entrapping Sal into SE-NPs can greatly reduce its adverse effects. For consideration of the physical traits and in vivo animal study, we conclude here that SE-NPs prepared in this study have a high potential to be used for Sal delivery.
cancer stem cells
enhanced permeation and retention effect
1-ethyl-3-[3-dimethylaminopropyl] carbodimide hydrochloride
N-hydroxysulfosuccinimide sodium salt
photon correlation spectroscopy
transmission electron microscope
This work was supported by the National Natural Science Foundation of China (nos. 81101751, 81220108023, 81302053), Nanjing Medical Science and Technique Development Foundation (Outstanding Youth Foundation JQX12003 and ZKX12012), and Jiangsu Medical Science Foundation (H201235).
- Levina V, Marrangoni AM, DeMarco R, Gorelik E, Lokshin AE: Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS One 2008, 3(8):e3077.View ArticleGoogle Scholar
- Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K: Molecular definition of breast tumor heterogeneity. Cancer Cell 2007, 11(3):259–273.View ArticleGoogle Scholar
- Dalerba P, Cho RW, Clarke MF: Cancer stem cells: models and concepts. Annu Rev Med 2007, 58: 267–284.View ArticleGoogle Scholar
- Eyler CE, Rich JN: Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 2008, 26(17):2839–2845.View ArticleGoogle Scholar
- Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM: WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci U S A 2007, 104(2):618–623.View ArticleGoogle Scholar
- Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, Paz B, Shen J, Lau SK, Quake SR, Brown JM, Weissman IL, Clarke MF: Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 2009, 458(7239):780–783.View ArticleGoogle Scholar
- Gopalan A, Yu W, Sanders BG, Kline K: Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol. Cancer Lett 2013, 328(2):285–296.View ArticleGoogle Scholar
- Mahmoudi N, de Julián-Ortiz JV, Ciceron L, Gálvez J, Mazier D, Danis M, Derouin F, García-Domenech R: Identification of new antimalarial drugs by linear discriminant analysis and topological virtual screening. J Antimicrob Chemother 2006, 57(3):489–497.View ArticleGoogle Scholar
- Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES: Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009, 138(4):645–659.View ArticleGoogle Scholar
- Zhou J, Li P, Xue X, He S, Kuang Y, Zhao H, Chen S, Zhi Q, Guo X: Salinomycin induces apoptosis in cisplatin-resistant colorectal cancer cells by accumulation of reactive oxygen species. Toxicol Lett 2013, 222(2):139–145.View ArticleGoogle Scholar
- Zhang GN, Liang Y, Zhou LJ, Chen SP, Chen G, Zhang TP, Kang T, Zhao YP: Combination of salinomycin and gemcitabine eliminates pancreatic cancer cells. Cancer Lett 2011, 313(2):137–144.View ArticleGoogle Scholar
- Zhi QM, Chen XH, Ji J, Zhang JN, Li JF, Cai Q, Liu BY, Gu QL, Zhu ZG, Yu YY: Salinomycin can effectively kill ALDH (high) stem-like cells on gastric cancer. Biomed Pharmacother 2011, 65(7):509–515.View ArticleGoogle Scholar
- Zhang Y, Zhang H, Wang X, Wang J, Zhang X, Zhang Q: The eradication of breast cancer and cancer stem cells using octreotide modified paclitaxel active targeting micelles and salinomycin passive targeting micelles. Biomaterials 2012, 3(2):679–91.View ArticleGoogle Scholar
- Kosal ME, Anderson DE: An unaddressed issue of agricultural terrorism: a case study on feed security. J Anim Sci 2004, 82(11):3394–3400.Google Scholar
- Aleman M, Magdesian KG, Peterson TS, Galey FD: Salinomycin toxicosis in horses. J Am Vet Med Assoc 2007, 230(12):1822–1826.View ArticleGoogle Scholar
- Story P, Doube A: A case of human poisoning by salinomycin, an agricultural antibiotic. N Z Med J 2004, 117(1190):U799.Google Scholar
- Dorne JL, Fernández-Cruz ML, Bertelsen U, Renshaw DW, Peltonen K, Anadon A, Feil A, Sanders P, Wester P, Fink-Gremmels J: Risk assessment of coccidostatics during feed cross-contamination: animal and human health aspects. Toxicol Appl Pharmacol 2013, 270(3):196–208.View ArticleGoogle Scholar
- Pridgen EM, Langer R, Farokhzad OC: Biodegradable polymeric nanoparticle delivery systems for cancer therapy. Nanomed 2007, 2(5):669–680.View ArticleGoogle Scholar
- Langer R: New methods of drug delivery. Science 1990, 249(4976):1527–1533.View ArticleGoogle Scholar
- Tan ML, Choong PF, Dass CR: Cancer, chitosan nanoparticles and catalytic nucleic acids. J Pharm Pharmacol 2009, 61(1):3–12.View ArticleGoogle Scholar
- Li B, Wang Q, Wang X, Wang C, Jiang X: Preparation, drug release and cellular uptake of doxorubicin-loaded dextran-b-poly(ε-caprolactone) nanoparticles. Carbohydr Polym 2013, 93(2):430–437.View ArticleGoogle Scholar
- Park K, Kim JH, Nam YS, Lee S, Nam HY, Kim K, Park JH, Kim IS, Choi K, Kim SY, Kwon IC: Effect of polymer molecular weight on the tumor targeting characteristics of self-assembled glycol chitosan nanoparticles. J Control Release 2007, 122(3):305–314.View ArticleGoogle Scholar
- Davis ME, Chen Z, Shin DM: Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov 2008, 7(9):771–782.View ArticleGoogle Scholar
- Panyam J, Labhasetwar V: Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev 2003, 55(3):329–347.View ArticleGoogle Scholar
- Zhang L, He Y, Yu M, Song C: Paclitaxel-loaded polymeric nanoparticles based on PCL-PEG-PCL: preparation, in vitro and in vivo evaluation. J Control Release 2011, 152(Suppl1):e114-e116.View ArticleGoogle Scholar
- Abu Lila AS, Kiwada H, Ishida T: The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J Control Release 2013, 172(1):38–47.View ArticleGoogle Scholar
- Hiremath JG, Khamar NS, Palavalli SG, Rudani CG, Aitha R, Mura P: Paclitaxel loaded carrier based biodegradable polymeric implants: preparation and in vitro characterization. Saudi Pharm J 2013, 21(1):85–91.View ArticleGoogle Scholar
- Larson N, Ghandehari H: Polymeric conjugates for drug delivery. Chem Mater 2012, 24(5):840–853.View ArticleGoogle Scholar
- Liu Q, Li R, Zhu Z, Qian X, Guan W, Yu L, Yang M, Jiang X, Liu B: Enhanced antitumor efficacy, biodistribution and penetration of docetaxel-loaded biodegradable nanoparticles. Int J Pharm 2012, 430(1–2):350–358.View ArticleGoogle Scholar
- Pan L, Liu J, He Q, Wang L, Shi J: Overcoming multidrug resistance of cancer cells by direct intranuclear drug delivery using TAT-conjugated mesoporous silica nanoparticles. Biomaterials 2013, 34(11):2719–2730.View ArticleGoogle Scholar
- Li R, Xie L, Zhu Z, Liu Q, Hu Y, Jiang X, Yu L, Qian X, Guo W, Ding Y, Liu B: Reversion of pH-induced physiological drug resistance: a novel function of copolymeric nanoparticles. PLoS One 2011, 6(9):e24172.View ArticleGoogle Scholar
- Li R, Wu W, Liu Q, Wu P, Xie L, Zhu Z, Yang M, Qian X, Ding Y, Yu L, Jiang X, Guan W, Liu B: Intelligently targeted drug delivery and enhanced antitumor effect by gelatinase-responsive nanoparticles. PLoS One 2013, 8(7):e69643.View ArticleGoogle Scholar
- Khaled G: Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targeting. Methods Mol Biol 2010, 624: 25–37.View ArticleGoogle Scholar
- Podduturi VP, Magaña IB, O'Neal DP, Derosa PA: Simulation of transport and extravasation of nanoparticles in tumors which exhibit enhanced permeability and retention effect. Comput Methods Programs Biomed 2013, 112(1):58–68.View ArticleGoogle Scholar
- Maeda H, Bharate GY, Daruwalla J: Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. Eru J Pharm Biopharm 2009, 71(3):409–419.View ArticleGoogle Scholar
- Mora-Huertas CE, Fessi H, Elaissari A: Polymer based nanocapsules for drug delivery. Int J Pharm 2010, 385(1–2):113–142.View ArticleGoogle Scholar
- Roy Boehm ALL, Zerrouk R, Fessi H: Poly epsilon-caprolactone nanoparticles containing a poorly soluble pesticide: formulation and stability study. J Microencapsul 2000, 17(2):195–205.View ArticleGoogle Scholar
- Aydın RS: Herceptin-decorated salinomycin-loaded nanoparticles for breast tumor targeting. J Biomed Mater Res A 2013, 101(5):1405–1415.View ArticleGoogle Scholar
- Lv S, Li M, Tang Z, Song W, Sun H, Liu H, Chen X: Doxorubicin-loaded amphiphilic polypeptide-based nanoparticles as an efficient drug delivery system for cancer therapy. Acta Biomater 2013, 9(12):9330–9342.View ArticleGoogle Scholar
- Liu Q, Li R, Qian H, Yang M, Zhu Z, Wu W, Qian X, Yu L, Jiang X, Liu B: Gelatinase-stimuli strategy enhances the tumor delivery and therapeutic efficacy of docetaxel-loaded poly(ethylene glycol)-poly(ε-caprolactone) nanoparticles. Int J Nanomedicine 2012, 7: 281–295.View ArticleGoogle Scholar
- Cohen SE, Teitiboim S, Chorny M, Koroukhov N, Danenberg HD, Gao J, Golomb G: Single and double emulsion manufacturing techniques of an amphiphilic drug in PLGA nanoparticles: formulations of mithramycin and bioactivity. J Pharm Sci 2009, 98(4):1452–1462.View ArticleGoogle Scholar
- Shi W, Zhang ZJ, Yuan Y, Xing EM, Qin Y, Peng ZJ, Zhang ZP, Yang KY: Optimization of parameters for preparation of docetaxel-loaded PLGA nanoparticles by nanoprecipitation method. J Huazhong Univ Sci Technolog Med Sci 2013, 33(5):754–758.View ArticleGoogle Scholar
- Dong Y, Feng SS: Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs. Biomaterials 2004, 25(14):2843–2849.View ArticleGoogle Scholar
- Hong JL, Hee HP, Jeong AK, Ju HP, Jina R, Jeongseon C, Jongmin L, Won JR, Tai HP: Enzyme delivery using the 30Kc19 protein and human serum albumin nanoparticles. Biomaterials 2014, 35(5):1696–1704.View ArticleGoogle Scholar
- Li R, Li X, Xie L, Ding D, Hu Y, Qian X, Yu L, Ding Y, Jiang X, Liu B: Preparation and evaluation of PEG-PCL nanoparticles for local tetradrine delivery. Int J Pharm 2009, 379(1):158–166.View ArticleGoogle Scholar
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