- Nano Express
- Open Access
Oral Delivery of DMAB-Modified Docetaxel-Loaded PLGA-TPGS Nanoparticles for Cancer Chemotherapy
- Hongbo Chen†1, 2,
- Yi Zheng†1, 2,
- Ge Tian3,
- Yan Tian3,
- Xiaowei Zeng4,
- Gan Liu4,
- Kexin Liu3,
- Lei Li3,
- Zhen Li3,
- Lin Mei1, 2, 3Email author and
- Laiqiang Huang1, 2Email author
© Chen et al. 2010
Received: 26 June 2010
Accepted: 5 August 2010
Published: 20 August 2010
Three types of nanoparticle formulation from biodegradable PLGA-TPGS random copolymer were developed in this research for oral administration of anticancer drugs, which include DMAB-modified PLGA nanoparticles, unmodified PLGA-TPGS nanoparticles and DMAB-modified PLGA-TPGS nanoparticles. Firstly, the PLGA-TPGS random copolymer was synthesized and characterized. DMAB was used to increase retention time at the cell surface, thus increasing the chances of particle uptake and improving oral drug bioavailability. Nanoparticles were found to be of spherical shape with an average particle diameter of around 250 nm. The surface charge of PLGA-TPGS nanoparticles was changed to positive after DMAB modification. The results also showed that the DMAB-modified PLGA-TPGS nanoparticles have significantly higher level of the cellular uptake than that of DMAB-modified PLGA nanoparticles and unmodified PLGA-TPGS nanoparticles. In vitro, cytotoxicity experiment showed advantages of the DMAB-modified PLGA-TPGS nanoparticle formulation over commercial Taxotere® in terms of cytotoxicity against MCF-7 cells. In conclusion, oral chemotherapy by DMAB-modified PLGA-TPGS nanoparticle formulation is an attractive and promising treatment option for patients.
Oncology is one of the few areas of medicine where most patients are treated intravenously rather than receiving oral medications. Oral chemotherapy is attractive because of its convenience and ease of administration, particularly in a palliative setting. In addition, the oral route facilitates the use of more chronic treatment regimens, which result in prolonged exposure to anticancer drugs. However, most anticancer drugs such as Taxoids (paclitaxel and docetaxel) are not orally bioavailable, i.e., not absorbable in the gastrointestinal (GI) tract. This is because Taxoids have a very low level of oral bioavailability at less than 10% [1, 2]. The low systemic exposure of Taxoids after oral drug administration is, at least in part, due to their high affinity for the multidrug efflux pump P-glycoprotein (P-gp) [3, 4]. P-gp in the mucosa of the GI tract limits the absorption of the orally administered Taxoids and mediates their direct excretion into the gut lumen . In addition, first-pass elimination by cytochrome P450 (CYP) isoenzymes in the liver and/or gut wall may also contribute to the low oral bioavailability of Taxoids [5, 6]. Possible solutions for oral delivery of Taxoids and other anticancer drugs are currently under extensive investigation . The general idea is to apply P-gp/P450 inhibitors such as cyclosporine to suppress the elimination process [7, 8]. However, P-gp/P450 inhibitors may suppress the body's immune system and thus cause severe medical complications. Polymeric nanoparticles are of special interest from the pharmaceutical point of view. Polymeric nanoparticles could escape from the recognition of P-gp and thus bear the most potential to enhance the oral bioavailability of drugs that are otherwise poorly absorbed when administered orally [9–11]. Their submicron size and their large specific surface area favor their absorption compared to larger carrier. The nanoparticles could also shield incorporated drug molecules from the gastrointestinal tract (GIT) degradation as well as gut wall metabolism. In addition, the nanoparticles could bypass the liver and prevent the first-pass metabolism of the incorporated drug . It has been fully accepted that nanoparticle surface properties are of outmost importance for their uptake by intestinal epithelial cells. Hence, many strategies have been developed to improve mucosal absorption of nanoparticles, either by modifying their surface properties or by coupling a targeting molecular at their surface . In the present study, we proposed a novel nanoparticle formulation, i.e., biodegradable PLGA-TPGS nanoparticles modified with a cationic surfactant, didodecyldimethylammonium bromide (DMAB) (named DMAB/PLGA-TPGS NPs hereinafter), for oral chemotherapy using docetaxel as a therapeutic drug due to its excellent therapeutic effects against a wide spectrum of cancers and its commercial success as one of the top-selling anticancer agents.
Reports on the positive surface charge of DMAB provided the incentive to aid drug adsorption and delivery, since it is expected to ensure better interaction with the negatively charged cell membrane [14–16]. This can result in increased retention time at the cell surface, thus increasing the chances of particle uptake and improving oral drug bioavailability . DMAB is capable of producing small and highly stable nanoparticles at 1% w/v concentration . Due to the charged surface, the particle agglomeration is impeded. Thus, in this research, DMAB was absorbed on the nanoparticle surface by electrostatic attraction between positive and negative charges. In our design, the FDA-approved biodegradable polymer PLGA was employed to maintain the mechanical strength of the copolymer. d-α-tocopheryl polyethylene glycol 1,000 succinate (TPGS) is a water-soluble derivative of natural vitamin E, which is formed by esterification of vitamin E succinate with polyethylene glycol (PEG) 1,000. TPGS could improve drug permeability through cell membranes by inhibiting P-glycoprotein, and thus enhance absorption of drugs and reduce P-glycoprotein-mediated multidrug resistance in tumor cells [19–21]. It was found that TPGS could also effectively inhibit the growth of human lung carcinoma cells from in vitro cell culture and implanted in nude mice . The superior anticancer efficacy of TPGS is associated with its increasing ability to induce apoptosis and not due to its increased cell uptake into cells [22–24]. Synergistic antitumor effects could be obtained by the use of combinations of vitamin E isomers or derivatives in the presence of other anticancer agents . In addition, TPGS-emulsified nanoparticles have been shown higher drug encapsulation and cellular uptake, longer half-life and higher therapeutic effects of the formulated drug than those emulsified by poly (vinyl alcohol) (PVA), a widely used emulsifier in nanoparticle technology . We were thus inspired to synthesize a novel biodegradable poly(lactide-co-glycolide)-d-a-tocopheryl polyethylene glycol 1,000 succinate (PLGA-TPGS) random copolymer for nanoparticle formulation of small molecule drug chemotherapy .
Materials and Methods
D,L-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione, C6H8O4) with purity above 99% and didodecyldimethylammonium bromide (DMAB) were purchased from Sigma–Aldrich (St. Louis, MO, USA). d-α-tocopheryl polyethylene glycol 1,000 succinate (TPGS, C33O5H54 (CH2CH2O)23), PLGA (50:50, MW 50,000), glycolide (1,4-Dioxane-2,5-dione, C4H4O4), stannous octoate (Sn(OOCC7H15)2) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were also supplied from Sigma–Aldrich (St. Louis, MO, USA). Docetaxel of purity 99.8% was purchased from Shanghai Jinhe Bio-Technology Co. Ltd (Shanghai, China). Acetonitrile and methanol were purchased from EM Science (ChromAR, HPLC grade, Mallinckrodt Baker, USA). All other chemicals used were of the highest quality commercially available. Ultrahigh pure water produced by Boon Environmental Tech. Industry Co., Ltd (Tianjin, China) was utilized throughout all experiments.
Synthesis and Characterization of PLGA-TPGS Random Copolymers
PLGA-TPGS random copolymers were synthesized from lactide, glycolide and TPGS in the presence of stannous octoate as a catalyst via ring opening polymerization . In brief, weighted amounts of lactide, glycolide, TPGS and 0.5 wt% stannous octoate (in distilled toluene) were added in a flask. The mixture was heated to 145°C and allowed to react for 12 h. Synthesis was carried out under an oxygen- and moisture-free environment. The product was dissolved in DCM and then precipitated in excess cold methanol to remove unreacted lactide monomers and TPGS. The final product was collected by filtration and vacuum dried at 45°C for 2 days. The TPGS content and number-averaged molecular weight of the copolymer were determined by 1H NMR in CDCl3 at 300 Hz (Bruker ACF300). The weight-averaged molecular weight and molecular weight distribution were determined by gel permeation chromatography (Waters GPC analysis system with RI-G1362A refractive index detector, Waters, Milford, USA).
Preparation of DMAB-Modified Nanoparticles
Nanoparticles were fabricated by a solvent extraction/evaporation method with slight modifications [25, 26]. Briefly, a given amount of docetaxel and 100 mg PLGA-TPGS copolymer were dissolved in 8 ml dichloromethane (DCM). The formed solution was poured into 120 ml of 0.03% (w/v) TPGS solution under gentle stirring. The mixture was sonicated for 120 s at 25 W output to form O/W emulsion. The emulsion was then evaporated overnight under reduced pressure to remove DCM. The particle suspension was centrifuged at 22,000 rpm for 20 min, and then washed three times to remove TPGS and unencapsulated drug. The resulted particles were resuspended in 10 ml DI water and freeze-dried. The surface modification of the PLGA-TPGS nanoparticles was carried out by a method described previously . DMAB was dissolved in DI water at a concentration of 0.5 mg/ml. Preweighed nanoparticles were suspended in this solution at a concentration of 9.5 mg/ml by sonication at 25 W power output for 60 s over an ice bath, and then were collected by ultracentrifugation. In addition, the fluorescent coumarin-6-loaded nanoparticles were prepared in the same way, except 0.1% (w/v) coumarin-6 was encapsulated instead of docetaxel. DMAB-modified PLGA nanoparticles were prepared by the same method.
Characterization of Nanoparticles
Size Analysis and Surface Charge
Size and size distribution of nanoparticles were determined by Dynamic Light Scattering (Zetasizer Nano ZS90, Malvern Instruments LTD., Malvern, UK). The particles (about 2 mg) were suspended in deionized water before measurement. Zeta potential of the nanoparticles was measured by Laser Doppler Anemometry (LDA; Zetasizer Nano ZS90, Malvern Instruments LTD., Malvern, UK). The measurement was performed triplicate.
The particle morphologies were examined by a field emission scanning electron microscopy (FESEM), using a JEOL JSM-6700F system operated at a 5.0 kV accelerating voltage. To prepare samples for FESEM, the particles were fixed on the stub by a double-sided sticky tape and then coated with platinum layer by JFC-1,300 automatic fine platinum coater (JEOL, Tokyo, Japan) for 40 s.
Drug Content and Entrapment Efficiency
Drug loading content and entrapment efficiency (EE) of the nanoparticles were determined by HPLC (LC 1200, Agilent Technologies, Santa Clara, CA) according to previously published methods [13, 14]. Briefly,5 mg nanoparticles were dissolved in 1 ml DCM under vigorous vortexing. This solution was transferred to 5 ml of mobile phase consisting of deionized water and acetonitrile (50:50, v/v). A nitrogen stream was introduced to evaporate the DCM for about 15 min, and then a clear solution was obtained for HPLC analysis. A reverse-phase Inertsil® C-18 column (150 mm × 4.6 mm, pore size 5 mm, GL science Inc, Tokyo, Japan) was used. The flow rate of mobile phase was 1 ml/min. The column effluent was detected at 227 nm with a UV/VIS detector. The drug EE was defined as the ratio between the amount of docetaxel encapsulated in the nanoparticles and that added in the process. Experiments were performed in triplicate, and results are expressed as mean ± standard deviation (SD).
In Vitro Drug Release
Fifteen milli-gram docetaxel-loaded nanoparticles were dispersed in 5 ml release medium (phosphate buffer solution of pH 7.4 containing 0.1% w/v Tween 80) to form a suspension. Tween 80 was used to increase the solubility of docetaxel in the buffer solution and avoid the binding of docetaxel to the tube wall. The suspension was transferred into a Regenerated Cellulose Dialysis Membrane (Spectra/Por 6, MWCO = 1,000, Spectrum, Houston, TX, USA). Then, the closed bag was put into a centrifuge tube and immersed in 15 ml release medium. The tube was put in an orbital water bath shaking at 120 rpm at 37.0°C. Ten milliliter of solutions were periodically removed for analysis and replaced with fresh medium. The collected samples were extracted with 2 ml DCM and reconstituted in 5 ml mobile phase. A nitrogen stream was introduced to evaporate the DCM. The analysis procedure was the same as for the measurement of encapsulation efficiency.
Cellular Uptake of Nanoparticles
Caco-2 cells of passage 30–35 (American Type Culture Collection, VA) were used in this study to simulate the GI barrier for oral chemotherapy, which were grown in 25-cm2 tissue culture flasks maintained at 37°C in a humidified environment of 5% CO2. The medium, Dubelco's modified essential medium (DMEM, Sigma D1152) supplemented with 20% fetal bovine serum, 100 U/ml penicillin and 100 (g/ml streptomycin (Sigma) was freshened every 3 days. After 90% confluence, the cells were collected by 0.25% of Trypsin–EDTA solution (Sigma) and cultured in 96-well black plate (Costa®, Corning Incorporated) at a density of 1.3 × 104 cells/well; after the cells reached confluence, the cells were equilibrated with HBSS at 37°C for 1 h and then incubated with coumarin-6-loaded nanoparticle suspension. The nanoparticles were dispersed in the medium at concentration of 100, 250 and 500 (g/ml). The wells with nanoparticles were incubated at 37°C for 2 h. After incubation, the suspension was removed and the wells were washed three times with 50 μl cold PBS to eliminate traces of nanoparticles left in the wells. After that, 50 μl of 0.5% Triton X-100 in 0.2 N NaOH was introduced into each sample wells to lyse the cells. The fluorescence intensity of each sample well was measured by microplate reader (GENios, Tecan, Switzerland) with excitation wave length at 430 nm and emission wavelength at 485 nm. Cell uptake efficiency was expressed as the percentage of cells associated fluorescence versus the fluorescence present in the feed solution. Culture of human breast adenocarcinoma cell line MCF-7 cells (passage 30–35, American Type Culture Collection) and their uptake of the coumarin-6-loaded nanoparticles were performed in the same way.
Caco-2 cells were re-seeded in the chambered cover glass system (LABTEK®, Nagle Nunc, IL). After the cells were incubated with 250 μg/ml coumarin-6-loaded DMAB-modified PLGA-TPGS nanoparticle suspension at 37°C for 2 h, the cells were rinsed with cold PBS for three times and then fixed by ethanol for 20 min. The cells were further washed twice with PBS, and the nuclei were counterstained with propidium iodide (PI) for 30 min. The cell monolayer was washed twice with PBS and mounted in Dako® fluorescent mounting medium (Dako, CA) to be observed by confocal laser scanning microscope (CLSM) (Zeiss LSM 410) with an imaging software, Fluoview FV500.
In Vitro Cell Viability
MCF-7 cells were seeded in 96-well plates at the density of 5,000 viable cells per well and incubated 24 h to allow cell attachment. The cells were incubated with docetaxel-loaded PLGA-TPGS nanoparticle suspension, DMAB-modified PLGA-TPGS nanoparticle suspension and commercial Taxotere® at 0.25, 2.5, 12.5 and 25 μg/ml equivalent docetaxel concentrations and drug-free DMAB-modified PLGA-TPGS nanoparticle suspension with the same amount of nanoparticles for 24, 48 and 72 h, respectively. At determined time, the formulations were replaced with DMEM containing MTT (5 mg/ml) and cells were then incubated for additional 4 h. MTT was aspirated off and DMSO was added to dissolve the formazan crystals. Absorbance was measured at 570 nm using a microplate reader (Bio-Rad Model 680, UK). Untreated cells were taken as control with 100% viability, and cells without addition of MTT were used as blank to calibrate the spectrophotometer to zero absorbance. IC50, the drug concentration at which inhibition of 50% cell growth was observed, in comparison with that of the control sample, was calculated by curve fitting of the cell viability data. Experiments were performed in triplicate and results are expressed as mean ± SD.
The results were expressed as mean ± SD. The significance of differences was assessed using Student's t-test and was termed significance when P < 0.05.
Results and Discussions
Characterization of PLGA-TPGS Random Copolymer
Characteristics of the PLGA-TPGS random copolymer
TPGS feed content (%)
PI (Mw / Mn)
Characterization of Drug-Loaded Nanoparticles
Size, Zeta Potential and Drug Entrapment Efficiency
Effects of DMAB modification on size, entrapment efficiency and zeta potential
Zeta Potential (mV)
Drug loading (%)
DMAB Modification (%)
239.82 ± 8.64
-28.58 ± 4.44
253.51 ± 5.38
-21.87 ± 2.11
226.33 ± 3.56
32.23 ± 3.55
219.42 ± 5.24
34.15 ± 4.28
As the drug entrapment efficiency (EE) regards, it can be seen from Table 2 that the 5% DMAB-modified PLGA-TPGS nanoparticles (CNP) achieved much higher EE than the 5% DMAB-modified PLGA nanoparticles (ANP). This might be contributed to the self-emulsification effect of the PLGA-TPGS copolymer [2, 21].
In vitro Drug Release
Uptake of Coumarin-6-Loaded Nanoparticles by Caco-2 and MCF-7 Cells
It can be observed from Figure 4a that there is an increasing trend in the Caco-2 cellular uptake which shows the 5% DMAB-modified PLGA-TPGS nanoparticles (CNP) >5% DMAB-modified PLGA nanoparticles (ANP) >unmodified PLGA-TPGS nanoparticles (BNP). Such advantages are particle concentration dependent. The 5% DMAB-modified PLGA-TPGS nanoparticles (CNP) resulted in 1.37-, 1.46- and 1.45-fold higher cellular uptake than that of 5% DMAB-modified PLGA nanoparticles (ANP), and 1.52-, 1.67- and 1.59-fold higher cellular uptake than that of unmodified PLGA-TPGS nanoparticles (BNP) at the incubated particle concentration of 100, 250 and 500 μg/ml, respectively.
Figure 4b shows that the cellular uptake efficiency of the coumarin-6-loaded DMAB-modified PLGA-TPGS nanoparticles (CNP) by MCF-7 cells is higher than that of 5% DMAB-modified PLGA nanoparticles (ANP) and unmodified PLGA-TPGS nanoparticles (BNP), which is also found dose-dependent. The 5% DMAB-modified PLGA-TPGS nanoparticles (CNP) resulted in 1.37-, 1.53- and 1.61-fold higher cellular uptake than that of 5% DMAB-modified PLGA nanoparticles (ANP), and 1.40-, 1.41- and 1.52-fold higher cellular uptake than that of unmodified PLGA-TPGS nanoparticles (BNP) at the incubated particle concentration of 100, 250 and 500 μg/ml, respectively. The positive surface charge of DMAB provided the incentive to aid drug delivery, since it is expected to ensure better interaction with the negatively charged cell membrane [14–16]. This resulted in increased retention time at the cell surface, thus increasing the chances of particle uptake and improving oral drug bioavailability .
IC50 of MCF-7 cells after 24-, 48-, 72-h incubation with docetaxel formulated in the Taxotere®, 5% DMAB-modified PLGA nanoparticles (ANP), unmodified PLGA-TPGS nanoparticles (BNP) and 5% DMAB-modified PLGA-TPGS nanoparticles (CNP)
Incubation time (h)
We developed three types of nanoparticle formulation from biodegradable PLGA-TPGS random copolymer for oral administration of anticancer drugs with docetaxel employed as a model drug, which include 5% DMAB-modified PLGA nanoparticles (ANP), unmodified PLGA-TPGS nanoparticles (BNP) and 5% DMAB-modified PLGA-TPGS nanoparticles (CNP). The design of the nanoparticle matrix material was made to take advantages of TPGS in nanoparticle preparation technology such as high emulsification effects and high drug entrapment efficiency, enhancement of therapeutic effects such as reducing P-glycoprotein-mediated multidrug resistance and superior anticancer efficacy as well as those in drug formulation such as high cellular adhesion and adsorption. DMAB was used to increase retention time at the cell surface, thus increasing the chances of particle uptake and improving oral drug bioavailability. The results showed that the DMAB-modified PLGA-TPGS nanoparticles have significantly higher level of the cellular uptake than that of DMAB-modified PLGA nanoparticles and unmodified PLGA-TPGS nanoparticles. In vitro, cytotoxicity experiment showed advantages of the DMAB-modified PLGA-TPGS nanoparticle formulation over commercial Taxotere® in terms of cytotoxicity against MCF-7 cells. In conclusion, oral chemotherapy by DMAB-modified PLGA-TPGS nanoparticle formulation is an attractive and promising treatment option for patients.
The authors are grateful for financial support from the National Natural Science Foundation of China (Grant No 30900291), China Postdoctoral Science Foundation (No. 20090450030), Shenzhen Bureau of Science, Technology & Information (No. JC200903180531A) and Shenzhen Nanshan Science and Technology Program (KJ02S0210900000109), and from the Shenzhen Municipal Government for the Shenzhen Key Lab of Gene & Antibody Therapy and for Upgrading the Construction of Shenzhen's National Key Lab of Health Science & Technology.
- Kuppens IE, Bosch TM, van Maanen MJ, Rosing H, Fitzpatrick A, Beijnen JH, Schellens JH: Oral bioavailability of docetaxel in combination with OC144–093 (ONT-093). Cancer Chemother Pharmacol 2005,55(1):72–78. 10.1007/s00280-004-0864-4View ArticleGoogle Scholar
- Feng SS, Mei L, Anitha P, Gan CW, Zhou W: Poly (lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel. Biomaterials 2009,30(19):3297–3306. 10.1016/j.biomaterials.2009.02.045View ArticleGoogle Scholar
- Sparreboom A, Van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DKF, Borst P, Nooijen WJ, Beijnen JH, van Tellingen O: Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 1997, 94: 2031–2035. 10.1073/pnas.94.5.2031View ArticleGoogle Scholar
- Wils P, Phung-Ba V, Warnery A, Lechardeur D, Raeissi S, Hidalgo IJ, Scherman D: Polarized transport of docetaxel and vinblastine mediated by P-glycoprotein in human intestinal epithelial cell monolayers. Biochem Pharmacol 1994, 48: 1528–1530. 10.1016/0006-2952(94)90580-0View ArticleGoogle Scholar
- Marre F, Sanderink GJ, de Sousa G, Gaillard C, Martinet M, Rahmani R: Hepatic biotransformation of docetaxel (Taxotere) in vitro: Involvement of the CYP3A subfamily in humans. Cancer Res 1996, 56: 1296–1302.Google Scholar
- Shou M, Martinet M, Korzekwa KR, Krausz KW, Gonzalez FJ, Gelboin HV: Role of human cytochrome P450 3A4 and 3A5 in the metabolism of Taxotere and its derivatives: enzyme specificity, interindividual distribution and metabolic contribution in human liver. Pharmacogenetics 1998, 8: 391–401. 10.1097/00008571-199810000-00004View ArticleGoogle Scholar
- Malingré MM, Richel DJ, Beijnen JH, Rosing H, Koopman FJ, Ten WW, Huinink Bokkel, Schot ME, Schellens JH: Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 2001,19(4):1160–1166.Google Scholar
- Ikezoe T, Hisatake Y, Takeuchi T, Ohtsuki Y, Yang Y, Said JW, Taguchi H, Koeffler HP: HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. Cancer Res 2004, 64: 7426–7431. 10.1158/0008-5472.CAN-03-2677View ArticleGoogle Scholar
- Florence AT, Hussain N: Transcytosis of nanoparticle and dendrimer delivery systems: evolving vistas. Adv Drug Deliv Rev 2001,50(suppl 1):S69-S89. 10.1016/S0169-409X(01)00184-3View ArticleGoogle Scholar
- Pandey R, Zahoor A, Sharma S, Khuller GK: Nano-encapsulation of azole antifungals: potential applications to improve oral drug delivery. Int J Pharm 2005, 301: 268–276. 10.1016/j.ijpharm.2005.05.027View ArticleGoogle Scholar
- Chen H, Langer R: Oral particulate delivery: status and future trends. Adv Drug Deliv Rev 1998, 34: 339–350. 10.1016/S0169-409X(98)00047-7View ArticleGoogle Scholar
- Italia JL, Bhatt DK, Bhardwaj V, Tikoo K, Kumar MN: PLGA nanoparticles for oral delivery of cyclosporine: nephrotoxicity and pharmacokinetic studies in comparison to Sandimmune Neoral. J Control Release 2007,119(2):197–206. 10.1016/j.jconrel.2007.02.004View ArticleGoogle Scholar
- des Rieux A, Fievez V, Garinot M, Schneider YJ, Préat V: Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Release 2006,116(1):1–27. 10.1016/j.jconrel.2006.08.013View ArticleGoogle Scholar
- Mei L, Sun H, Song C: Local delivery of modified paclitaxel-loaded PCL/F68 nanoparticles for long-term inhibition of hyperplasia in a rabbit arterial balloon injury model. J Pharm Sci 2009,98(6):2040–2050. 10.1002/jps.21581View ArticleGoogle Scholar
- Mei L, Sun H, Jin X, Zhu D, Sun R, Zhang M, Song C: Modified paclitaxel-loaded nanoparticles for inhibition of hyperplasia in a rabbit arterial balloon injury model. Pharm Res 2007,24(5):955–962. 10.1007/s11095-006-9214-zView ArticleGoogle Scholar
- Song C, Labhasetwar V, Cui X, Underwood T, Levy RJ: Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: results with an acute dog model. J Control Release 1998, 54: 201–211. 10.1016/S0168-3659(98)00016-9View ArticleGoogle Scholar
- Bhardwaj V, Ankola DD, Gupta SC, Schneider M, Lehr CM, Kumar MN: PLGA nanoparticles stabilized with cationic surfactant: safety studies and application in oral delivery of paclitaxel to treat chemical-induced breast cancer in rat. Pharm Res 2009,26(11):2495–2503. 10.1007/s11095-009-9965-4View ArticleGoogle Scholar
- Hariharan S, Bhardwaj V, Bala I, Sitterberg J, Bakowsky U, Ravi Kumar MN: Design of estradiol loaded PLGA nanoparticulate formulations: a potential oral delivery system for hormone therapy. Pharm Res 2006, 23: 184–196. 10.1007/s11095-005-8418-yView ArticleGoogle Scholar
- Dintaman JM, Silverman JA: Inhibition of P-glycoprotein by Dalpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharm Res 1999, 16: 1550–1556. 10.1023/A:1015000503629View ArticleGoogle Scholar
- Yu L, Bridgers A, Polli J, Vicker A, Long S, Roy A, Winnike R, Coffin M: Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability. Pharm Res 1999, 16: 1812–1817. 10.1023/A:1018939006780View ArticleGoogle Scholar
- Ma Y, Zheng Y, Liu K, Tian G, Tian Y, Xu L, Yan F, Huang L, Mei L: Nanoparticles of poly(lactide-co-glycolide)-d-a-tocopheryl polyethylene glycol succinate random copolymer for cancer treatment. Nanoscale Res Lett 2010,5(7):1161–1169. 1000 1000 10.1007/s11671-010-9620-3View ArticleGoogle Scholar
- Youk HJ, Lee E, Choi MK, Lee YJ, Chung JH, Kim SH, Lee CH, Lim SJ: Enhanced anticancer efficacy of alpha-tocopheryl succinate by conjugation with polyethylene glycol. J Control Release 2005, 107: 43–52. 10.1016/j.jconrel.2005.05.014View ArticleGoogle Scholar
- Constantinou C, Papas A, Constantinou AI: Vitamin E and cancer: an insight into the anticancer activities of vitamin E isomers and analogs. Int J Cancer 2008,123(4):739–752. 10.1002/ijc.23689View ArticleGoogle Scholar
- Neuzil J, Tomasetti M, Zhao Y, Dong LF, Birringer M, Wang XF, Low P, Wu K, Salvatore BA, Ralph SJ: Vitamin E analogs a novel group of "mitocans", as anticancer agents: the importance of being redox-silent. Mol Pharmacol 2007,71(5):1185–1199. 10.1124/mol.106.030122View ArticleGoogle Scholar
- Gu H, Song C, Long D, Mei L, Sun H: Controlled release of recombinant human nerve growth factor (rhNGF) from poly[(lactic acid)-co-(glycolic acid)] microspheres for the treatment of neurodegenerative disorders. Polym Int 2007, 56: 1272–1280. 10.1002/pi.2272View ArticleGoogle Scholar
- Mei L, Zhang Y, Zheng Y, Tian G, Song C, Yang D, Chen H, Sun H, Tian Y, Liu K, Li Z, Huang L: A novel docetaxel-loaded poly (ε-caprolactone)/pluronic F68 nanoparticle overcoming multidrug resistance for breast cancer treatment. Nanoscale Res Lett 2009, 4: 1530–1539. 10.1007/s11671-009-9431-6View ArticleGoogle Scholar
- Florence AT: Nanoparticle uptake by the oral route: Fulfilling its potential? Drug Discovery Today 2005, 2: 75–81. 10.1016/j.ddtec.2005.05.019View ArticleGoogle Scholar
- Norris DA, Puri N, Sinko PJ: The effect of physical barriers and properties on the oral absorption of particulates. Adv Drug Deliv Rev 1998,34(2–3):135–154. 10.1016/S0169-409X(98)00037-4View ArticleGoogle Scholar
- Labhasetwar V, Song C, Humphrey W, Shebuski R, Levy RJ: Arterial uptake of biodegradable nanoparticles: effect of surface modifications. J Pharm Sci 1998,87(10):1229–1234. 10.1021/js980021fView ArticleGoogle Scholar
- Artursson P, Palm K, Luthman K: Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev 2001, 46: 27–43. 10.1016/S0169-409X(00)00128-9View ArticleGoogle Scholar
- Nabholtz JM, Tonkin K, Smylie M, Au HJ, Lindsay MA, Mackey J: Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer? Expert Opin. Pharmacother 2000,1(2):187–206.Google Scholar
- Yan F, Zhang C, Zheng Y, Mei L, Tang L, Song C, Sun H, Huang L: The effect of poloxamer 188 on nanoparticle morphology size, cancer cell uptake, and cytotoxicity. Nanomedicine 2010,6(1):170–178.View ArticleGoogle Scholar
- Zhang Y, Tang L, Sun L, Bao J, Song C, Huang L, Liu K, Tian Y, Tian G, Li Z, Sun H, Mei L: A novel paclitaxel-loaded Poly (ε-caprolactone)/Poloxamer 188 blend nanoparticle overcoming multidrug resistance for cancer treatment. Acta Biomater 2010,6(6):2045–2052. 10.1016/j.actbio.2009.11.035View ArticleGoogle Scholar
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