Dong Yuancai
Email Address
chedy@nus.edu.sg
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Publication Nanoparticles of poly(D,L-lactide)/methoxy poly(ethylene glycol)-poly(D,L-lactide) blends for controlled release of paclitaxel(2006-07) Dong, Y.; Feng, S.-S.; CHEMICAL & BIOMOLECULAR ENGINEERINGPaclitaxel is one of the best antineoplastic drugs found in nature in the past decades, which has excellent therapeutic effects against a wide spectrum of cancers. Because of its high hydrophobicity, Cremophor EL has to be used as adjuvant in its clinical dosage form (Taxol®), which has been found to cause serious side effects. Nanoparticles of biodegradable polymers may provide an ideal solution. In this research, paclitaxel-loaded nanoparticles of poly(D,L-lactide)/methoxy poly(ethylene glycol)-polylactide (PLA/ MPEG-PLA) blends of various blend ratio 100/0, 75/25, 50/50, 25/75, and 0/100 were formulated by the nanoprecipitation method for controlled release of paclitaxel. It was found that increasing the proportion of MPEG-PLA component in the blend from O to 100% resulted in a progressive decrease of the particle size from 230.6 ± 11.1 nm to 74.8 ± 14.0 nm. The zeta potential of the drug-loaded nanoparticles was increased accordingly from -19.60 ± 1.13 mV to a nearly neutral, that is, -0.33 ± 0.28 mV, which indicates the gradual enrichment of PEG segments on the particle surface. The findings were further confirmed by X-Ray Photoelectron Spectroscopy (XPS) analysis. Differential scanning calorimetry (DSC) analysis showed that the glass transition temperature of PLA was significantly decreased from 58.7 to 52.1°C with an increase of MPEG-PLA proportion from 0 to 75%, suggesting the miscibility of PLA and MPEG-PLA. The pure PLA nanoparticles (100/0) exhibited the slowest drug-release rate with 37.3% encapsulated drug released from the nanoparticles for 14 days while the MPEG-PLA nanoparticles (0/100) achieved the fastest drug release with 95.9% drug release in the same period. © 2006 Wiley Periodicals, Inc.Publication Chemotherapeutic engineering: Vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168 h in vivo(2007-12) Feng, S.-S.; Zhao, L.; Zhang, Z.; Bhakta, G.; Yin Win, K.; Dong, Y.; Chien, S.; NATIONAL UNIVERSITY MEDICAL INSTITUTES; BIOENGINEERING; CHEMICAL & BIOMOLECULAR ENGINEERINGA full spectrum of proof-of-concept research from nanoparticle preparation and characterization, in vitro drug release, cellular uptake and cytotoxicity, to in vivo pharmacokinetics and xenograft tumor model is developed in this paper to demonstrate how nanoparticles of biodegradable polymers can be applied to formulate anticancer drugs to avoid use of toxic adjuvant and to enable sustained and controlled chemotherapy. Paclitaxel-loaded poly(lactic-co-glycolic acid) nanoparticles were prepared by solvent extraction/evaporation with vitamin E TPGS as the emulsifier, which has much higher emulsification effects and better biocompatibility than other chemical emulsifiers such as polyvinyl alcohol (PVA), resulting in a high drug encapsulation efficiency, high uptake of nanoparticles by cancer cells, and sustainable pharmacokinetics. In vitro C6 cell mortality experiments demonstrated that the nanoparticle formulation was five times more effective than Taxol®. In vivo pharmacokinetics measurements showed that the nanoparticle formulation had a comparable value of the area-under-the-curve (AUC) with that of Taxol®, but never exceeded the maximum tolerance level, and hence should greatly reduce the side effects compared with Taxol®. Moreover, the nanoparticle formulation realized a sustainable therapeutic time of 168 h in comparison with 22 h for Taxol® at a same dose of 10 mg/kg and achieved four times greater drug tolerance than Taxol®. © 2007 Elsevier Ltd. All rights reserved.Publication Poly(D,L-lactide-co-glycolide)/montmorillonite nanoparticles for oral delivery of anticancer drugs(2005-10) Dong, Y.; Feng, S.-S.; CHEMICAL & BIOMOLECULAR ENGINEERINGThis research developed a novel bioadhesive drug delivery system, poly(d,l-lactide-co-glycolide)/montmorillonite (PLGA/MMT) nanoparticles, for oral delivery of paclitaxel. Paclitaxel-loaded PLGA/MMT nanoparticles were prepared by the emulsion/solvent evaporation method. MMT was incorporated in the formulation as a matrix material component, which also plays the role of a co-emulsifier in the nanoparticle preparation process. Paclitaxel-loaded PLGA/MMT nanoparticles were found to be of spherical shape with a mean size of around 310 nm and polydispersity of less than 0.150. Adding MMT component to the matrix material appears to have little influence on the particles size and the drug encapsulation efficiency. The drug release pattern was found biphasic with an initial burst followed by a slow, sustained release, which was not remarkably affected by the MMT component. Cellular uptake of the fluorescent coumarin 6-loaded PLGA/MMT nanoparticles showed that MMT enhanced the cellular uptake efficiency of the pure PLGA nanoparticles by 57-177% for Caco-2 cells and 11-55% for HT-29 cells, which was dependent on the amount of MMT and the particle concentration in incubation. Such a novel formulation is expected to possess extended residence time in the gastrointestinal (GI) tract, which promotes oral delivery of paclitaxel. © 2005 Elsevier Ltd. All rights reserved.Publication Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs(2004-06) Dong, Y.; Feng, S.-S.; CHEMICAL & BIOMOLECULAR ENGINEERINGMethoxy poly(ethylene glycol)-poly(lactide) copolymer (MPEG-PLA) was synthesized and used to make nanoparticles by the nanoprecipitation method for clinical administration of antineoplastic drugs. Paclitaxel was used as a prototype drug due to its excellent efficacy and commercially great success. The size and size distribution, surface morphology, surface charge and surface chemistry of the paclitaxel-loaded nanoparticles were then investigated by laser light scattering, atomic force microscopy, zeta-potential analyzer and X-ray photoelectron spectroscopy (XPS). The drug encapsulation efficiency (EE) and in vitro release profile were measured by high-performance liquid chromatography. The effects of various formulation parameters were evaluated. The prepared nanoparticles were found of spherical shape with size less than 100nm. Zeta potential measurement and XPS analysis demonstrated the presence of PEG layer on the particle surface. Viscosity of the organic phase was found to be one of the main process factors for the size determination. The EE was found to be greatly influenced by the drug loading. The drug release pattern was biphasic with a fast release rate followed by a slow one. The particle suspension exhibited good steric stability in vitro. Such a nanoparticle formulation of paclitaxel can be expected to have long-circulating effects in circulation. © 2003 Elsevier Ltd. All rights reserved.Publication Poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles prepared by high pressure homogenization for paclitaxel chemotherapy(2007-09-05) Dong, Y.; Feng, S.-S.; CHEMICAL & BIOMOLECULAR ENGINEERINGHigh pressure homogenization was employed in the current work to prepare poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for controlled release of paclitaxel. The prepared drug-loaded PLGA NPs were found of spherical shape with a size of 200-300 nm. The drug encapsulation efficiency ranged from 34.8 ± 1.6 to 62.6 ± 7.9% depending on the homogenization pressure and cycles. Paclitaxel was released from the nanoparticles in a biphasic profile with a fast release rate in the first 3 days followed by a slow first-order release. A higher or comparable cytotoxicity against glioma C6 cells was found for the drug formulated in the PLGA NPs in comparison with the free drug Taxol®. Confocal laser scanning microscopy (CLSM) evidenced internalization of the fluorescent coumarin 6-loaded PLGA NPs by the C6 cells. The freeze-dried nanoparticles were found to possess excellent water redispersability. The high pressure homogenization could be applied for large industrial scale production of nanoparticles for drug delivery. © 2007 Elsevier B.V. All rights reserved.Publication Poly(D,L-lactide-co-glycolide)/montmorillonite nanoparticles for oral delivery of anticancer drugs(2005-10) Dong, Y.; Feng, S.-S.; CHEMICAL & BIOMOLECULAR ENGINEERINGThis research developed a novel bioadhesive drug delivery system, poly(d,l-lactide-co-glycolide)/montmorillonite (PLGA/MMT) nanoparticles, for oral delivery of paclitaxel. Paclitaxel-loaded PLGA/MMT nanoparticles were prepared by the emulsion/solvent evaporation method. MMT was incorporated in the formulation as a matrix material component, which also plays the role of a co-emulsifier in the nanoparticle preparation process. Paclitaxel-loaded PLGA/MMT nanoparticles were found to be of spherical shape with a mean size of around 310 nm and polydispersity of less than 0.150. Adding MMT component to the matrix material appears to have little influence on the particles size and the drug encapsulation efficiency. The drug release pattern was found biphasic with an initial burst followed by a slow, sustained release, which was not remarkably affected by the MMT component. Cellular uptake of the fluorescent coumarin 6-loaded PLGA/MMT nanoparticles showed that MMT enhanced the cellular uptake efficiency of the pure PLGA nanoparticles by 57-177% for Caco-2 cells and 11-55% for HT-29 cells, which was dependent on the amount of MMT and the particle concentration in incubation. Such a novel formulation is expected to possess extended residence time in the gastrointestinal (GI) tract, which promotes oral delivery of paclitaxel. © 2005 Elsevier Ltd. All rights reserved.Publication d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) modified poly(l-lactide) (PLLA) films for localized delivery of paclitaxel(2008-02-28) Dong, Y.; Zhang, Z.; Feng, S.-S.; CHEMICAL & BIOMOLECULAR ENGINEERINGd-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) was used as a novel additive to the poly(l-lactide) (PLLA) films for local drug delivery with paclitaxel as a prototype therapeutic agent. Paclitaxel-loaded PLLA/TPGS films were prepared by the solvent casting technique with dichloromethane as the solvent. Effects of TPGS component on the films' physicomechanical properties and the drug release profile were investigated. It was found by field emission scanning microscopy (FESEM) that a biphasic honeycomb surface was formed for the PLLA/TPGS films, while the PLLA film exhibited a smooth and homogeneous surface. There was no significant effect of the drug loading on the morphological structure of the PLLA/TPGS films. Differential scanning calorimetry (DSC) demonstrated that the PLLA/TPGS films was a phase-separated system. Tensile testing showed that the flexibility of the PLLA/TPGS films was much higher than that of the PLLA film. The elongation at break for the PLLA/TPGS film of 5%, 10% and 15% TPGS content was 6.8, 8.9 and 19.4 times of that for the PLLA film, respectively. In vitro drug release studies found that incorporation of TPGS considerably facilitated paclitaxel release. © 2007 Elsevier B.V. All rights reserved.Publication In vitro and in vivo evaluation of methoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles for small-molecule drug chemotherapy(2007-10) Dong, Y.; Feng, S.-S.; CHEMICAL & BIOMOLECULAR ENGINEERINGMethoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles (NPs) were prepared by the nanoprecipitation method with particle size of 140±21 nm in diameter and drug encapsulation efficiency of 87.6±3.1%. In vitro cytotoxicity of the drug formulated in the NPs was investigated with MCF-7 cancer cells in close comparison with that of Taxol®. The in vitro cytotoxicity with MCF-7 cells showed that the NP formulation could be 33.3, 10.7, 7.7 times more effective than Taxol® after 24, 48, 72 h culture at the same drug concentration of 1 μg/ml. Confocal laser scanning microscopy (CLSM) visualized cellular internalization of the coumarin 6-loaded MPEG-PLA NPs. The in vitro results were further confirmed by the in vivo pharmacokinetic analysis with SD rats. The total area-under-the-curve (AUC0-∞), which determines the therapeutic effects of a dose, was found to be 29,600±1690 ng-h/ml for the NP formulation, which is 3.09 times of 9570±1480 ng-h/l for Taxol® with 10 mg/kg dose i.v. injection. The half-life (t1/2) of the drug formulated in the NPs was found to be 18.80±3.14 h, which is 2.75 times of 6.84±1.39 h for Taxol®. The distribution volume at steady state for the drug loaded in the NPs was 7.21±2.17 l/kg, which was 2.93 times of 2.46±1.41 l/kg for Taxol®. Our proof-of-concept in vitro and in vivo valuation shows that our MPEG-PLA NP formulation could have great advantages versus the original drug in small-molecule drug chemotherapy as well as in various applications in nanomedicine. © 2007 Elsevier Ltd. All rights reserved.