The poor therapeutic efficacy of hydrophobic chemotherapeutic drugs is an intrinsic limitation to successful chemotherapy. In the present study, a multitask delivery system based on arginine-glycine-aspartic acid peptide (RGD) decorated vitamin E succinate (VES)-grafted-chitosan oligosaccharide (CSO)/RGD-conjugated d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS-RGD) mixed micelles (VeC/T-RGD MM) was first prepared for targeted delivery of a hydrophobic anticancer drug, paclitaxel (PTX), to improve the efficacy of U87MG tumor therapy. VES grafted CSO (VES-g-CSO) and TPGS-RGD were synthesized as nanocarriers, and PTX loaded VeC/T-RGD MM (PTX@VeC/T-RGD MM) was prepared via the organic solvent emulsification–evaporation method. The PTX@VeC/T-RGD MM was 150.2 nm in diameter with uniform size distribution, 5.92% drug loading coefficient, and no obvious particle size changes within 7 days. The PTX@VeC/T-RGD MM showed sustained-release properties in vitro and high cytotoxicity, and could be efficiently taken up by human glioma U87MG cells. The tumor inhibitory rate of PTX@VeC/T-RGD MM treatment in U87MG tumor spheroids and U87MG tumor bearing mice was 49.3% and 88.4%, respectively, which indicated a superior therapeutic effect. PTX@VeC/T-RGD MM did not damage normal tissues in safety evaluations. These findings suggested that PTX@VeC/T-RGD MM could be developed for the delivery of hydrophobic drugs to U87MG tumors.Keywords: mixed micelles; PTX; TPGS-RGD; U87MG tumor inhibition; VES-grafted-CSO;

β-cyclodextrin (CD) grafted N-maleoyl chitosan (CD-g-NMCS) with two different degrees of substitution (DS) of N-maleoyl (DS = 21.2% and 30.5%) were synthesized from maleic anhydride and chitosan bearing pendant cyclodextrin (CD-g-CS). CD-g-NMCS based nanoparticles were prepared via an ionic gelation method together with chitosan and CD-g-CS nanoparticles. The size and zeta potential of prepared CD-g-NMCS nanoparticles were 179.2~274.0 nm and 36.2~42.4 mV, respectively. In vitro stability test indicated that CD-g-NMCS nanoparticles were more stable in phosphate-buffered saline compared with chitosan nanoparticles. Moreover, a poorly water-soluble drug, ketoprofen (KTP), was selected as a model drug to study the obtained nanoparticle's potentials as drug delivery carriers. The drug loading efficiency of CD-g-NMCS20 nanoparticles were 14.8% for KTP. MTT assay showed that KTP loaded CD-g-NMCS nanoparticles were safe drug carriers. Notably, in vitro drug release studies showed that KTP was released in a sustained-release manner for the nanoparticles. The pharmacokinetic of drug loaded CD-g-NMCS20 nanoparticles were evaluated in rats after intravenous administration. The results of studies revealed that, compared with free KTP, KTP loaded CD-g-NMCS20 nanoparticles exhibited a significant increase in AUC0→24h and mean residence time by 6.6-fold and 2.9-fold, respectively. Therefore, CD-g-NMCS nanoparticles could be used as a novel promising nanoparticle-based drug delivery system for sustained release of poorly water-soluble drugs. The carboxylic acid groups of the CD-g-NMCS molecule provide convenient sites for further structural modifications including introduction of tissue- or disease- specific targeting groups.Download high-res image (41KB)Download full-size image

A major challenge in cancer photodynamic therapy (PDT) is the poor tumor selectivity of the photosensitizer. Therefore, temoporfin (mTHPC)-loaded nanoparticles, based on vitamin-E-succinate-grafted chitosan oligosaccharide and cyclic (arginine-glycine-aspartic acid-d-phenylalanine-lysine) (c[RGDfK])-modified d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared (RGD-NPs) and were expected to enhance the accumulation of mTHPC in integrin-rich U87MG tumors. The RGD-NPs generated were 144.9 nm in diameter and uniformly spherical. After irradiation, RGD-NPs effectively generated singlet oxygen, and displayed enhanced cellular uptake and cytotoxicity in U87MG cells. The RGD-NPs also penetrated deep into U87MG tumor spheroids, with a tumor-targeting ability and antitumor efficacy superior to those of unmodified nanoparticles in subcutaneous-tumor-bearing nude mice. A histopathological analysis confirmed the increased anticancer efficacy of RGD-NPs, with less systemic toxicity than unmodified nanoparticles. Therefore, the RGD-NPs developed in this study potentially target integrin-rich tumors and enhance the efficiency of PDT.Download high-res image (236KB)Download full-size image

This research was aim to develop novel cyclodextrin/chitosan (CD/CS) nanocarriers for insoluble drug delivery through the mild ionic gelation method previously developed by our lab. A series of different β-cyclodextrin (β-CD) derivatives were incorporated into CS nanoparticles including hydroxypropyl-β-cyclodextrin (HP-β-CD), sulphobutylether-β-cyclodextrin (SB-β-CD), and 2,6-di-O-methy-β-cyclodextrin (DM-β-CD). Various process parameters for nanoparticle preparation and their effects on physicochemical properties of CD/CS nanoparticles were investigated, such as the type of CD derivatives, CD and CS concentrations, the mass ratio of CS to TPP (CS/TPP), and pH values. In the optimal condition, CD/CS nanoparticles were obtained in the size range of 215–276 nm and with the zeta potential from 30.22 mV to 35.79 mV. Moreover, the stability study showed that the incorporation of CD rendered the CD/CS nanocarriers more stable than CS nanoparticles in PBS buffer at pH 6.8. For their easy preparation and adjustable parameters in nanoparticle formation as well as the diversified hydrophobic core of CD derivatives, the novel CD/CS nanoparticles developed herein might represent an interesting and versatile drug delivery platform for a variety of poorly water-soluble drugs with different physicochemical properties.Cyclodextrin/chitosan (CD/CS) nanocarriers were successfully prepared with controlled size, spherical morphology and exhibited good stability. This carrier would have a potential application in controlled release of insoluble drugs.

The objective of this study was to investigate the potential of methoxy polyethylene glycol (mPEG) grafted chitosan (mPEG-g-CS) to be used as a drug carrier. mPEG-g-CS was successfully synthesized by one-step method with formaldehyde. The substitution degree of mPEG on chitosan was calculated by elemental analysis and was found to be (3.23 ± 0.25)%. mPEG-g-CS self-assembled micelles were prepared by ultrasonic method with the controlled size of 178.5–195.1 nm and spherical morphology. Stable dispersion of the micelles was formed with the zeta potential of 2.3–30.2 mV. 5-Fluorouracil (5-FU), an anticancer chemotherapy drug, was used as a model drug to evaluate the efficiency of the new drug delivery carrier. The loading efficiency of 5-FU was (4.01 ± 0.03)%, and the drug-loaded mPEG-g-CS self-assembled micelle showed a controlled-release effect. In summary, the mPEG-g-CS self-assembled micelle is proved to be a promising carrier with controlled particle size and controlled-release effect. Therefore, it has great potential for the application as 5-FU carriers for effective anti-tumor activity.Methoxy polyethylene glycol (mPEG) grafted chitosan (mPEG-g-CS) self-assembled micelles were successfully prepared with controlled size and spherical morphology. This carrier would have a potential application in controlled release of 5-fluorouracil for effective anti-tumor activity.