Polymer micelle-based combination therapy of paclitaxel and resveratrol with enhanced and selective antitumor activity

Abstract

5Owing to low therapeutic efficacy and high toxicity associated with conventional single drug chemotherapy, combination therapy has been adopted in clinics. We employed polymer micelles for sequential delivery of resveratrol (RES) and paclitaxel (PTX) to obtain a synergistic anticancer activity. Briefly, PTX and RES co-encapsulated micelles were prepared by thin film method using mPEG-b-PLA block copolymers as carriers with a particle diameter of 20 nm and high encapsulation efficiencies of 95% for both PTX and RES. Furthermore, time-dependent sequential release of two drugs resulted in sensitizing the cancer cells to apoptosis. In vitro cytotoxicity 10 test, the combination strategy exerted synergistic effect (combination index, CI=0.7~0.8) both in the PTX-resistant human lung adenocarcinoma epithelial (A549/T) cell line and mice sarcoma 180 (S180) cells while showing very limited toxicity towards the normal human hepatic (L02) cell strain and normal human kidney (HK-2) cell line, which could be illustrated from manipulating ROS levels by redox modulation and reducing protective autophagy. In vivo, the combination therapy achieved the best antitumor effect in all treatment groups in S180 bearing mice and evoked the most significant changes in the cytoarchitecture leading to tumor regression according to the 15 histological studies. In conclusion, PTX and RES co-encapsulated micelles would provide a potential strategy to selectively treat cancers by inducing ROS-dependent apoptosis and inhibiting autophagy.

In Situ Generated Gold Nanoparticle Hybrid Polymersomes for Water‐Soluble Chemotherapeutics: Inhibited Leakage and pH‐Responsive Intracellular Release

“…Cytotoxicity Studies : 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide colorimetric assay was performed to determine the effects of drug‐loaded formulations on S180 cells, according to the manufacturer's suggested procedures (Sigma‐Aldrich). Typically, S180 cells were plated in a 96‐well plate (8 × 10 3 cells per well) and cultured in RPMI 1640 containing 10% fetal bovine serum at 37 °C with 5% CO 2 and 95% humidity, as previously described . Cells were exposed to increasing concentrations of different formulations for 24 h. Culture medium‐treated cells were used as controls.…”

Polymer encapsulation of ruthenium complexes for biological and medicinal applications

“…The ratio of hydrophilic to hydrophobic block size can be controlled during synthesis to obtain micelles of a desired size. The physicochemical properties of the amphiphilic polymer determine the choice of polymer micelle preparation method, which include emulsion-solvent evaporation 94 , nanoprecipitation 95 , dialysis 96 and a thin-film method 97 . The size and morphology of micelles can be modulated by the choice of copolymer molecular weight, block length, composition and the preparation method.…”

Drug resistance reversal by combretastatin-A4 phosphate loaded with doxorubicin in polymersomes independent of angiogenesis effect

“…On the other hand, conventional single drug chemotherapy is commonly associated with low therapeutic efficacy and tends to generate drug resistance after repeated treatment . Co‐delivery of a chemotherapeutic agent and a drug resistance reversal agent through nanoparticles has attracted significant attentions.…”

“…On the other hand, conventional single drug chemotherapy is commonly associated with low therapeutic efficacy and tends to generate drug resistance after repeated treatment. [12] Co-delivery of a chemotherapeutic agent and a drug resistance reversal agent through nanoparticles has attracted significant attentions. Based on the enhanced permeability and retention effect of nanoparticles at tumour sites, combination of chemotherapeutic and drug resistance reversal agents would result in their simultaneous accumulation in tumour tissue and incorporation into the same tumour cells via endocytosis, thus exerting a powerful synergistic effect.…”