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Preparation and Characterization of Individual and Multi-drug Loaded Physically Entrapped Polymeric Micelles
Published on: August 28, 2015
Systematic evaluation of multifunctional paclitaxel-loaded polymeric mixed micelles as a potential anticancer remedy
Jiulong Zhang1, Xiufeng Zhao2, Qing Chen3
1Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Abstract:
Multidrug resistance (MDR) of tumor cells is becoming the main reason for the failure of chemotherapy and P-glycoprotein (P-gp) mediated drug efflux has demonstrated to be the key factor for MDR. To address this issue, a novel pH-responsive mixed micelles drug delivery system composed of dextran-g-poly(lactide-co-glycolide)-g-histidine (HDP) and folate acid-D-α-tocopheryl polyethylene glycol 2000 (FA-TPGS2K) copolymers has been designed for the delivery of antitumor agent, paclitaxel (PTX) via FA-receptor mediated cell endocytosis, into PTX-resistant breast cancer MCF-7 cells (MCF-7/PTX). PTX-loaded FA-TPGS2K/HDP mixed micelles were characterized to have a small size distribution, high loading content and excellent pH-responsive drug release profiles. Compared with HDP micelles, FA-TPGS2K/HDP mixed micelles showed a higher cytotoxicity against MCF-7 and MCF-7/PTX cells due to the synergistic effect of FA-receptor mediated cell endocytosis, pH-responsive drug release and TPGS mediated P-gp inhibition. P-gp expression level, ATP content and mitochondrial membrane potential change have been measured, the results indicated blank FA-TPGS2K/HDP mixed micelles could inhibit the P-gp activity by reducing the mitochondrial membrane potential and depleting ATP content but not down-regulating the P-gp expression. In vivo antitumor activities demonstrated FA-TPGS2K/HDP mixed micelles could reach higher antitumor activity compared with HDP micelles for MCF-7/PTX tumor cells. Histological assay also indicated that FA-TPGS2K/HDP mixed micelles showed strongly apoptosis inducing effect, anti-proliferation effect and anti-angiogenesis effect. All these evidences demonstrated this pH-sensitive FA-TPGS2K/HDP micelle-based drug delivery system is a promising approach for overcoming MDR.
Statement Of Significance:
In this work, a novel FA-TPGS2K copolymer has been synthesized and used it to construct mixed micelles with HDP copolymer to overcome MDR effect. Furthermore, a series in vitro and in vivo evaluations have been made, which supported enough evidences for the efficient delivery of antitumor drug to MDR cells.
Insights
This study developed pH-sensitive mixed micelles loaded with paclitaxel to overcome multidrug resistance (MDR) in breast cancer. The novel system enhanced drug delivery and antitumor efficacy in resistant cells by inhibiting P-glycoprotein (P-gp).
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Multidrug resistance (MDR) in tumor cells, primarily mediated by P-glycoprotein (P-gp) efflux, is a major cause of chemotherapy failure.
- Developing effective drug delivery systems is crucial to overcome MDR and improve cancer treatment outcomes.
Purpose of the Study:
- To design and evaluate a novel pH-responsive mixed micelle system (FA-TPGS2K/HDP) for delivering paclitaxel (PTX) to P-gp-mediated MDR breast cancer cells (MCF-7/PTX).
- To investigate the synergistic effects of folate receptor-mediated endocytosis, pH-responsive drug release, and P-gp inhibition by the developed micelles.
Main Methods:
- Synthesis of FA-TPGS2K copolymer and its combination with HDP copolymer to form mixed micelles loaded with PTX.
- Characterization of mixed micelles for size, drug loading, and pH-responsive release.
- In vitro evaluation of cytotoxicity, P-gp activity inhibition (ATP content, mitochondrial membrane potential), and cellular uptake in MCF-7 and MCF-7/PTX cells.
- In vivo antitumor efficacy studies and histological analysis (apoptosis, proliferation, angiogenesis) in tumor-bearing mice.
Main Results:
- PTX-loaded FA-TPGS2K/HDP mixed micelles exhibited small size, high drug loading, and excellent pH-responsive release.
- FA-TPGS2K/HDP mixed micelles demonstrated superior cytotoxicity against MCF-7/PTX cells compared to HDP micelles.
- Blank FA-TPGS2K/HDP micelles inhibited P-gp activity by affecting mitochondrial membrane potential and ATP levels without altering P-gp expression.
- In vivo studies showed enhanced antitumor activity, apoptosis, anti-proliferation, and anti-angiogenesis effects of FA-TPGS2K/HDP mixed micelles.
Conclusions:
- The pH-sensitive FA-TPGS2K/HDP mixed micelle system effectively delivers PTX to MDR breast cancer cells.
- This novel drug delivery system shows significant potential in overcoming P-gp-mediated multidrug resistance and enhancing chemotherapy efficacy.
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