Paclitaxel-loaded N-octyl-O-sulfate chitosan micelles for superior cancer therapeutic efficacy and overcoming drug resistance.

Abstract

The nanoparticle-based drug delivery system holds great attraction to overcome or circumvent multidrug resistance (MDR) in cancer to date. In this work, a synthesized amphiphilic graft copolymer, N-octyl-O-sulfate chitosan (NOSC), and its paclitaxel (PTX)-encapsulated micelles (PTX-M) have been systematically investigated on the MDR reversal effect in vitro and in vivo as well as the mechanism of P-glycoprotein (P-gp) inhibition. NOSC in a wide concentration range even above the critical micelle concentration showed an effective effect on inhibiting P-gp-mediated PTX efflux, which was remarkably different from the surfactants and the Pluronic copolymers. Multiple mechanisms were involved in this effect of NOSC, such as stimulating P-gp ATPase, competitively impeding the binding of PTX with P-gp and reducing the fluidity of the cell membrane. PTX-M presented the highest cellular uptake and the lowest efflux rate of PTX, thereby yielding the optimal cytotoxicity on both the human hepatocellular liver carcinoma (HepG2) cells and the multidrug resistance HepG2 (HepG2-P) cells, which resulted from a combination of the inhibiting P-gp effect of NOSC and the bypassing P-gp action of the intact PTX-M. Additionally, PTX-M had superior blood persistence, tumor accumulation, and therapeutic efficacy after intravenous injection into the tumor-bearing mice. Furthermore, it was demonstrated that most of PTX-M as an intact form was delivered at the tumor site, which ensures the synergetic effect of NOSC micelles on drug delivery and P-gp inhibition. The aforementioned results suggested that NOSC micelles presented promising potential as an anticancer drug carrier for enhanced MDR cancer therapy.

• Authors: Xiang Jin, Ran Mo, Ya Ding, Wei Zheng, Can Zhang
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 11 Issue 1 Pg. 145-57 (Jan 06 2014) ISSN: 1543-8392 [Electronic] United States
• PMID: 24261922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• Drug Carriers
• Micelles
• N-octyl-O-sulfate chitosan
• Chitosan
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Chitosan (analogs & derivatives, chemistry)
• Drug Carriers
• Drug Delivery Systems
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Male
• Membrane Fluidity (drug effects)
• Mice
• Mice, Inbred ICR
• Micelles
• Paclitaxel (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays