Abstract

A DEAE-dextran-MMA copolymer (DDMC)-paclitaxel(PTX) complex was obtained by using PTX as the guest and DDMC as the host. The resulting nanoparticles of the DDMC/PTX complex were 50-300 nm in diameter and are confirmed to be useful as an anti-cancer drug forming a stable polymeric micelle in water. The drug resistance of B16F10 melanoma cells to paclitaxel was observed using survival curve analysis. On the other hand, there is no drug resistance of melanoma cells to the DDMC/PTX complex. The DDMC/PTX complex showed superior anticancer activity to paclitaxel alone in vitro. The cell death rate was determined using Michaelis-Menten kinetics, as the DDMC/PTX complex promoted allosteric supramolecular reaction to tubulin. The DDMC/PTX complex showed a very superior anti-cancer activity to paclitaxel alone in vivo in mouse skin. The median survival time (MST) of the saline, PTX, DDMC/PTX4 (particle size 50 nm) and DDMC/PTX5 (particle size 290 nm) groups were 120 hours (T/C, 1.0), 176 hours (T/C, 1.46), 328 hours (T/C, 2.73), and 280 hours (T/C, 2.33), respectively. It will be deduced different chemo-effect on melanoma cells between PTX group and DDMC/PTX-treated mice group from this result. From our results, the DDMC/PTX complex was not extensively degraded in cells, and achieved good efficacy as an intact supramolecular anti-cancer agent. The DDMC/PTX complex showed high reactivity and specificity of anti-melanoma cells, depending on its supramolecular facilities. The DDMC/PTX complex represents the efficacy as supramolecular intact such as artificial enzymes having substrate-selective. These supramolecular facilities to melanoma cells will be very helpful to overcome cancer diseases.

Highlights

  • The resistance of cancer cells to chemotherapeutic drugs (MDR) is a major problem to successful cancer chemotherapy

  • The results will indicate that these enzymatic reactions allosterically promote tubulin polymerization in cells for DEAE-dextran-MMA copolymer (DDMC)/ PTX complex

  • In DDMC/PTX complex, hydrophobic interactions between the polymer and substrate, with PTX located in so-called the hydrophobic pocket, allow PTX to selectively react with tubulin as indicated in figure 4A

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Summary

Introduction

The resistance of cancer cells to chemotherapeutic drugs (MDR) is a major problem to successful cancer chemotherapy. The resist ability of cancer cells to survive exposure to various anticancer drugs presents the biggest obstacle to successful cancer chemotherapy [1]. Drug delivery systems (DDS) based on polymers have been used as important carriers for targeted drug delivery because of their enhanced permeability and retention (EPR) effect [2] and their avoidance of the reticuloendothelial system (RES) [3,4]. The cellular distribution of the micelle could be altered, and could increase the amount of drug delivered to the cells. These micelles may be worth exploring for their potential to selectively deliver drugs to specified sub-cellular targets [7]. Supramolecule is the compounds of the intermolecular bond, covering the structures and functions of molecular self-assembly, folding, molecular recognition and host-guest chemistry formed by association of two or more chemical species [8]

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