Anticancer efficacy of a supramolecular complex of a 2-diethylaminoethyl–dextran–MMA graft copolymer and paclitaxel used as an artificial enzyme

Abstract

SummaryThe anticancer efficacy of a supramolecular complex that was used as an artificial enzyme against multi-drug-resistant cancer cells was confirmed. A complex of diethylaminoethyl–dextran–methacrylic acid methylester copolymer (DDMC)/paclitaxel (PTX), obtained with PTX as the guest and DDMC as the host, formed a nanoparticle 50–300 nm in size. This complex is considered to be useful as a drug delivery system (DDS) for anticancer compounds since it formed a stable polymeric micelle in water. The resistance of B16F10 melanoma cells to PTX was shown clearly through a maximum survival curve. Conversely, the DDMC/PTX complex showed a superior anticancer efficacy and cell killing rate, as determined through a Michaelis–Menten-type equation, which may promote an allosteric supramolecular reaction to tubulin, in the same manner as an enzymatic reaction. The DDMC/PTX complex showed significantly higher anticancer activity compared to PTX alone in mouse skin in vivo. The median survival times of the saline, PTX, DDMC/PTX4 (particle size 50 nm), and DDMC/PTX5 (particle size 290 nm) groups were 120 h (treatment (T)/control (C), 1.0), 176 h (T/C, 1.46), 328 h (T/C, 2.73), and 280 h (T/C, 2.33), respectively. The supramolecular DDMC/PTX complex showed twice the effectiveness of PTX alone (p < 0.036). Above all, the DDMC/PTX complex is not degraded in cells and acts as an intact supramolecular assembly, which adds a new species to the range of DDS.

New Strategies in Melanoma Therapy: Can Nanoparticles Overcome Chemoresistance?

“…This study demonstrated the ability of the targeted liposomal combination to act synergistically and overcome resistance to doxorubicin [8]. A nanosized polymeric complex of paclitaxel showed reversal of drug resistance by mimicking a catalytic reaction, thereby recovering the ability of the paclitaxel to react with its intracellular target at low concentrations [9]. Our group designed and developed cyclodextrin-conjugated lipid nanoparticles, which increased the efficiency of melphalan and were able to recover the cytotoxic activity of the drug in melanoma cells rendered resistant to the free drug [10].…”

Medicinal facilities to B16F10 melanoma cells for distant metastasis control with a supramolecular complex by DEAE-dextran-MMA copolymer/paclitaxel

“…The stability of the enzyme-substrate complex is shown as 1/K m , and larger for DDMC/PTX complex than for PTX alone, corresponding to [S] 0 n >>K m . From our previous report [14,[25][26][27], the DDMC/ PTX complex may promote enzymically tubulin polymerization that can be expressed using Michaelis-Menten kinetics added the Hill coefficient [33]. These phenomena also show the supramolecular properties of the DDMC/ PTX complex.…”

“…It has been reported that DDMC is superior to other transfection agents with safety efficacy by autoclaved as a non-viral carrier for gene introduction [16][17][18][19][20][21][22][23][24]. On the other hand, the paclitaxel is well known as a strong anti-cancer drug to introduce cancer cells to apoptosis in stabilization of tubulin (i.e., tubulin polymerization) [14,[25][26][27].…”

Lymph Nodes and Cancer Metastasis: New Perspectives on the Role of Intranodal Lymphatic Sinuses

“…The anticancer efficacy of a supramolecular complex was reported to be used as an artificial enzyme against multi-drug-resistant cancer cells. Tumor actively-targeted theranostic nanoparticles have been developed for therapeutic and diagnostic applications [ 136 , 189 ]. In addition, despite small-molecule drugs, biologics, miRNA, RNA interference (RNAi) and vaccines are under active investigation, the cancer stem cell (CSCs) involved in tumor-induced lymphangiogenesis are now emerging as a plausible target for new drug discovery [ 190 , 191 ].…”