Polyethylenimine modified with 2,3-dimethylmaleic anhydride potentiates the antitumor efficacy of conventional chemotherapy

Huang, X (Huang, Xin)^{[ 1 ]} ; Cao, J (Cao, Jun)^{[ 1 ]} ; Zhang, Y (Zhang, Yan)^{[ 2,3 ]} ; Liu, TJ (Liu, Tianjun)^{[ 2,3 ]} ; Yan, HS (Yan, Husheng)^{[ 1,4 ]}

MATERIALS SCIENCE & ENGINEERING C-MATERIALS FOR BIOLOGICAL APPLICATIONS, 2019, 102: 558-568

DOI: 10.1016/j.msec.2019.04.081

摘要

Conventional chemotherapy is a standard care for many cancers at present. However, their severe dose-dependent side effects are the major impediment for successful cancer therapy. Herein nanoparticles were used as a potentiator to enhance the uptake of free chemotherapeutic agents by cancer cells during chemotherapy. A pH-sensitive beta-carboxylate amide group-containing polymer, bPEI-DMA, was obtained by a one-step chemical reaction of commercially available branched polyethyleneimine with 2,3-dimethylmaleic anhydride. The obtained single-macromolecule nanoparticles with a size of 6.4 nm possessed zwitterions and a slight net negative charge at neutral pH, and thereby showed low cytotoxicity. Incubation of MCF-7 cells with bPEI-DMA at tumor acidic pHs led to leakage of lactate dehydrogenase from the cells. Sequential incubation of bPEI-DMA and doxorubicin with MCF-7 cells at tumor acidic pHs caused enhanced uptake of doxorubicin by the cells. These results can be attributed to the tumor pH-triggered positive charge generation on the nanoparticles due to the hydrolysis of the beta-carboxylate amide groups, and subsequently the positive charge caused an increase in cell membrane permeability. Sequential injection of bPEI-DMA and free doxorubicin or free cisplatin into nude mice bearing human tumors markedly inhibited the tumor growth, leading to a similar to 68% decrease in tumor volumes compared to injection of the free drugs alone. Sequential injection of bPEI-DMA and a half dose of free doxorubicin resulted in even greater tumor inhibition but less side effects than injection of a full dose of doxorubicin alone.