Reductively cleavable polymer-drug conjugates based on dendritic polyglycerol sulfate and monomethyl auristatin E as anticancer drugs

Journal of Controlled Release : Official Journal of the Controlled Release Society
Nadine RadesKai Licha

Abstract

Stimuli-responsive polymer-drug conjugates (PDCs) provide promising approaches in anticancer treatment. Here, we report the synthesis and biological evaluation of PDCs made of the highly potent antimitotic agent monomethyl auristatin E conjugated to dendritic polyglycerol and dendritic polyglycerol sulfate via a reductively cleavable, self-immolative disulfide linker. Cell viability assays with the human cancer cell lines A549 (lung carcinoma) and HeLa (cervix carcinoma) revealed that the drug's cytotoxicity was reduced by conjugation to the polymers, with the sulfated conjugates being more effective than the non-sulfated ones. Kinetic studies using real-time cell analysis indicated a retarded drug release from the polymers, with a much later cytotoxic response after treatment with the non-sulfated conjugates due to less cellular uptake, as confirmed by flow cytometry and confocal laser scanning microscopy. In contrast, the non-cleavable dPGS-MMAE conjugate that was synthesized for comparison was not cytotoxic under the same conditions. Overall, reductively cleavable dPGS-SS-MMAE conjugates showed promising results in vitro and good tolerability in vivo. Further in vivo studies are planned.

Citations

Nov 23, 2019·Macromolecular Rapid Communications·Zhengyu DengShiyong Liu
May 6, 2020·Pharmaceutics·Sibusiso AlvenBlessing A Aderibigbe
Oct 23, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Haroon IqbalHuabing Chen
Dec 25, 2019·International Journal of Pharmaceutics·Mahboobeh JafariAli Mohammad Tamaddon
Mar 5, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Chen ZhaoHaifeng Liu

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