Polymeric modification of gemcitabine via cyclic acetal linkage for enhanced anticancer potency with negligible side effects

• Published in: Biomaterials Vol. 235; p. 119804
• Main Authors: Takemoto, Hiroyasu, Inaba, Takanori, Nomoto, Takahiro, Matsui, Makoto, Liu, Xiaomeng, Toyoda, Masahiro, Honda, Yuto, Taniwaki, Kaori, Yamada, Naoki, Kim, Junhyun, Tomoda, Keishiro, Nishiyama, Nobuhiro
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.03.2020
• Subjects: Acetals; Animals; antineoplastic agents; apoptosis; biocompatible materials; blood flow; cancer therapy; Cell Line, Tumor; Deoxycytidine - analogs & derivatives; Drug delivery system; gastrointestinal system; Gemcitabine; lysosomes; Mice; Pancreatic Neoplasms; pH-responsiveness; Polymers; Side effects; toxicity; Side effects; Gemcitabine; Polymers; Drug delivery system; pH-responsiveness
• ISSN: 0142-9612; 1878-5905; 1878-5905
• DOI: 10.1016/j.biomaterials.2020.119804

Gemcitabine (GEM) is a powerful anticancer drug for various cancers. However, the anticancer efficacy and the side effects should be addressed for effective therapeutics. To this end, we created a GEM-conjugated polymer (P-GEM) based on cyclic acetal linkage as a delivery carrier of GEM. The obtained P-GEM stably conjugated GEM at physiological pH (i.e., bloodstream), but released GEM in response to acidic environments such as endosome/lysosome. After systemic administration of P-GEM for mice bearing subcutaneous tumors, it achieved prolonged blood circulation and enhanced tumor accumulation relative to free GEM system. In addition, the polymer-drug conjugate structure of P-GEM realized effective distribution in the tumor tissues toward the induction of apoptosis in most areas of the tumor sites. Of note, the molecular design of P-GEM achieved minimal accumulation in normal tissues, resulting in negligible GEM-derived adverse effects (e.g., gastrointestinal toxicity and hematotoxicity). Ultimately, even four times smaller dose of P-GEM on a GEM basis realized comparable/higher tumor growth suppression effect for two distinct pancreatic tumor models, compared to free GEM system. The obtained results suggest the huge potential of the present design of GEM-conjugated polymer for anticancer therapeutics.