Polymeric modification of gemcitabine via cyclic acetal linkage for enhanced anticancer potency with negligible side effects. (March 2020)

• Record Type: Journal Article
• 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
• Is Part Of: Biomaterials. Volume 235(2020)
• Publication Date: 2020-03
• Subjects: Polymers -- Drug delivery system -- Gemcitabine -- Side effects -- pH-responsiveness; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2020.119804
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: 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.