Bottlebrush Polymer-Conjugated Melittin Exhibits Enhanced Antitumor Activity and Better Safety Profile

• Published in: ACS applied materials & interfaces 2021-09, Vol.13 (36), p.42533-42542
• Main Authors: Jia, Fei, Chen, Peiru, Wang, Dali, Sun, Yehui, Ren, Mengqi, Wang, Yuyan, Cao, Xueyan, Zhang, Lei, Fang, Yang, Tan, Xuyu, Lu, Hao, Cai, Jiansong, Lu, Xueguang, Zhang, Ke
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Biological and Medical Applications of Materials and Interfaces; Cell Line, Tumor; Female; Humans; Melitten - analogs & derivatives; Melitten - pharmacokinetics; Melitten - therapeutic use; Melitten - toxicity; Mice; Mice, Inbred C57BL; Neoplasms - drug therapy; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - therapeutic use; Polyethylene Glycols - toxicity; Xenograft Model Antitumor Assays
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.1c14285

Despite potency against a variety of cancers in preclinical systems, melittin (MEL), a major peptide in bee venom, exhibits non-specific toxicity, severe hemolytic activity, and poor pharmacological properties. Therefore, its advancement in the clinical translation system has been limited to early-stage trials. Herein, we report a biohybrid involving a bottlebrush-architectured poly­(ethylene glycol) (PEG) and MEL. Termed pacMEL, the conjugate consists of a high-density PEG arrangement, which provides MEL with steric inhibition against protein access, while the high molecular weight of pacMEL substantially enhances plasma pharmacokinetics with a ∼10-fold increase in the area under the curve (AUC∞) compared to free MEL. pacMEL also significantly reduces hepatic damage and unwanted innate immune response and all but eliminated hemolytic activities of MEL. Importantly, pacMEL passively accumulates at subcutaneously inoculated tumor sites and exhibits stronger tumor-suppressive activity than molecular MEL. Collectively, pacMEL makes MEL a safer and more appealing drug candidate.