Novel Self-Assembled Micelles Based on Cholesterol-Modified Antimicrobial Peptide (DP7) for Safe and Effective Systemic Administration in Animal Models of Bacterial Infection

• Published in: Antimicrobial agents and chemotherapy 2018-11, Vol.62 (11)
• Main Authors: Zhang, Rui, Wu, Fengbo, Wu, Lei, Tian, Yaomei, Zhou, Bailing, Zhang, Xueyan, Huang, Rong, Yu, Chaoheng, He, Gu, Yang, Li
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Infections; Cholesterol; Experimental Therapeutics
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00368-18

Owing to their broad-spectrum antibacterial properties, multitarget effects, and low drug resistance, antimicrobial peptides (AMPs) have played critical roles in the clinical therapy of drug-resistant bacterial infections. However, the potential hazard of hemolysis following systemic administration has greatly limited their application. Here, we developed a novel AMP derivative, DP7-C, by modifying a formerly identified highly active AMP (DP7) with cholesterol to form an amphiphilic conjugate. The prepared DP7-C easily self-assembled into stable nanomicelles in aqueous solution. The DP7-C micelles showed lower hemolytic activity than their unconjugated counterparts toward human red blood cells and a maximum tolerated dose of 80 mg/kg of body weight in mice via intravenous injection, thus demonstrating improved safety. Moreover, by eliciting specific immunomodulatory activities in immune cells, the DP7-C micelles exerted distinct therapeutic effects in zebrafish and mouse models of infection. In conclusion, DP7-C micelles may be an excellent candidate for the treatment of bacterial infections in the clinic.