Zhang Ding-Yi, Cao Rui-Ge, Cheng Yin-Jia, Liu Wen-Long, Huang Rong, Zhang Ai-Qing, Qin Si-Yong
Hubei Engineering Technology Research Centre of Energy Polymer Materials, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan 430074, China.
School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, PR China.
J Control Release. 2023 Oct;362:565-576. doi: 10.1016/j.jconrel.2023.09.009. Epub 2023 Sep 9.
Tumor recurrence and chronic bacterial infection constitute two major criteria in postsurgical intervention for malignant melanoma. One plausible strategy is the equipment of consolidation therapy after surgery, which relies on adjuvants to eliminate the residual tumor cells and inhibit bacterial growth. Until now, a number of proof-of-concept hybrid nanoadjuvants have been proposed to combat tumor recurrence and postsurgical bacterial infection, which may suffer from the potential bio-unsafety or involve complex design and synthesis. The batch-to-batch inconsistencies in drug composition further delay the clinical trials. To circumvent these issues, herein we develop a programmable strategy to generate lipopeptide nanotherapeutics with identical constitution for tandem intervention of postsurgical bacterial infection and cancer recurrence of melanoma. Increasing the number of hydrophobic linoleic acid within lipopeptides has been found to be a simple and practical strategy to improve the therapeutic outcomes for both tumor cells and bacteria. Self-assembled lipopeptide nanotherapeutics with two linoleic acid molecules possesses excellent antitumor activity and antimicrobial function toward both susceptible strains and drug-resistant bacteria. Arising from the incorporation of unsaturated linoleic acid, the unavoidable hemolysis of cationic peptide drugs was effectively alleviated. In vivo therapeutic abilities of postsurgical infection and tumor recurrence were investigated in BALB/c nude mice bearing a B16-F10 tumor model, with an incomplete surgical resection and in situ infection by methicillin-resistant Staphylococcus aureus (MRSA). Self-assembled lipopeptide nanotherapeutics could effectively inhibit cancer cell growth and bacterial infection, as well as promote wound healing. The easily scalable large-scale production, broad-spectrum antitumor and antibacterial bioactivities as well as fixed component endows lipopeptide nanotherapeutics as promising adjuvants for clinically postsurgical therapy of melanoma.
肿瘤复发和慢性细菌感染是恶性黑色素瘤术后干预的两个主要标准。一种可行的策略是术后进行巩固治疗，依靠佐剂来消除残留的肿瘤细胞并抑制细菌生长。到目前为止，已经提出了一些概念验证性的混合纳米佐剂来对抗肿瘤复发和术后细菌感染，但这些佐剂可能存在潜在的生物安全性问题，或者涉及复杂的设计和合成。药物成分的批次间不一致进一步延迟了临床试验。为了规避这些问题，我们在此开发了一种可编程策略，以生成具有相同组成的脂肽纳米治疗剂，用于串联干预黑色素瘤术后细菌感染和癌症复发。已发现增加脂肽内疏水性亚油酸的数量是一种简单实用的策略，可改善对肿瘤细胞和细菌的治疗效果。含有两个亚油酸分子的自组装脂肽纳米治疗剂对敏感菌株和耐药细菌均具有优异的抗肿瘤活性和抗菌功能。由于不饱和亚油酸的掺入，阳离子肽药物不可避免的溶血现象得到有效缓解。在携带B16-F10肿瘤模型、手术切除不完全且原位感染耐甲氧西林金黄色葡萄球菌（MRSA）的BALB/c裸鼠中研究了术后感染和肿瘤复发的体内治疗能力。自组装脂肽纳米治疗剂可以有效抑制癌细胞生长和细菌感染，并促进伤口愈合。易于扩大规模的大规模生产、广谱抗肿瘤和抗菌生物活性以及固定的成分，使脂肽纳米治疗剂成为黑色素瘤临床术后治疗有前景的佐剂。
