Abstract：
Antimicrobial peptides (AMPs) are promising alternatives to antibiotics for treatment of antimicrobial resistant (AMR) bacterial infections. However, their narrow therapeutic window due to in vivo toxicity and limited stability hampers their clinical use. Here, we evaluated encapsulation of two amphiphilic AMPs, SAAP-148 and snake cathelicidin Ab-Cath, into oleyl-modified hyaluronic acid (OL-HA) nanogels to improve their selectivity index. The AMP-loaded OL-HA nanogels ranged 181-206 nm in size with a PDI of 0.2, highly negative surface charge (-47 to -48 mV) and moderate encapsulation efficiency (53-63%). The AMP-loaded OL-HA nanogels displayed similar activity in vitro as AMP solutions against AMR Staphylococcus aureus and Acinetobacter baumannii, with a dose-dependent effect over time. Importantly, the AMP-loaded OL-HA nanogels showed decreased cytotoxicity towards human erythrocytes and primary skin fibroblast, thereby improving the selectivity index of SAAP-148 and Ab-Cath by 2- and 16.8-fold, respectively. Particularly, the selectivity of Ab-Cath-loaded OL-HA nanogels has great clinical potential, with an index that reached ≥ 300 for S. aureus and ≥ 3000 for A. baumannii. These findings indicate that OL-HA nanogels are a promising drug delivery system to reduce the cytotoxicity of AMPs without substantially affecting their antimicrobial activity, thereby increasing their selectivity index and potential as therapeutics to combat AMR bacterial infections.
摘要：
抗微生物肽(AMP)是用于治疗抗微生物剂抗性(AMR)细菌感染的抗生素的有希望的替代物。然而,由于体内毒性和有限的稳定性，它们狭窄的治疗窗口阻碍了它们的临床应用。这里,我们评估了两种两亲性AMP的包封，SAAP-148和蛇cathelicidinAb-Cath，加入油基修饰的透明质酸(OL-HA)纳米凝胶以提高其选择性指数。负载AMP的OL-HA纳米凝胶的尺寸范围为181-206nm，PDI为0.2，高度负表面电荷（-47至-48mV）和中等封装效率（53-63％）。负载AMP的OL-HA纳米凝胶在体外表现出与AMP溶液对AMR金黄色葡萄球菌和鲍曼不动杆菌相似的活性。随着时间的推移具有剂量依赖性效应。重要的是,负载AMP的OL-HA纳米凝胶显示对人红细胞和原代皮肤成纤维细胞的细胞毒性降低，从而将SAAP-148和Ab-Cath的选择性指数提高了2倍和16.8倍，分别。特别是,载Ab-Cath的OL-HA纳米凝胶的选择性具有巨大的临床潜力，金黄色葡萄球菌指数≥300，鲍曼不动杆菌指数≥3000。这些发现表明OL-HA纳米凝胶是一种有前途的药物递送系统，可以降低AMP的细胞毒性，而不会实质上影响其抗微生物活性。从而增加它们的选择性指数和作为对抗AMR细菌感染的治疗剂的潜力。
