van Gent Miriam E, van Baaren Tom, Kłodzińska Sylvia N, Ali Muhanad, Dolezal Natasja, van Doodewaerd Bjorn R, Bos Erik, de Waal Amy M, Koning Roman I, Drijfhout Jan Wouter, Nielsen Hanne Mørck, Nibbering Peter H
Department of Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Center for Biopharmaceuticals and Biobarriers in Drug Delivery (BioDelivery), Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
Pharmaceutics. 2023 Jan 28;15(2):429. doi: 10.3390/pharmaceutics15020429.
Chronic wound infections colonized by bacteria are becoming more difficult to treat with current antibiotics due to the development of antimicrobial resistance (AMR) as well as biofilm and persister cell formation. Synthetic antibacterial and antibiofilm peptide (SAAP)-148 is an excellent alternative for treatment of such infections but suffers from limitations related to its cationic peptidic nature and thus instability and possible cytotoxicity, resulting in a narrow therapeutic window. Here, we evaluated SAAP-148 encapsulation in nanogels composed of octenyl succinic anhydride (OSA)-modified hyaluronic acid (HA) to circumvent these limitations. SAAP-148 was efficiently (>98%) encapsulated with high drug loading (23%), resulting in monodispersed anionic OSA-HA nanogels with sizes ranging 204-253 nm. Nanogel lyophilization in presence of polyvinyl alcohol maintained their sizes and morphology. SAAP-148 was sustainedly released from lyophilized nanogels (37-41% in 72 h) upon reconstitution. Lyophilized SAAP-148-loaded nanogels showed similar antimicrobial activity as SAAP-148 against planktonic and biofilm-residing AMR and . Importantly, formulated SAAP-148 showed reduced cytotoxicity against human erythrocytes, primary human skin fibroblasts and human keratinocytes. Additionally, lyophilized SAAP-148-loaded nanogels eradicated AMR and colonizing a 3D human epidermal model, without inducing any cytotoxicity in contrast to SAAP-148. These findings indicate that OSA-HA nanogels increase SAAP-148's therapeutic potential for treatment of skin wound infections.
由于抗菌药物耐药性（AMR）的发展以及生物膜和持留菌细胞的形成，由细菌定植的慢性伤口感染越来越难以用目前的抗生素进行治疗。合成抗菌和抗生物膜肽（SAAP）-148是治疗此类感染的一种极佳替代方案，但由于其阳离子肽性质而存在局限性，从而导致不稳定性和可能的细胞毒性，致使治疗窗口狭窄。在此，我们评估了将SAAP-148封装于由辛烯基琥珀酸酐（OSA）修饰的透明质酸（HA）组成的纳米凝胶中，以规避这些局限性。SAAP-148以高载药量（23%）被高效封装（>98%），形成了尺寸范围在204 - 253 nm的单分散阴离子型OSA-HA纳米凝胶。在聚乙烯醇存在下对纳米凝胶进行冻干可保持其尺寸和形态。重新溶解后，SAAP-148从冻干的纳米凝胶中持续释放（72小时内释放37 - 41%）。冻干的负载SAAP-148的纳米凝胶对浮游菌和生物膜中的AMR 以及 显示出与SAAP-148相似的抗菌活性。重要的是，配制后的SAAP-148对人红细胞、原代人皮肤成纤维细胞和人角质形成细胞的细胞毒性降低。此外，冻干的负载SAAP-148的纳米凝胶根除了在三维人表皮模型中定植的AMR 以及 ，与SAAP-148相比未诱导任何细胞毒性。这些发现表明，OSA-HA纳米凝胶增加了SAAP-148治疗皮肤伤口感染的治疗潜力。
