Abstract：
Novel amphiphilic nanoconjugates of hyaluronic acid (HA), 50 kDa (HA50) and 100 kDa (HA100), and the lipopeptide biosurfactant surfactin (SF) were developed for potential anticancer applications. Physicochemical characterization indicated the formation of an ester conjugate (HA: SF molar ratio 1: 40) with the HA50-SF derivative exhibiting higher degree of substitution, hydrolytic stability, and surface activity. Self-assembly resulted in nanomicelles with smaller size and greater negative charge relative to SF micelles. Biological data demonstrated distinct anticancer activity of HA50-SF which displayed greater synergistic cytotoxicity and selectivity for MDA-MB 231 and MCF-7 breast cancer cells alongside greater modulation of apoptosis-related biomarkers leading to apoptosis. As bioactive vector for chemotherapeutic agents, the selected HA50-SF nanoconjugate efficiently (70 %) entrapped berberine (BER) producing a sustained release BER-HA50-SF synergistic anticancer nanoformulation. Lactoferrin (Lf) coating for dual HA/Lf targeting endowed Lf/BER-HA50-SF with significantly greater selectivity for both cell lines. A murine Ehrlich breast cancer model provided evidence for the efficacy and safety of Lf/BER-HA50-SF via tumoral, histological, immunohistochemical, molecular and systemic toxicity assessments. Thus, HA-SF nanoconjugates integrating the HA and SF properties and biofunctionalties present a novel biopolymer-biosurfactant platform of benefit to oncology nanomedicine and possibly other applications.
摘要：
透明质酸（HA）的新型两亲性纳米缀合物，50kDa(HA50)和100kDa(HA100)，脂肽生物表面活性剂表面活性素（SF）被开发用于潜在的抗癌应用。物理化学表征表明形成酯缀合物（HA：SF摩尔比1：40），HA50-SF衍生物具有较高的取代度，水解稳定性，表面活动。相对于SF胶束，自组装导致纳米胶束具有更小的尺寸和更大的负电荷。生物学数据证明了HA50-SF的独特抗癌活性，其对MDA-MB231和MCF-7乳腺癌细胞显示出更大的协同细胞毒性和选择性，以及对导致凋亡的凋亡相关生物标志物的更大调节。作为化学治疗剂的生物活性载体，所选择的HA50-SF纳米缀合物有效地(70%)包封小檗碱(BER),产生持续释放的BER-HA50-SF协同抗癌纳米制剂。用于双重HA/Lf靶向的乳铁蛋白(Lf)涂层赋予Lf/BER-HA50-SF对两种细胞系具有显著更大的选择性。鼠埃利希乳腺癌模型通过肿瘤提供了Lf/BER-HA50-SF的有效性和安全性的证据，组织学,免疫组织化学，分子和系统毒性评估。因此，整合HA和SF性质和生物功能的HA-SF纳米缀合物提供了有益于肿瘤学纳米医学和可能的其他应用的新型生物聚合物-生物表面活性剂平台。
