National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
School of Chemical Engineering, Sichuan University, Chengdu 610065, China.
J Mater Chem B. 2020 May 6;8(17):3939-3948. doi: 10.1039/d0tb00327a.
Doxorubicin (DOX) is a widely-used anticancer drug, but its cardiotoxicity severely hampers its potency in chemotherapy. Herein, human serum albumin (HSA) is engaged as a biocompatible nanocarrier to load a pH-sensitive DOX prodrug, DMDOX, generating HSA-DMDOX nanoparticles via self-assembly driven by hydrophobic interactions. HSA-DMDOX disperses well in a physiological environment (∼40 nm) but aggregates in a tumor acidic microenvironment (pH 6.5, ∼140 nm) owing to the hydrophobicity increase of DMDOX by protonation of carboxylic groups. In vitro anticancer study showed that HSA-DMDOX exhibited enhanced cellular uptake by 4T1 cells and superior cytotoxicity in comparison to HSA-DOX nanoparticles. In vivo study suggested that HSA-DMDOX achieved long blood circulation, aggregation enhanced tumor retention, comparable antitumor efficacy and reduced cardiotoxicity relative to free DOX. Our work presents a facile and effective approach to delivering anthracyclines by HSA-based tumor pH-responsive nanoparticles with aggregation-enhanced tumor retention and reduced toxicity.
多柔比星（DOX）是一种广泛使用的抗癌药物，但它的心脏毒性严重限制了其在化疗中的效力。在此，人血清白蛋白（HSA）被用作生物相容性的纳米载体来负载 pH 敏感的 DOX 前药 DMDOX，通过疏水相互作用驱动的自组装生成 HSA-DMDOX 纳米粒子。HSA-DMDOX 在生理环境中（约 40nm）分散良好，但在肿瘤酸性微环境（pH6.5，约 140nm）中聚集，这是由于 DMDOX 的质子化导致羧酸基团的疏水性增加。体外抗癌研究表明，与 HSA-DOX 纳米粒子相比，HSA-DMDOX 对 4T1 细胞具有增强的细胞摄取和更高的细胞毒性。体内研究表明，与游离 DOX 相比，HSA-DMDOX 实现了更长的血液循环、聚集增强的肿瘤滞留、相当的抗肿瘤疗效和降低的心脏毒性。我们的工作提出了一种通过基于 HSA 的肿瘤 pH 响应性纳米粒子传递蒽环类药物的简便有效方法，该方法具有聚集增强的肿瘤滞留和降低的毒性。
