人血清白蛋白（HSA）由于其生物相容性、生物可吸收性、不具免疫原性和固有的靶向性是重要的疏水药物的纳米载体。然而，HSA/药物纳米复合物必须经历复杂的制造过程，包括多次高压均质和在减压条件下去除有机溶剂。此外，这些HSA/药物纳米复合物的临床应用往往受到其不稳定性和剂量限制的制约。为了解决这些问题，在本研究中开发了一种氧化还原响应型紫杉醇-十五碳酸前药共轭物嵌入的人血清白蛋白纳米粒子（NPs）作为模型。首先，通过二硫键连接激活和结合紫杉醇和十一硫辛酸，得到了产物紫杉醇-二硫化物-十碳酸共轭物（PTX-SS-C10-COOH），通过核磁共振和质谱进行了表征。然后，PTX-SS-C10-COOH在乙醇中溶解，与水中的HSA混合，并经过冷冻干燥，生成HSA/PTX-SS-C10-COOH纳米粒子（HPTX NPs）。动态光散射和透射电子显微镜表征表明，HPTX NPs具有球形结构，平均直径约为120 nm。荧光猝灭技术证实了HSA/PTX-SS-C10-COOH纳米粒子的形成，归因于静电和疏水相互作用。HPTX NPs具有29.78％的高药物载荷和94.16％的包封效率。它们的氧化还原响应性由谷胱甘肽（GSH）引发的快速PTX释放得到验证。评估了HPTX NPs的药代动力学、抗肿瘤效能和全身毒性。结果表明，与商业化的Taxol®相比，HPTX NPs具有更长的保留时间、更有效的肿瘤生长抑制和更低的毒性。重要的是，与Abraxane®相比，HPTX NPs可用于更高剂量的给药，以实现显著的肿瘤生长抑制。因此，高药物载荷的氧化还原响应型HPTX NPs是传递PTX用于癌症化疗的一种有前途的策略。 Copyright © 2023 Elsevier B.V. All rights reserved.

Human serum albumin (HSA) is an important nanocarrier of hydrophobic drugs due to its biocompatibility, bioresorbability, non-immunogenicity and intrinsic targetability. However, HSA/drug nanocomplexes have to experience complicated manufacturing process including multiple high-pressure homogenization and removing organic solvent under reduced pressure condition. Besides, the clinical application of these HSA/drug nanocomplexes is often limited because of their unsatisfactory stability and restricted dose. To overcome these issues, a redox-responsive paclitaxel-pentadecanoic acid prodrug conjugate embedded human serum albumin nanoparticles (NPs) was developed as a model in this report. First, PTX was activated and conjugated with 11-mercaptoundecanoic acid through a disulfide bond. The resultant disulfide bond bridged paclitaxel-pentadecanoic acid conjugate (PTX-SS-C10-COOH) was characterized by NMR and MS. After that, PTX-SS-C10-COOH dissolved in ethanol was mixed with HSA in water followed by lyophilization to generate HSA/PTX-SS-C10-COOH nanoparticles (HPTX NPs). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) characterization indicated that the HPTX NPs have spherical structure with an average diameter of approximately 120 nm. The formation of HSA/PTX-SS-C10-COOH NPs was confirmed by fluorescence quenching technology, ascribed to electrostatic and hydrophobic interactions. The HPTX NPs displayed a highdrug loading of 29.78 % and an entrapment efficiency of 94.16 %. Their reduced responsiveness was validated by glutathione (GSH)-triggered fast release of PTX. The pharmacokinetics, antitumor efficacy and systemic toxicity of HPTX NPs were thoroughly evaluated. The results showed that the HPTX NPs had longer retention, more effective tumor growth inhibition and lower toxicity compared with commercialized Taxol®. Importantly, the HPTX NPs could be administered at much high dose to achieve a significant tumor growth inhibition compared with Abraxane®. Together, the redox-responsive HPTX NPs with high drug loading is a promising strategy to deliver PTX for cancer chemotherapy.Copyright © 2023 Elsevier B.V. All rights reserved.