School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
Int J Pharm. 2023 Mar 25;635:122761. doi: 10.1016/j.ijpharm.2023.122761. Epub 2023 Feb 21.
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.
人血清白蛋白（HSA）由于其生物相容性、生物可降解性、非免疫原性和固有靶向性，是疏水性药物的重要纳米载体。然而，HSA/药物纳米复合物必须经历复杂的制造过程，包括多次高压均质化和减压去除有机溶剂。此外，由于其稳定性不理想和剂量受限，这些 HSA/药物纳米复合物的临床应用常常受到限制。为了克服这些问题，本研究开发了一种氧化还原响应性紫杉醇-十五烷酸前药缀合物嵌入人血清白蛋白纳米粒子（NPs）作为模型。首先，通过二硫键将紫杉醇与 11-巯基十一酸激活并连接。所得二硫键桥联的紫杉醇-十五烷酸缀合物（PTX-SS-C10-COOH）通过 NMR 和 MS 进行了表征。然后，将 PTX-SS-C10-COOH 溶解在乙醇中，与 HSA 混合在水中，然后冻干生成 HSA/PTX-SS-C10-COOH 纳米粒（HPTX NPs）。动态光散射（DLS）和透射电子显微镜（TEM）分析表明，HPTX NPs 具有约 120nm 的球形结构。荧光猝灭技术证实了 HSA/PTX-SS-C10-COOH NPs 的形成，这归因于静电和疏水相互作用。HPTX NPs 的载药量高达 29.78%，包封率为 94.16%。谷胱甘肽（GSH）触发的 PTX 快速释放验证了 HPTX NPs 的还原响应性。彻底评估了 HPTX NPs 的药代动力学、抗肿瘤功效和全身毒性。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 可以在更高剂量下给药，以实现显著的肿瘤生长抑制。总之，具有高载药量的氧化还原响应性 HPTX NPs 是一种有前途的策略，可以将 PTX 递送至癌症化疗。
