Yu Changjun, Huang Faqing, Chow Warren A, Cook-Wiens Galen, Cui Xiaojiang
Division of Chemistry & Chemical Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, CA 91125, Sunstate Biosciences, LLC, 870 S. Myrtle Ave, Monrovia, CA91016.
Department of Chemistry and Biochemistry, the University of Southern Mississippi, Hattiesburg, Mississippi.
Adv Ther (Weinh). 2020 Nov;3(11). doi: 10.1002/adtp.202000135. Epub 2020 Oct 12.
Small-molecule chemotherapeutics are potent and effective against a variety of malignancies, but common and severe side effects restrict their clinical applications. Nanomedicine approaches represent a major focus for improving chemotherapy, but have met limited success. To overcome the limitations of chemotherapy drugs, we have developed a novel Single Protein Encapsulation (SPE)-based drug formulation and delivery platform and tested its utility in improving doxorubicin (DOX) treatment. Using this methodology, a series of SPEDOX complexes were generated by encapsulating various numbers of DOX molecules into a single human serum albumin (HSA) molecule. UV/fluorescence spectroscopy, membrane dialysis, and dynamic light scattering techniques showed that SPEDOXs are stable and uniform as monomeric HSA and display unique properties distinct from those of DOX and DOX-HSA mixture. Furthermore, detailed procedures to precisely monitor and control both DOX payload and binding strength to HSA were established. Breast cancer xenograft tumor studies revealed that SPEDOX-6 treatment displays improved pharmacokinetic profiles, higher antitumor efficacy, and lower DOX accumulation in the heart tissue compared with unformulated DOX. This SPE technology, which does not involve nanoparticle assembly and modifications to either small-molecule drugs or HSA, may open up a new avenue for developing new drug delivery systems to improve anticancer therapeutics.
小分子化疗药物对多种恶性肿瘤有效，但常见且严重的副作用限制了它们的临床应用。纳米医学方法是改善化疗的主要研究方向，但成效有限。为克服化疗药物的局限性，我们开发了一种基于新型单蛋白封装（SPE）的药物制剂和递送平台，并测试了其在改善阿霉素（DOX）治疗方面的效用。使用这种方法，通过将不同数量的DOX分子封装到单个人类血清白蛋白（HSA）分子中，生成了一系列SPEDOX复合物。紫外/荧光光谱、膜透析和动态光散射技术表明，SPEDOXs作为单体HSA是稳定且均匀的，并且具有与DOX和DOX-HSA混合物不同的独特性质。此外，还建立了精确监测和控制DOX负载量以及与HSA结合强度的详细程序。乳腺癌异种移植肿瘤研究表明，与未配制的DOX相比，SPEDOX-6治疗显示出更好的药代动力学特征、更高的抗肿瘤疗效以及更低的DOX在心脏组织中的蓄积。这种不涉及纳米颗粒组装以及对小分子药物或HSA进行修饰的SPE技术，可能为开发新的药物递送系统以改善抗癌治疗开辟一条新途径。
