Department of Chemical and Biomolecular Engineering and Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
J Am Chem Soc. 2014 Oct 29;136(43):15319-25. doi: 10.1021/ja508083g. Epub 2014 Oct 17.
Encapsulating anticancer protein therapeutics in nanocarriers is an attractive option to minimize active drug destruction, increase local accumulation at the disease site, and decrease side effects to other tissues. Tumor-specific ligands can further facilitate targeting the nanocarriers to tumor cells and reduce nonspecific cellular internalization. Rationally designed non-covalent protein nanocapsules incorporating copper-free "click chemistry" moieties, polyethylene glycol (PEG) units, redox-sensitive cross-linker, and tumor-specific targeting ligands were synthesized to selectively deliver intracellular protein therapeutics into tumor cells via receptor-mediated endocytosis. These nanocapsules can be conjugated to different targeting ligands of choice, such as anti-Her2 antibody single-chain variable fragment (scFv) and luteinizing hormone releasing hormone (LHRH) peptide, resulting in specific and efficient accumulation within tumor cells overexpressing corresponding receptors. LHRH-conjugated nanocapsules selectively delivered recombinant human tumor suppressor protein p53 and its tumor-selective supervariant into targeted tumor cells, which led to reactivation of p53-mediated apoptosis. Our results validate a general approach for targeted protein delivery into tumor cells using cellular-responsive nanocarriers, opening up new opportunities for the development of intracellular protein-based anticancer treatment.
将抗癌蛋白治疗剂封装在纳米载体中是一种很有吸引力的选择，可以最大限度地减少活性药物的破坏，增加在疾病部位的局部积累，并减少对其他组织的副作用。肿瘤特异性配体可以进一步促进纳米载体靶向肿瘤细胞，并减少非特异性细胞内摄取。合理设计的非共价结合的蛋白质纳米胶囊，其中包含无铜“点击化学”部分、聚乙二醇（PEG）单元、氧化还原敏感的交联剂和肿瘤特异性靶向配体，用于通过受体介导的内吞作用选择性地将细胞内蛋白质治疗剂递送至肿瘤细胞。这些纳米胶囊可以与不同的靶向配体结合，如抗 Her2 抗体单链可变片段（scFv）和黄体生成素释放激素（LHRH）肽，导致在过度表达相应受体的肿瘤细胞中特异性和高效地积累。LHRH 缀合的纳米胶囊选择性地将重组人肿瘤抑制蛋白 p53 及其肿瘤选择性超变体递送至靶向肿瘤细胞，导致 p53 介导的细胞凋亡的重新激活。我们的结果验证了使用细胞响应性纳米载体将靶向蛋白递送至肿瘤细胞的一般方法，为开发基于细胞内蛋白质的抗癌治疗方法开辟了新的机会。
