Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.
Biomaterials. 2020 Jul;248:120032. doi: 10.1016/j.biomaterials.2020.120032. Epub 2020 Apr 11.
Patients with advanced cancers are treated with combined radiotherapy and chemotherapy, however curability is poor and treatment side effects severe. Drugs sensitizing tumors to radiotherapy have been developed to improve cell kill, but tumor specificity remains challenging. To achieve tumor selectivity of small molecule radiosensitizers, we tested as a strategy active tumor targeting using peptide-based drug conjugates. We attached an inhibitor of the DNA damage response to antibody or cell penetrating peptides. Antibody drug conjugates honed in on tumor overexpressed cell surface receptors with high specificity but lacked efficacy when conjugated to the DNA damage checkpoint kinase inhibitor AZD7762. As an alternative approach, we synthesized activatable cell penetrating peptide scaffolds that accumulated within tumors based on matrix metalloproteinase cleavage. While matrix metalloproteinases are integral to tumor progression, they have proven therapeutically elusive. We harnessed these pro-tumorigenic extracellular proteases to spatially guide radiosensitizer drug delivery using cleavable activatable cell penetrating peptides. Here, we tested the potential of these two drug delivery platforms targeting distinct tumor compartments in combination with radiotherapy and demonstrate the advantages of protease triggered cell penetrating peptide scaffolds over antibody drug conjugates to deliver small molecule amine radiosensitizers.
晚期癌症患者接受联合放化疗，但治愈率低，治疗副作用严重。已经开发出了使肿瘤对放疗敏感的药物来提高细胞杀伤率，但肿瘤特异性仍然具有挑战性。为了实现小分子放射增敏剂的肿瘤选择性，我们采用了使用基于肽的药物偶联物进行主动肿瘤靶向的策略。我们将 DNA 损伤反应抑制剂连接到抗体或细胞穿透肽上。抗体药物偶联物能够针对肿瘤表面过度表达的受体进行高特异性靶向，但与 DNA 损伤检查点激酶抑制剂 AZD7762 偶联时效果不佳。作为替代方法，我们合成了基于基质金属蛋白酶切割的可激活细胞穿透肽支架，这些支架可以在肿瘤内积累。虽然基质金属蛋白酶是肿瘤进展的重要组成部分，但它们在治疗上一直难以捉摸。我们利用这些促进肿瘤发生的细胞外蛋白酶，使用可切割的激活细胞穿透肽来空间引导放射增敏剂的药物传递。在这里，我们测试了这两种药物传递平台针对不同肿瘤部位与放疗联合使用的潜力，并证明了蛋白酶触发的细胞穿透肽支架优于抗体药物偶联物，可用于传递小分子胺类放射增敏剂。
