Redirecting extracellular proteases to molecularly guide radiosensitizing drugs to tumors
Redirecting extracellular proteases to molecularly guide radiosensitizing drugs to tumors
复制标题
DOI：
10.1016/j.biomaterials.2020.120032
复制
发表时间：
2020-07-01
期刊：
影响因子：
14
通讯作者：
Advani, Sunil J.
中科院分区：
文献类型：
--
作者：
Hingorani, Dina, V;Crisp, Jessica L.;Advani, Sunil J.
晚期癌症患者采用放疗和化疗联合治疗，但治愈率低，治疗副作用严重。已经开发了使肿瘤对放射治疗敏感的药物来提高细胞杀伤，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，我们测试了使用基于肽的药物缀合物作为主动肿瘤靶向的策略。我们将DNA损伤反应的抑制剂附着在抗体或细胞穿透肽上。抗体药物偶联物以高特异性在肿瘤过表达的细胞表面受体上磨练，但当与DNA损伤检查点激酶抑制剂AZD 7762偶联时缺乏功效。作为替代方法，我们合成了基于基质金属蛋白酶切割在肿瘤内积累的可活化细胞穿透肽支架。虽然基质金属蛋白酶是肿瘤进展的组成部分，但已证明它们在治疗上是难以捉摸的。我们利用这些促肿瘤细胞外蛋白酶空间引导放射增敏剂药物递送使用可裂解的可活化的细胞穿透肽。在这里，我们测试了这两种药物递送平台靶向不同肿瘤区室与放射疗法组合的潜力，并证明了蛋白酶触发的细胞穿透肽支架相对于抗体药物缀合物递送小分子胺放射增敏剂的优势。
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.