Miyamura Norio, Yamazaki Chisato M, Anami Yasuaki, Tsuchikama Kyoji, Sugahara Kazuki N
Department of Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, United States of America.
Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Center at Houston, Houston, Texas, United States of America.
PLoS One. 2025 Sep 2;20(9):e0331564. doi: 10.1371/journal.pone.0331564. eCollection 2025.
An ideal cancer therapy enhances anti-tumor effects while minimizing side effects. iRGD, a non-cytotoxic peptide that activates a tumor-specific molecular transport machinery, promotes the penetration of co-injected drugs into tumor tissues. Clinical trials have demonstrated its potential as a tumor-specific delivery scaffold and potentiator of anti-cancer agents. In this study, we synthesized an iRGD conjugate containing monomethyl auristatin F (MMAF), a highly toxic antimitotic agent, and characterized its dual function as a tumor-specific cytotoxic agent and co-injected drug delivery scaffold. The iRGD-MMAF conjugate internalized and killed cultured tumor cells in an αv integrin-dependent manner. When injected systemically, iRGD-MMAF homed selectively to tumors in mice, and extensively spread in the extravascular tumor tissue in line with the tumor-penetrating capacity of iRGD. iRGD-MMAF also significantly enhanced tumor-specific entry of a co-injected molecule by serving as an effective drug delivery scaffold. The results indicate that a chemically modified iRGD peptide with an added therapeutic benefit retains its ability to deliver co-injected agents to tumors.
理想的癌症治疗方法应在将副作用降至最低的同时增强抗肿瘤效果。iRGD是一种非细胞毒性肽，可激活肿瘤特异性分子转运机制，促进共注射药物渗透到肿瘤组织中。临床试验已证明其作为肿瘤特异性递送支架和抗癌药物增效剂的潜力。在本研究中，我们合成了一种包含单甲基奥瑞他汀F（MMAF，一种高毒性抗有丝分裂剂）的iRGD缀合物，并表征了其作为肿瘤特异性细胞毒性剂和共注射药物递送支架的双重功能。iRGD-MMAF缀合物以内皮细胞整合素αv依赖的方式内化并杀死培养的肿瘤细胞。全身注射时，iRGD-MMAF选择性地归巢到小鼠肿瘤中，并根据iRGD的肿瘤穿透能力在血管外肿瘤组织中广泛扩散。iRGD-MMAF还通过作为有效的药物递送支架，显著增强了共注射分子的肿瘤特异性进入。结果表明，具有额外治疗益处的化学修饰iRGD肽保留了将共注射剂递送至肿瘤的能力。
