Mortaja Mahsa, Cheng Marcus M, Ali Alina, Lesperance Jacqueline, Hingorani Dina V, Allevato Mike M, Dhawan Kanika, Camargo Maria F, McKay Rana R, Adams Stephen R, Gutkind J Silvio, Advani Sunil J
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.
Molecules. 2024 Nov 27;29(23):5618. doi: 10.3390/molecules29235618.
Chemotherapies remain standard therapy for cancers but have limited efficacy and cause significant side effects, highlighting the need for targeted approaches. In the progression of cancer, tumors increase matrix metalloproteinase (MMP) activity. Leveraging and therapeutically redirecting tumor MMPs through activatable cell-penetrating peptide (ACPP) technology offers new approaches for tumor-selective drug delivery and for studying how drug payloads engage the tumor immune microenvironment. ACPPs are biosensing peptides consisting of a drug-conjugated polycationic cell-penetrating peptide masked by an autoinhibitory polyanionic peptide through an interlinking peptide linker. Since tumors overexpress MMPs, ACPP tumor-targeting is achieved using an MMP cleavable linker. Monomethyl auristatin E (MMAE) is a potent anti-tubulin and common drug payload in antibody drug conjugates; however there are limited pre-clinical studies on how this clinically effective drug modulates the interplay of cancer cells and the immune system. Here, we report the versatility of ACPP conjugates in syngeneic murine cancer models and interrogate how MMAE temporally alters the tumor immune microenvironment. We show that cRGD-ACPP-MMAE preferentially delivered MMAE to tumors in murine models. Targeted cRGD-ACPP-MMAE demonstrated anti-tumor kill activity that activated the innate and adaptive arms of the immune system. Understanding how targeted MMAE engages tumors can optimize MMAE tumor kill activity and inform rational combinations with other cancer therapeutics.
化疗仍然是癌症的标准治疗方法，但疗效有限且会引起严重的副作用，这凸显了靶向治疗方法的必要性。在癌症进展过程中，肿瘤会增加基质金属蛋白酶（MMP）的活性。通过可激活细胞穿透肽（ACPP）技术利用并在治疗上重新引导肿瘤MMP，为肿瘤选择性药物递送以及研究药物载荷如何与肿瘤免疫微环境相互作用提供了新方法。ACPP是一种生物传感肽，由通过连接肽连接子被自抑制性聚阴离子肽掩盖的药物偶联聚阳离子细胞穿透肽组成。由于肿瘤过度表达MMP，因此使用MMP可裂解连接子实现ACPP对肿瘤的靶向作用。单甲基澳瑞他汀E（MMAE）是一种有效的抗微管蛋白药物，也是抗体药物偶联物中常用的药物载荷；然而，关于这种临床有效药物如何调节癌细胞与免疫系统相互作用的临床前研究有限。在这里，我们报告了ACPP偶联物在同基因小鼠癌症模型中的多功能性，并研究了MMAE如何随时间改变肿瘤免疫微环境。我们表明，cRGD-ACPP-MMAE在小鼠模型中优先将MMAE递送至肿瘤。靶向的cRGD-ACPP-MMAE表现出抗肿瘤杀伤活性，激活了免疫系统的固有和适应性分支。了解靶向MMAE如何作用于肿瘤可以优化MMAE的肿瘤杀伤活性，并为与其他癌症治疗方法的合理联合提供依据。
