Zhao Zhen, Fetse John, Mamani Umar-Farouk, Guo Yuhan, Li Yuanke, Patel Pratikkumar, Liu Yanli, Lin Chien-Yu, Li Yongren, Mustafa Bahaa, Cheng Kun
Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA.
Acta Biomater. 2025 Jan 24;193:484-497. doi: 10.1016/j.actbio.2024.12.051. Epub 2024 Dec 22.
Antibody-based checkpoint inhibitors have achieved great success in cancer immunotherapy, but their uncontrollable immune-related adverse events remain a major challenge. In this study, we developed a tumor-activated nanoparticle that is specifically active in tumors but not in normal tissues. We discovered a short anti-PD-L1 peptide that blocks the PD-1/PD-L1 interaction. The peptide was modified with a PEG chain through a novel matrix metalloproteinase-2 (MMP-2)-specific cleavage linker. The modified TR3 peptide self-assembles into a micelle-like nanoparticle (TR3-M-NP), which remains inactive and unable to block the PD-1/PD-L1 interaction in its native form. However, upon cleavage by MMP-2 in tumors, it releases the active peptide. The TR3-M-NP nanoparticle was specifically activated in tumors through enzyme-mediated cleavage, leading to the inhibition of tumor growth and extended survival compared to control groups. In summary, TR3-M-NP shows great potential as a tumor-responsive immunotherapy agent with reduced toxicities. STATEMENT OF SIGNIFICANCE: In this study, we developed a bioactive peptide-based checkpoint inhibitor that is active only in tumors and not in normal tissues, thereby potentially avoiding immune-related adverse effects. We discovered a short anti-PD-L1 peptide, TR3, that blocks the PD-1/PD-L1 interaction. We chemically modified the TR3 peptide to self-assemble into a micelle-like nanoparticle (TR3-M-NP), which itself cannot block the PD-1/PD-L1 interaction but releases the active TR3 peptide in tumors upon cleavage by MMP-2. In contrast, the nanoparticle is randomly degraded in normal tissues into peptides fragments that cannot block the PD-1/PD-L1 interaction. Upon intraperitoneal injection, TR3-M-NP was activated specifically in tumors through enzyme cleavage, leading to the inhibition of tumor growth and extended survival compared to the control groups. In summary, TR3-M-NP holds significant promise as a tumor-responsive immunotherapy agent with reduced toxicities. The bioactive platform has the potential to be used for other types of checkpoint inhibitor.
基于抗体的检查点抑制剂在癌症免疫治疗中取得了巨大成功，但其不可控的免疫相关不良事件仍然是一个重大挑战。在本研究中，我们开发了一种肿瘤激活纳米颗粒，其在肿瘤中具有特异性活性，但在正常组织中无活性。我们发现了一种短的抗PD-L1肽，它能阻断PD-1/PD-L1相互作用。该肽通过一种新型基质金属蛋白酶-2（MMP-2）特异性切割连接子用聚乙二醇链进行修饰。修饰后的TR3肽自组装成胶束样纳米颗粒（TR3-M-NP），其在天然形式下无活性且无法阻断PD-1/PD-L1相互作用。然而，在肿瘤中被MMP-2切割后，它会释放出活性肽。TR3-M-NP纳米颗粒通过酶介导的切割在肿瘤中被特异性激活，与对照组相比，导致肿瘤生长受到抑制且生存期延长。总之，TR3-M-NP作为一种毒性降低的肿瘤反应性免疫治疗药物具有巨大潜力。重要性声明：在本研究中，我们开发了一种基于生物活性肽的检查点抑制剂，其仅在肿瘤中具有活性，而在正常组织中无活性，从而有可能避免免疫相关不良反应。我们发现了一种短的抗PD-L1肽TR3，它能阻断PD-1/PD-L1相互作用。我们对TR3肽进行化学修饰，使其自组装成胶束样纳米颗粒（TR3-M-NP），其本身无法阻断PD-1/PD-L1相互作用，但在被MMP-2切割后在肿瘤中释放出活性TR3肽。相比之下，该纳米颗粒在正常组织中随机降解为无法阻断PD-1/PD-L1相互作用的肽片段。腹腔注射后，TR3-M-NP通过酶切割在肿瘤中被特异性激活，与对照组相比，导致肿瘤生长受到抑制且生存期延长。总之，TR3-M-NP作为一种毒性降低的肿瘤反应性免疫治疗药物具有重大前景。该生物活性平台有潜力用于其他类型的检查点抑制剂。
