以 tenascin-C 为靶点的蛋白酶活化 CendR 肽:减轻脱靶组织积累。

IF 5.7 3区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Drug Delivery and Translational Research Pub Date : 2024-10-01 Epub Date: 2024-07-16 DOI:10.1007/s13346-024-01670-2
Allan Tobi, Maarja Haugas, Kristina Rabi, Jhalak Sethi, Kristina Põšnograjeva, Päärn Paiste, Toomas Jagomäe, Karlis Pleiko, Prakash Lingasamy, Tambet Teesalu
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引用次数: 0

摘要

为了实现精确性和选择性,抗癌化合物和纳米粒子(NPs)可以通过与血管中的恶性肿瘤相关分子接触的亲和配体进行靶向。虽然肿瘤穿透C端规则(CendR)肽有望实现肿瘤精准给药,但C端暴露的CendR肽可能会在表达神经纤蛋白-1(NRP-1)的非恶性组织(如肺部)中不良累积。PL3(序列:AGRGRLVR)就是这种杂乱多肽的一个例子,它是一种通过其C端CendR元件RLVR与NRP-1结合的多肽。在这里,我们报告了PL3衍生物的开发情况,这种衍生物只有在经过尿激酶型纤溶酶原激活剂(uPA)的蛋白水解处理后才与NRP-1结合,同时与多肽的另一个受体--tenascin-C(TNC-C)的C域保持结合。通过合理的设计方法和在重组 NRP-1 上筛选 uPA 处理过的肽-噬菌体库(PL3 肽后有四个随机氨基酸),成功鉴定出了仅能在 uPA 处理后与 NRP-1 结合的 PL3 肽衍生物。体外裂解、结合和内化试验以及在正位胶质母细胞瘤小鼠体内的生物分布研究证实了两种新型多肽 PL3uCendR (AGRGRLVR↓SAGGSVA) 和 SKLG (AGRGRLVR↓SKLG) 的疗效,它们表现出与 NRP-1 的 uPA 依赖性结合,减少了与健康 NRP-1 表达组织的脱靶结合。我们的研究不仅揭示了新型uPA依赖性TNC-C靶向CendR多肽,还引入了更广泛的范式,建立了筛选蛋白水解激活肿瘤穿透多肽的技术。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Protease-activated CendR peptides targeting tenascin-C: mitigating off-target tissue accumulation.

Protease-activated CendR peptides targeting tenascin-C: mitigating off-target tissue accumulation.

To achieve precision and selectivity, anticancer compounds and nanoparticles (NPs) can be targeted with affinity ligands that engage with malignancy-associated molecules in the blood vessels. While tumor-penetrating C-end Rule (CendR) peptides hold promise for precision tumor delivery, C-terminally exposed CendR peptides can accumulate undesirably in non-malignant tissues expressing neuropilin-1 (NRP-1), such as the lungs. One example of such promiscuous peptides is PL3 (sequence: AGRGRLVR), a peptide that engages with NRP-1 through its C-terminal CendR element, RLVR.Here, we report the development of PL3 derivatives that bind to NRP-1 only after proteolytic processing by urokinase-type plasminogen activator (uPA), while maintaining binding to the other receptor of the peptide, the C-domain of tenascin-C (TNC-C). Through a rational design approach and screening of a uPA-treated peptide-phage library (PL3 peptide followed by four random amino acids) on the recombinant NRP-1, derivatives of the PL3 peptide capable of binding to NRP-1 only post-uPA processing were successfully identified. In vitro cleavage, binding, and internalization assays, along with in vivo biodistribution studies in orthotopic glioblastoma-bearing mice, confirmed the efficacy of two novel peptides, PL3uCendR (AGRGRLVR↓SAGGSVA) and SKLG (AGRGRLVR↓SKLG), which exhibit uPA-dependent binding to NRP-1, reducing off-target binding to healthy NRP-1-expressing tissues. Our study not only unveils novel uPA-dependent TNC-C targeting CendR peptides but also introduces a broader paradigm and establishes a technology for screening proteolytically activated tumor-penetrating peptides.

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来源期刊
Drug Delivery and Translational Research
Drug Delivery and Translational Research MEDICINE, RESEARCH & EXPERIMENTALPHARMACOL-PHARMACOLOGY & PHARMACY
CiteScore
11.70
自引率
1.90%
发文量
160
期刊介绍: The journal provides a unique forum for scientific publication of high-quality research that is exclusively focused on translational aspects of drug delivery. Rationally developed, effective delivery systems can potentially affect clinical outcome in different disease conditions. Research focused on the following areas of translational drug delivery research will be considered for publication in the journal. Designing and developing novel drug delivery systems, with a focus on their application to disease conditions; Preclinical and clinical data related to drug delivery systems; Drug distribution, pharmacokinetics, clearance, with drug delivery systems as compared to traditional dosing to demonstrate beneficial outcomes Short-term and long-term biocompatibility of drug delivery systems, host response; Biomaterials with growth factors for stem-cell differentiation in regenerative medicine and tissue engineering; Image-guided drug therapy, Nanomedicine; Devices for drug delivery and drug/device combination products. In addition to original full-length papers, communications, and reviews, the journal includes editorials, reports of future meetings, research highlights, and announcements pertaining to the activities of the Controlled Release Society.
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