Cohen Anna, Kashkoosh Maysoon, Sharma Vipin, Panja Akash, Shpitzer Sagi A, Golan Shay, Bazylevich Andrii, Gellerman Gary, Luboshits Galia, Firer Michael A
Department of Chemical Engineering, Ariel University, Ariel 40700, Israel.
Department of Chemical Sciences, Ariel University, Ariel 40700, Israel.
Pharmaceutics. 2025 Jul 1;17(7):866. doi: 10.3390/pharmaceutics17070866.
Metastatic prostate cancer (mPrC), with a median survival of under 2 years, represents an important unmet medical need which may benefit from the development of more effective targeted drug delivery systems. Several cell surface receptors have been identified as candidates for targeted drug delivery to mPrC cells; however, these receptors were selected for their overabundance on PrC cells rather than for their suitability for targeted delivery and uptake of cytotoxic drug payloads. We describe a novel, unbiased strategy to isolate peptides that fulfill functional criteria required for effective intracellular drug delivery and the specific cytotoxicity of PrC cells without prior knowledge of the targeted receptor. Phage clones displaying 7-mer cyclic peptides were negatively selected in vivo and then positively biopanned through a series of parent and drug-resistant mPrC cells. Peptides from the internalized clones were then subjected to a panel of biochemical and functional tests that led to the selection of several peptide candidates. The selected peptides do not bind PSMA. Peptide-drug conjugates (PDCs) incorporating one of the peptides selectively killed wild-type and drug-resistant PrC cell lines and patient PrC cells but not normal prostate tissue cells in vitro. The PDC also halted the growth of PC3 tumors in a xenograft model. Our study demonstrates that adding unbiased, functional criteria into drug carrier selection protocols can lead to the discovery of novel peptides with appropriate properties required for effective targeted drug delivery into target cancer cells.
转移性前列腺癌（mPrC）的中位生存期不足2年，这是一个重要的未满足医疗需求，可能会从更有效的靶向给药系统的开发中受益。几种细胞表面受体已被确定为向mPrC细胞进行靶向给药的候选受体；然而，选择这些受体是因为它们在前列腺癌细胞上的过度表达，而不是因为它们适合靶向递送和摄取细胞毒性药物载荷。我们描述了一种新的、无偏见的策略，用于分离满足有效细胞内药物递送和前列腺癌细胞特异性细胞毒性所需功能标准的肽，而无需事先了解靶向受体。展示7聚体环肽的噬菌体克隆在体内进行负筛选，然后通过一系列亲本和耐药mPrC细胞进行正筛选。然后对内化克隆的肽进行一系列生化和功能测试，从而筛选出几种候选肽。所选肽不与前列腺特异性膜抗原（PSMA）结合。掺入其中一种肽的肽-药物缀合物（PDC）在体外选择性杀死野生型和耐药前列腺癌细胞系以及患者前列腺癌细胞，但不杀死正常前列腺组织细胞。该PDC还在异种移植模型中抑制了PC3肿瘤的生长。我们的研究表明，在药物载体选择方案中加入无偏见的功能标准，可以发现具有有效靶向给药至靶癌细胞所需适当特性的新型肽。
