Borbély Adina, Figueras Eduard, Martins Ana, Bodero Lizeth, Raposo Moreira Dias André, López Rivas Paula, Pina Arianna, Arosio Daniela, Gallinari Paola, Frese Marcel, Steinkühler Christian, Gennari Cesare, Piarulli Umberto, Sewald Norbert
Organic and Bioorganic Chemistry, Department of Chemistry Bielefeld University Universitätsstraße 25 DE-33615 Bielefeld Germany.
Exiris s.r.l. Via di Castel Romano 100 IT-00128 Rome Italy.
ChemistryOpen. 2019 Jun 7;8(6):737-742. doi: 10.1002/open.201900110. eCollection 2019 Jun.
RGD-cryptophycin and DGR-cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin-binding antimitotic agent across lysosomally cleavable Val-Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin αβ, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21-L with different expression levels of integrin αβ, showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin-based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin αβ expression level was observed, which is presumably due to a non-integrin-mediated uptake. This reveals the complexity of effective and selective αβ integrin-mediated drug delivery.
通过将拟肽整合素配体与隐藻素（一种通过可被溶酶体切割的缬氨酸 - 丙氨酸或不可切割的连接子与微管蛋白结合的高效抗有丝分裂剂）相结合，合成了RGD - 隐藻素和DGR - 隐藻素缀合物。这些缀合物能够有效抑制生物素化玻连蛋白与整合素αβ的结合，其结合亲和力与游离配体处于相同范围。在具有不同整合素αβ表达水平的人黑素瘤细胞M21和M21 - L上评估了新型缀合物的抗增殖活性，结果显示所有四种化合物对这两种细胞系均具有纳摩尔级别的效力。与相应的可切割缀合物相比，含有不可切割连接子的缀合物活性降低，这表明基于隐藻素的小分子双功能偶联物（SMDCs）能够在细胞内有效释放药物。然而，未观察到缀合物的体外生物学活性与整合素αβ表达水平之间存在显著相关性，这可能是由于非整合素介导的摄取所致。这揭示了有效且选择性的αβ整合素介导的药物递送的复杂性。
