通过与可释放物质 P 缀合来提高喜树碱的抗癌活性和选择性。

Improving anticancer activity and selectivity of camptothecin through conjugation with releasable substance P.

机构信息

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.

出版信息

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1452-5. doi: 10.1016/j.bmcl.2011.01.013. Epub 2011 Jan 8.

DOI:10.1016/j.bmcl.2011.01.013

PMID:21282053

Abstract

Substance P, an 11-residue neuropeptide, can be rapidly internalized through specific interaction with the neurokinin-1 receptor. Therefore, we designed and synthesized the substance P targeted camptothecin (CPT) conjugates via a releasable disulfide carbonate linker. All the conjugates exhibited comparable or stronger cytotoxicity to cancer cells that highly over-express neurokinin-1 receptor than free CPT. More importantly, the selectivity of conjugates was significantly improved compared with CPT. Our results indicated that these conjugates can be promising candidates for new chemotherapeutic drugs. In addition, increasing CPT loading or attachment of CPT to the C-terminal hexapeptide of substance P are useful strategies to enhance the therapeutic efficacy of substance P targeted conjugates.

摘要

P 物质是一种 11 个氨基酸组成的神经肽，可通过与神经激肽-1 受体的特异性相互作用而迅速内化。因此，我们设计并合成了通过可释放的二硫碳酸酯键连接的 P 物质靶向喜树碱（CPT）缀合物。所有缀合物对高表达神经激肽-1 受体的癌细胞的细胞毒性与游离 CPT 相当或更强。更重要的是，与 CPT 相比，缀合物的选择性显著提高。我们的结果表明，这些缀合物可能是新型化疗药物的有前途的候选药物。此外，增加 CPT 的载药量或将 CPT 连接到 P 物质的 C 末端六肽上是增强 P 物质靶向缀合物治疗效果的有用策略。