Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
Department of Radiology, the Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China.
Bioorg Med Chem. 2024 May 15;106:117754. doi: 10.1016/j.bmc.2024.117754. Epub 2024 May 7.
To improve the biodistribution of the drug in the tumor, a supramolecular prodrug of SN38 was fabricated in situ between endogenous albumin and SN38 prodrug modified with semaglutide side chain. Firstly, SN38 was conjugated with semaglutide side chain and octadecanedioic acid via glycine linkers to obtain SI-Gly-SN38 and OA-Gly-SN38 prodrugs, respectively. Both SI-Gly-SN38 and OA-Gly-SN38 exhibited excellent stability in PBS for over 24 h. Due to the strong binding affinity of the semaglutide side chain with albumin, the plasma half-life of SI-Gly-SN38 was 2.7 times higher than that of OA-Gly-SN38. Furthermore, with addition of HSA, the fluorescence intensity of SI-Gly-SN38 was 4 times higher than that of OA-Gly-SN38, confirming its strong binding capability with HSA. MTT assay showed that the cytotoxicity of SI-Gly-SN38 and OA-Gly-SN38 was higher than that of Irinotecan. Even incubated with HSA, the SI-Gly-SN38 and OA-Gly-SN38 still maintained high cytotoxicity, indicating minimal influence of HSA on their cytotoxicity. In vivo pharmacokinetic studies demonstrated that the circulation half-life of SI-Gly-SN38 was twice that of OA-Gly-SN38. SI-Gly-SN38 exhibited significantly reduced accumulation in the lungs, being only 0.23 times that of OA-Gly-SN38. The release of free SN38 in the lungs from SI-Gly-SN38 was only 0.4 times that from OA-Gly-SN38 and Irinotecan. The SI-Gly-SN38 showed the highest accumulation in tumors. The tumor inhibition rate of SI-Gly-SN38 was 6.42% higher than that of OA-Gly-SN38, and 8.67% higher than that of Irinotecan, respectively. These results indicate that the supramolecular prodrug delivery system can be constructed between SI-Gly-SN38 and endogenous albumin, which improves drug biodistribution in vivo, enhances tumor accumulation, and plays a crucial role in tumor growth inhibition.
为了提高药物在肿瘤中的生物分布，我们在内源性白蛋白和用 semaglutide 侧链修饰的 SN38 前药之间原位构建了超分子前药。首先，通过甘氨酸接头将 SN38 与 semaglutide 侧链和十八烷二酸分别缀合，得到 SI-Gly-SN38 和 OA-Gly-SN38 前药。SI-Gly-SN38 和 OA-Gly-SN38 在 PBS 中均表现出超过 24 小时的优异稳定性。由于 semaglutide 侧链与白蛋白具有很强的结合亲和力，因此 SI-Gly-SN38 的血浆半衰期是 OA-Gly-SN38 的 2.7 倍。此外，加入 HSA 后，SI-Gly-SN38 的荧光强度是 OA-Gly-SN38 的 4 倍，证实了其与 HSA 的强结合能力。MTT 测定表明，SI-Gly-SN38 和 OA-Gly-SN38 的细胞毒性均高于伊立替康。即使与 HSA 孵育，SI-Gly-SN38 和 OA-Gly-SN38 仍保持高细胞毒性，表明 HSA 对其细胞毒性的影响很小。体内药代动力学研究表明，SI-Gly-SN38 的循环半衰期是 OA-Gly-SN38 的两倍。SI-Gly-SN38 在肺部的积累明显减少，仅为 OA-Gly-SN38 的 0.23 倍。从 SI-Gly-SN38 中在肺部释放的游离 SN38 仅为 OA-Gly-SN38 和伊立替康的 0.4 倍。SI-Gly-SN38 在肿瘤中的积累最高。SI-Gly-SN38 的肿瘤抑制率比 OA-Gly-SN38 高 6.42%，比伊立替康高 8.67%。这些结果表明，超分子前药给药系统可以在 SI-Gly-SN38 和内源性白蛋白之间构建，从而改善药物在体内的生物分布，增强肿瘤积累，并在肿瘤生长抑制中发挥关键作用。
