Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d'Alcontres 31, 98166 Messina, Italy.
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d'Alcontres 31, 98166 Messina, Italy; Center of Innovation and Research in Materials and Polymers (CIRMAP), Laboratory of Polymeric and Composite Materials, University of Mons, Place du Parc 23, 7000 Mons, Belgium.
Int J Pharm. 2024 May 25;657:124183. doi: 10.1016/j.ijpharm.2024.124183. Epub 2024 Apr 30.
We developed cyclic RGD-tagged polymeric micellar nanoassemblies for sustained delivery of Doxorubicin (Dox) endowed with significant cytotoxic effect against MG63, SAOS-2, and U2-OS osteosarcoma cells without compromising the viability of healthy osteoblasts (hFOBs). Targeted polymeric micellar nanoassemblies (RGD-NanoStar@Dox) enabled Dox to reach the nucleus of MG63, SAOS-2, and U2-OS cells causing the same cytotoxic effect as free Dox, unlike untargeted micellar nanoassemblies (NanoStar@Dox) which failed to reach the nucleus and resulted ineffective, demonstrating the crucial role of cyclic RGD peptide in driving cellular uptake and accumulation mechanisms in osteosarcoma cells. Micellar nanoassemblies were obtained by nanoformulation of three-armed star PLA-PEG copolymers properly synthetized with and without decoration with the cyclic-RGDyK peptide (Arg-Gly-Asp-D-Tyr-Lys). The optimal RGD-NanoStar@Dox nanoformulation obtained by nanoprecipitation method (8 % drug loading; 35 % encapsulation efficiency) provided a prolonged and sustained drug release with a rate significantly lower than the free drug under the same experimental conditions. Moreover, the nanosystem preserved Dox from the natural degradation occurring under physiological conditions (i.e., dimerization and consequent precipitation) serving as a slow-release "drug reservoir" ensuring an extended biological activity over the time.
我们开发了环状 RGD 标记的聚合物胶束纳米组装体，用于持续递送达比柔比星（Dox），其对 MG63、SAOS-2 和 U2-OS 骨肉瘤细胞具有显著的细胞毒性作用，而不会损害健康成骨细胞（hFOBs）的活力。靶向聚合物胶束纳米组装体（RGD-NanoStar@Dox）使 Dox 能够到达 MG63、SAOS-2 和 U2-OS 细胞的细胞核，产生与游离 Dox 相同的细胞毒性作用，而无靶向胶束纳米组装体（NanoStar@Dox）则无法到达细胞核，因此无效，表明环状 RGD 肽在驱动骨肉瘤细胞摄取和积累机制方面发挥着关键作用。胶束纳米组装体通过适当合成的三臂星形 PLA-PEG 共聚物的纳米制剂获得，并且不与环状-RGDyK 肽（Arg-Gly-Asp-D-Tyr-Lys）进行修饰。通过纳米沉淀法获得的最佳 RGD-NanoStar@Dox 纳米制剂（载药量为 8%；包封效率为 35%）在相同实验条件下提供了延长和持续的药物释放，其释放速度明显低于游离药物。此外，该纳米系统防止 Dox 在生理条件下（即二聚化和随后的沉淀）发生的自然降解，作为一个缓慢释放的“药物库”，确保在一段时间内延长生物活性。
