Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Allston, MA 02134, United States.
Int J Pharm. 2021 Dec 15;610:121287. doi: 10.1016/j.ijpharm.2021.121287. Epub 2021 Nov 11.
Negatively charged dextran sulfate (DS)-chitosan nanoparticles (DSCS NPs) contain a DS outer shell with binding properties similar to those of heparin and are useful for the incorporation and delivery of therapeutic heparin-binding proteins. These particles, however, are unstable in physiological salt solutions due to their formation through electrostatic interactions. In the present study, a method was developed to covalently crosslink chitosan in the core of the DSCS NP with a short chain dicarboxylic acid (succinate), while leaving the outer shell of the particle untouched. The crosslinked particles, XDSCS NPs, are stable in NaCl solutions up to 3 M. XDSCS NPs were able to incorporate heparin-binding proteins (VEGF and SDF-1α) rapidly and efficiently, and maintain the full biological activity of the proteins. The incorporated proteins were not released from the particles after a 14-day incubation period at 37 °C in PBS, but retained the same activity as those stored at 4 °C. When aerosolized for delivery to the lungs of rats, XDSCS NP-incorporated SDF-1α showed a ∼17-fold greater retention time compared to that of free protein. These properties suggest that XDSCS NPs could be beneficial for the delivery of therapeutic heparin-binding proteins to achieve sustained in vivo effects.
带负电荷的葡聚糖硫酸酯（DS）-壳聚糖纳米颗粒（DSCS NPs）具有与肝素相似结合特性的 DS 外壳，可用于掺入和递送治疗性肝素结合蛋白。然而，由于这些粒子是通过静电相互作用形成的，因此在生理盐溶液中不稳定。在本研究中，开发了一种方法，通过短链二羧酸（琥珀酸）将 DSCS NP 核中的壳聚糖共价交联，而不影响粒子的外壳。交联的粒子 XDSCS NPs 在高达 3 M 的 NaCl 溶液中稳定。XDSCS NPs 能够快速有效地掺入肝素结合蛋白（VEGF 和 SDF-1α），并保持蛋白质的全部生物学活性。在 PBS 中 37°C 孵育 14 天后，掺入的蛋白质不会从粒子中释放出来，但保留与 4°C 下储存的相同活性。当雾化用于递送至大鼠肺部时，与游离蛋白质相比，XDSCS NP 掺入的 SDF-1α 的保留时间延长了约 17 倍。这些特性表明，XDSCS NPs 可能有益于递送治疗性肝素结合蛋白以实现持续的体内效果。
