Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, PR China.
Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, PR China.
Int J Pharm. 2022 Jan 5;611:121301. doi: 10.1016/j.ijpharm.2021.121301. Epub 2021 Nov 15.
A bioadhesive nanocarrier, PTNP, was constructed by utilizing a novel poly(methyl vinyl ether-co-maleic anhydride)- D-α-Tocopheryl polyethylene glycol succinate (PVMMA-TPGS) copolymer in the PLGA/lipid hybrid nanoparticles (PLGA NPs) for improving oral delivery of cabazitaxel (CTX). The PVMMA-TPGS was synthesized by the ring-opening polymerization of the anhydride groups with the hydroxyl groups, combining the bioadhesive property of PVMMA with P-glycoprotein (P-gp) inhibitory effect of TPGS. The CTX-loaded PTNPs (CTX-PTNPs) were prepared by an emulsification-solvent evaporation method and performed a spherical appearance with a uniform particle size of 192.2 nm. The CTX-PTNPs were surface negatively charged, and exhibited good drug loading (10.2%) and encapsulation efficiency (92.1%). A sustained drug release and high stability in simulated gastrointestinal environment were confirmed in in vitro studies. The in vitro mucin adhesion and in vivo intestinal retention experiments indicated that the PTNPs had a stronger bioadhesive effect and a notably longer intestinal retention than the control PLGA NPs, due to the interaction of PVMMA on the PTNP surface with the intestinal mucosa. Moreover, an enhanced intestinal permeability of the PTNPs was also verified in in vivo and ex vivo intestinal permeation studies, which was probably attributed to the extended retention of PTNPs in intestinal mucosa and the P-gp inhibitory effect of TPGS. As respected, in in vivo pharmacokinetic study, the T and oral bioavailability of CTX were dramatically improved to 1.08 h and 28.84% by the PTNPs, respectively, obviously superior to the CTX solution and the PLGA NPs, further demonstrating the high-efficiency in oral delivery of CTX. Hence, this bioadhesive carrier is proposed to be a potential and promising strategy for increasing oral absorption of small molecule insoluble drugs.
一种生物黏附性纳米载体 PTNP 是利用新型聚（甲基乙烯基醚-马来酸酐）-D-α-生育酚聚乙二醇琥珀酸酯（PVMMA-TPGS）共聚物构建而成的，用于改善紫杉醇（CTX）的口服递送。PVMMA-TPGS 是通过开环聚合使酐基与羟基反应合成的，结合了 PVMMA 的生物黏附性和 TPGS 对 P-糖蛋白（P-gp）的抑制作用。通过乳化-溶剂蒸发法制备载 CTX 的 PTNP（CTX-PTNPs），其呈现出球形外观，粒径均匀，为 192.2nm。CTX-PTNPs 表面带负电荷，具有良好的载药（10.2%）和包封效率（92.1%）。在体外研究中证实了 CTX-PTNPs 具有持续的药物释放和在模拟胃肠道环境中的高稳定性。体外黏蛋白黏附实验和体内肠道滞留实验表明，由于 PTNP 表面的 PVMMA 与肠黏膜相互作用，PTNPs 具有比对照 PLGA NPs 更强的生物黏附作用和更长的肠道滞留时间。此外，在体内和离体肠渗透研究中也验证了 PTNPs 具有增强的肠道通透性，这可能归因于 PTNPs 在肠黏膜中的延长滞留时间和 TPGS 的 P-gp 抑制作用。因此，在体内药代动力学研究中，PTNPs 使 CTX 的 T 和口服生物利用度分别显著提高到 1.08h 和 28.84%，明显优于 CTX 溶液和 PLGA NPs，进一步证明了 CTX 口服递送的高效性。因此，这种生物黏附载体被提出是增加小分子难溶性药物口服吸收的一种有潜力和有前途的策略。
