State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
J Nanobiotechnology. 2022 Jun 15;20(1):281. doi: 10.1186/s12951-022-01460-3.
Oral chemotherapy is preferred for patients with cancer owing to its multiple advantages, including convenience, better patient compliance, and improved safety. Nevertheless, various physical barriers exist in this route that hamper the development of oral chemotherapeutic formulations, including destruction of drugs in the gastrointestinal tract (GIT), low permeability in enterocytes, and short residence time in the intestine. To overcome these limitations, it is necessary to design an efficient oral drug delivery system with high efficacy and improved safety.
Herein, we designed novel glycocholic acid (GCA)-functionalized double layer nanoparticles (GCA-NPs), which can act via an endogenous pathway and in a temporally controlled manner in the intestine, to enhance the oral bioavailability of hydrophobic chemotherapeutic drugs such as paclitaxel (PTX). GCA-NPs were composed of quercetin (Qu)-modified liposomes (QL) coated with GCA-chitosan oligosaccharide conjugate (GCOS). The GCA-NPs thus prepared showed prolonged intestinal retention time and good GIT stability due to the presence of chitosan oligosaccharide (COS) and enhanced active transportation via intestinal apical sodium-dependent bile acid transporter (ASBT) due to the presence of GCA. GCA-NPs also efficiently inhibited intestinal P-gp induced by Qu. PTX-loaded GCA-NPs (PTX@GCA-NPs) had a particle size of 84 nm and an entrapment efficiency of 98% with good stability. As a result, the oral bioavailability of PTX was increased 19-fold compared to that of oral Taxol at the same dose. Oral PTX@GCA-NPs displayed superior antitumor efficacy and better safety than Taxol when administered intravenously.
Our novel drug delivery system showed remarkable efficacy in overcoming multiple limitations and is a promising carrier for oral delivery of multiple drugs, which addresses several challenges in oral delivery in the clinical context.
由于具有诸多优势，包括方便、更好的患者依从性和提高的安全性，癌症患者更倾向于接受口服化疗。然而，该途径存在多种物理障碍，阻碍了口服化疗制剂的发展，包括胃肠道（GIT）中药物的破坏、肠细胞内的低渗透性和在肠道中的短停留时间。为了克服这些限制，有必要设计一种高效的口服药物递送系统，具有高效和改善的安全性。
在此，我们设计了新型甘氨胆酸（GCA）功能化双层纳米粒（GCA-NPs），它可以通过内源性途径并在肠道中以时间控制的方式发挥作用，以提高疏水性化疗药物如紫杉醇（PTX）的口服生物利用度。GCA-NPs 由槲皮素（Qu）修饰的脂质体（QL）组成，其表面涂有 GCA-壳聚糖寡糖缀合物（GCOS）。由于壳聚糖寡糖（COS）的存在，所制备的 GCA-NPs 具有延长的肠道保留时间和良好的 GIT 稳定性，并且由于 GCA 的存在，通过肠顶侧钠依赖性胆汁酸转运蛋白（ASBT）增强了主动转运。GCA-NPs 还能有效抑制 Qu 诱导的肠道 P-gp。载紫杉醇的 GCA-NPs（PTX@GCA-NPs）的粒径为 84nm，包封率为 98%，具有良好的稳定性。结果，与相同剂量的口服 Taxol 相比，PTX 的口服生物利用度提高了 19 倍。与 Taxol 静脉给药相比，口服 PTX@GCA-NPs 表现出更好的抗肿瘤疗效和更好的安全性。
我们的新型药物递送系统在克服多种限制方面表现出显著的疗效，是一种有前途的口服递药载体，可解决临床口服递药中的多个挑战。
