Polymer-lipid hybrid nanoparticles, PMONPs, were developed to improve the oral absorption of cabazitaxel (CTX), a semi-synthetic taxane derivative, by overcoming multiple gastrointestinal barriers. The nano-carrier is comprised of a poly(ε-caprolactone) (PCL) and chain triglyceride (MCT) hybrid core for drug loading, and a positively charged surface while slightly concealed with a polyethylene oxide (PEO) shell by insertion of poloxamer 188, with the aim of improving the intestinal mucus permeation and epithelial cell uptake. The CTX-loaded PMONPs (CTX-PMONPs) were optimized with 10% MCT content in the core, and characterization showed they were on the nanoscale with a size of 170.2 ± 5.7 nm, zeta potential of + 40.90 ± 3.05 mV, drug loading of 11.5%, and sustained release property. Enhanced mucus permeation of PMONPs were confirmed in a bulk permeation test, in situ SPIP and intestinal distribution study, and is likely attributed to the combined effect of positive charge and hydrophilic PEO layer on the surface. Meanwhile, promoted cellular uptake was found in mucus-secreting cells evaluation, in which potential adsorptive transcytosis, caused by positively charged surface, played a key role. Furthermore, lymphatic transport was positively demonstrated, contributing to the high oral absorption of CTX-PMONPs. The oral bioavailability of CTX was elevated from 7.7% (CTX solution (CTX-Sol)) to 56.6% after oral administration of CTX-PMONPs, approximately 7.3 times higher than that of CTX-Sol. An in vivo anticancer efficiency study showed that CTX-PMONPs orally exhibited a good tumor inhibition effect, and reduced the CTX-caused systemic toxicity compared with intravenous CTX-Sol. In conclusion, PMONPs are able to efficiently orally deliver the anticancer drug, CTX, into systemic circulation, and can achieve the desired oral anticancer effect. This surface modified polymer-lipid hybrid nanoparticle is likely to be a promising carrier for oral delivery of small molecule anticancer drugs.

通过克服多种胃肠道障碍，开发了聚合物-脂质杂化纳米颗粒PMONP，以提高半合成紫杉烷衍生物卡巴他赛（CTX）的口服吸收。纳米载体由聚（ε-己内酯）（PCL）和链甘油三酸酯（MCT）杂化核心组成，用于载药，表面带正电，并通过插入泊洛沙姆188稍微掩盖在聚环氧乙烷（PEO）壳中目的在于改善肠粘液的渗透和上皮细胞的吸收。对CTX负载的PMONP（CTX-PMONP）进行了优化，核心中的MCT含量为10％，表征表明它们处于纳米级，尺寸为170.2±5.7 nm，ζ电位为+ 40.90±3.05 mV，载药量为11.5％，并具有持续释放特性。SPIP和肠道分布的原位研究，很可能归因于表面正电荷和亲水性PEO层的联合作用。同时，在分泌粘液的细胞评估中发现促进的细胞摄取，其中由带正电荷的表面引起的潜在的吸附转胞作用起关键作用。此外，积极地证明了淋巴运输，促进了CTX-PMONPs的高口服吸收。口服CTX-PMONP后，CTX的口服生物利用度从7.7％（CTX溶液（CTX-Sol））提高到56.6％，约为CTX-Sol的7.3倍。一个在体内抗癌功效研究表明，口服CTX-PMONPs与静脉注射CTX-Sol相比具有良好的抑瘤作用，并降低了CTX引起的全身毒性。总之，PMONPs可以有效地将抗癌药物CTX口服递送至全身循环，并可以达到所需的口服抗癌效果。这种表面改性的聚合物-脂质杂化纳米颗粒可能是小分子抗癌药物口服给药的有前途的载体。