N-Deoxycholic acid-N,O-hydroxyethyl Chitosan with a Sulfhydryl Modification To Enhance the Oral Absorptive Efficiency of Paclitaxel,Molecular Pharmaceutics

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N-Deoxycholic acid-N,O-hydroxyethyl Chitosan with a Sulfhydryl Modification To Enhance the Oral Absorptive Efficiency of Paclitaxel
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-11-08 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00662
Yanfang Yu ₁ , Meirong Huo ₁ , Ying Fu ₁ , Wei Xu ₂ , Han Cai ₁ , Lingling Yao ₁ , Qingyu Chen ₁ , Yan Mu ₂ , Jianping Zhou ₁ , Tingjie Yin ₁

Affiliation

Currently, the most prominent barrier to the success of orally delivered paclitaxel (PTX) is the extremely limited bioavailability of delivered therapeutic. In light of this issue, an amphiphilic sulfhydrylated N-deoxycholic acid-N,O-hydroxyethyl chitosan (TGA-DHC) was synthesized to improve the oral bioavailability of PTX. First, TGA-DHC demonstrated substantial loading of PTX into the inner hydrophobic core. A desirable enhancement in the bioavailability of PTX by TGA-DHC was verified by pharmacokinetic studies on rats against Taxol and non-sulfhydrylated DHC micelles. Moreover, cellular uptake studies revealed significant accumulation of TGA-DHC micelles encapsulating PTX or rhodamine-123 into Caco-2 cells via clathrin/caveolae-mediated endocytosis and inhibition of P-gp efflux of substrates. The results of the Caco-2 transport study further confirmed the mechanistic basis of TGA-DHC efficacy; which was attributed to permeabilized tight junctions, clathrin-mediated transcytosis across the endothelium, and inhibition of P-gp. Finally, in vitro mucoadhesion investigations on freshly excised rat intestine intuitively confirmed increased intestinal retention of drug-loaded TGA-DHC through thiol-mediated mucoadhesion. TGA-DHC has demonstrated the capability to overcome what is perhaps the most prominent barrier to oral PTX efficacy, low bioavailability, and serves as a prominent platform for oral delivery of P-gp substrates.

中文翻译：

N-脱氧胆酸-N，O-羟乙基壳聚糖经巯基修饰可提高紫杉醇的口服吸收效率

目前，口服紫杉醇（PTX）成功的最主要障碍是治疗药物的生物利用度极为有限。鉴于此问题，两亲性巯基化的N-脱氧胆酸-N，O合成了羟乙基壳聚糖（TGA-DHC）以改善PTX的口服生物利用度。首先，TGA-DHC证明PTX大量负载到内部疏水核中。通过针对大鼠的紫杉醇和非巯基化DHC胶束的药代动力学研究，证实了TGA-DHC可提高PTX的生物利用度。此外，细胞摄取研究显示，通过网格蛋白/小泡介导的内吞作用，将PTX或若丹明-123封装的TGA-DHC胶束大量积累到Caco-2细胞中，并抑制了底物的P-gp外排。Caco-2转运研究的结果进一步证实了TGA-DHC功效的机制基础。这归因于通透性紧密连接，网格蛋白介导的跨内皮细胞吞噬作用以及对P-gp的抑制作用。最后，体外对新鲜切除的大鼠肠的粘膜粘附研究直观地证实了通过硫醇介导的粘膜粘附增加了载药的TGA-DHC在肠道中的保留。TGA-DHC已证明有能力克服可能是口服PTX功效最突出的障碍，低生物利用度，并且可以作为口服P-gp底物的重要平台。

更新日期：2017-11-08

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