当前位置: X-MOL 学术Eur. J. Pharm. Biopharm. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Collagenase loaded chitosan nanoparticles for digestion of the collagenous scar in liver fibrosis: The effect of chitosan intrinsic collagen binding on the success of targeting.
European Journal of Pharmaceutics and Biopharmaceutics ( IF 4.4 ) Pub Date : 2020-01-13 , DOI: 10.1016/j.ejpb.2020.01.003
Sara El-Safy 1 , Salma N Tammam 1 , Mohammad Abdel-Halim 2 , Mohamed E Ali 3 , John Youshia 4 , Maryam A Shetab Boushehri 5 , Alf Lamprecht 6 , Samar Mansour 1
Affiliation  

A variety of hepatic insults result in the accumulation of collagen-rich new extracellular matrix in the liver, ultimately culminating in liver fibrosis and cirrhosis. For such reasons, approaches looking into digestion of the collagen-rich extracellular matrix present an interesting therapeutic approach for cases of chronic liver disease, where the fibrotic scar is well established. Portal collagenase administration has recently led to the successful reversion of cirrhosis in an experimental rabbit model. Notwithstanding, the question of how such a sensitive therapeutic macromolecule could be administered in a less invasive manner, and in a way that preserves its functionality and avoids digestion of other non-hepatic vital collagen presents itself. Chitosan is a biodegradable polymer that has been reported to interact and bind to collagen. Chitosan nanoparticles (CS NPs) have also been reported to encapsulate therapeutic proteins, maintaining their functional form and protecting them from in-vivo degradation. For such reasons, CS NPs were loaded with collagenase and evaluated in-vitro and in-vivo for their ability to target and digest collagen. CS NPs were able to encapsulate collagenase (≈ 60% encapsulation efficiency) and release its content in active form. To determine whether chitosan's collagen interaction would enable NP collagen binding or whether the modification with collagen binding peptides (CBPs) is necessary, CS NPs were modified with the CBP; CCQDSETRTFY. Since the density of targeting ligand and the length of tether play a significant role in the success of active targeting, the surface of NPs was modified with different densities of the CBP either directly or using a polyethylene glycol (PEG) spacer. PEGylated NPs showed higher levels of CBP tagging; high, intermediate and low density of CBPs corresponded to 585.8 ± 33, 252.9 ± 25.3 and 56.5 ± 8.8 µg/mL for PEGylated NPs and 425.56 ± 12.67, 107.91 ± 10.3 and 49.86 ± 3.2 µg/mL for unPEGylated NPs, respectively. In-vitro collagen binding experiments showed that unmodified CS NPs were able to bind collagen and that modification with CBPs either directly or via PEG did not enhance collagen binding. In-vivo experiments demonstrated that unmodified CS NPs were able to reverse fibrosis with a survival rate of 100% at the end of the study, indicating the ability of CS NPs to deliver functional collagenase to the fibrotic liver and making the use of CBPs unnecessary.

中文翻译:

负载胶原酶的壳聚糖纳米颗粒可消化肝纤维化中的胶原疤痕:壳聚糖固有胶原结合对靶向成功的影响。

各种肝损伤导致富含胶原的新细胞外基质在肝脏中积累,最终导致肝纤维化和肝硬化。由于这些原因,研究富含胶原的细胞外基质的消化的方法为慢性肝病的病例提供了一种有趣的治疗方法,其中已充分确定了纤维化疤痕。最近,在实验兔模型中,门脉胶原酶的施用已成功治愈肝硬化。尽管如此,如何敏感地治疗性大分子如何以较小的侵入性方式施用以及如何保持其功能性并避免其他非肝重要胶原的消化的问题本身还是存在的问题。壳聚糖是一种可生物降解的聚合物,据报道可与胶原蛋白相互作用并结合。还已经报道了壳聚糖纳米颗粒(CS NPs)封装治疗性蛋白质,维持其功能形式并保护它们免受体内降解。由于这些原因,CS NPs装有胶原酶,并在体内和体外评估了其靶向和消化胶原蛋白的能力。CS NP能够包裹胶原酶(约60%的包裹效率)并以活性形式释放其含量。为了确定壳聚糖的胶原蛋白相互作用是否能够使NP胶原蛋白结合或是否需要使用胶原蛋白结合肽(CBPs)进行修饰,CS NPs已通过CBP进行了修饰。CCQDSETRTFY。由于靶向配体的密度和系链的长度在主动靶向成功中起着重要作用,可以直接或使用聚乙二醇(PEG)间隔物以不同密度的CBP修饰NPs的表面。PEG化的NPs显示出更高水平的CBP标签;CBP的高,中和低密度分别对应于PEG化NP的585.8±33、252.9±25.3和56.5±8.8 µg / mL,未PEG化NP的分别为425.56±12.67、107.91±10.3和49.86±3.2 µg / mL。体外胶原蛋白结合实验表明,未修饰的CS NPs能够结合胶原蛋白,并且直接或通过PEG用CBP修饰不会增强胶原蛋白的结合。体内实验表明,未修饰的CS NPs能够逆转纤维化,在研究结束时生存率为100%,这表明CS NPs将功能性胶原酶递送至纤维化肝脏的能力,使CBP的使用成为不必要。
更新日期:2020-01-13
down
wechat
bug