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Injectable chitosan hydrogels as doxycycline delivery system for abdominal aortic aneurysm treatment

机译：注射用壳聚糖水凝胶作为强力霉素的输送系统，用于治疗腹主动脉瘤

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Introduction: Sac embolization has potential to treat and prevent endoleak after endovascular aneurysm repair (EVAR), but presently commercialized embolizing materials have several drawbacks and lead to frequent recurrence. Previously, our team showed that the endothelial lining, a thin layer of cells at interior surface of blood vessels, has an important role in endoleak persistence and recurrence. A promising strategy consists in developing a sclerosing occlusive agent to be injected by catheter in aneurysm to prevent endoleaks. The injected matrix should present strong mechanical properties after gelation, be biodegradable, induce endothelial denudation but then become biocompatible for allow cell invasion and tissue healing. To that purpose, an injectable radiopaque chitosan-based thermogel containing doxycycline (DOX) was developed. DOX presents sclerosing properties at high concentrations. In addition it is a well-known inhibitor of matrix metalloproteinases (MMPs) a family of zinc endopeptidases responsible for extracellular matrix degradation characterizing aneurysmal pathology. This project's hypothesis is based on two-stage release of the drug from the hydrogel: a fast burst release leading to sclerosing effect and a slow release of the remaining drug giving MMP inhibition properties. Here we report preliminary results of the characterization and optimization of chitosan-hydrogels prepared with three different gelation solutions combined with DOX and a radiopaque agent (lodixanol), in regards to rheological, occlusive and injectability properties, biocompatibility and drug release rate. Methods: CH-DOX and CH gels were prepared by mixing a) a solution of CH dissolved in acidic solution containing lodixanol (GE Healthcare, USA) and b) a solution of gelation agent (BGP0.4M, SHC075MPB04M, SHC075MPB08M) with and without c) a solution containing DOX (Sigma). To increase the stability of DOX in solution, an antioxidant and a stabilizer was added. The gelation kinetic at 37°C was studied by rheology on a Physica MCR301 (Anton Paar). Cytotoxicity was evaluated on L929 fibroblasts and HUVEC, while the injectability through catheter (0.53 mm diameter) and the efficiency to occlude blood flow were evaluated on custom-made in vitro bench tests. Drug release rate was evaluated using an USP apparatus Ⅰ (Distek Dissolution equipment) at 37 °C during 60 hours. Results: All formulations immediately formed gels at physiological pH and body temperature. Adding lodixanol and DOX decelerate gelation, but to some extent increasing PB to 0.08M was able to counteract this effect. This formulation was injectable and immediately blocked the flow up to the maximum pressure generated by the bench system (＞220 mmHg). CH-OOX gels showed a two-stage release, with a burst release within the first 6 hours, followed by slow and continuous release (Fig 1). In vitro cytotoxicity test showed decrease of HUVEC viability for DOX concentrations higher than 1 mg/ml, suggesting that those concentrations could led to a sclerosing effect in vivo. Conclusion: Although further tests are required to confirm the endothelial removal and MMP inhibition effect, CH-DOX gel appears as a promising candidate for aneurysm embolization.
机译：简介：囊内栓塞术具有治疗和预防血管内动脉瘤修复（EVAR）后内漏的潜力，但是目前商业化的栓塞材料存在一些缺点，并导致频繁复发。以前，我们的研究小组表明，内皮内层是血管内表面的一层薄细胞，在内漏持续性和复发中起着重要作用。一项有前途的策略包括开发一种硬化闭塞剂，以通过导管将其注入动脉瘤中以防止内漏。注入的基质在胶凝后应具有很强的机械性能，可生物降解，诱导内皮剥脱，但随后具有生物相容性，可用于细胞浸润和组织愈合。为了这个目的，开发了一种含有多西环素（DOX）的可注射的不透射线的基于壳聚糖的热凝胶。 DOX在高浓度下具有硬化特性。此外，它是基质金属蛋白酶（MMPs）的著名抑制剂，MMPs是锌内肽酶家族，负责细胞外基质降解，表征动脉瘤病理。该项目的假设基于药物从水凝胶中的两阶段释放：快速爆发释放导致硬化作用，而剩余药物释放缓慢则具有MMP抑制特性。在这里，我们就流变学，闭塞性和可注射性，生物相容性和药物释放速率方面，报道了用三种不同的凝胶溶液与DOX和不透射线的试剂（洛地沙酚）组合制备的壳聚糖水凝胶的表征和优化的初步结果。方法：CH-DOX和CH凝胶的制备方法是：将a）溶解于含碘克沙醇的酸性溶液中的CH溶液（GE Healthcare，美国）和b）胶凝剂溶液（BGP0.4M，SHC075MPB04M，SHC075MPB08M）在有和无的情况下进行混合c）含有DOX（Sigma）的溶液。为了增加溶液中DOX的稳定性，添加了抗氧化剂和稳定剂。在Physica MCR301（Anton Paar）上通过流变学研究了在37℃下的胶凝动力学。在L929成纤维细胞和HUVEC上评估了细胞毒性，而在定制的体外实验中评估了通过导管（直径0.53 mm）的可注射性和阻塞血流的效率。使用USP装置Ⅰ（Distek溶出度仪）在37°C下60小时评估药物释放速率。结果：所有制剂均在生理pH和体温下立即形成凝胶。加入碘克沙醇和DOX可以减缓凝胶作用，但在一定程度上将PB增加至0.08M可以抵消这种作用。该制剂是可注射的，可立即阻止流量上升至台式系统产生的最大压力（＞ 220 mmHg）。 CH-OOX凝胶显示了两个阶段的释放，在最初的6个小时内爆发性释放，随后缓慢而连续地释放（图1）。体外细胞毒性试验显示，DOX浓度高于1 mg / ml时，HUVEC活力降低，表明这些浓度可能导致体内的硬化作用。结论：尽管需要进一步的试验来确认内皮细胞的去除和MMP抑制作用，但是CH-DOX凝胶似乎是动脉瘤栓塞的有希望的候选者。

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