MicroEncapsDelivery · MicroEncapsDelivery

MicroEncapsDelivery

Overview: Angiogenesis is a normal physiological process by which new blood vessels develop from pre-existing ones. The growth and progression of solid tumours depends on their ability to form new vascular networks. Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide with a rising incidence in first world countries. HCC is a highly vascularised cancer that is primarily fed by the hepatic arteries, whereas the normal liver tissue receives most of its blood supply from the portal vein. Therefore, antiangiogenic treatment is very promising in HCC therapy. Transarterial chemoembolization (TACE) with embolic materials such as microbeads or oily contrast medium loaded with drug enables tumour ischemia and necrosis to occur, while it preserves as much of the functional liver tissue as possible. It has the double merit of the cytotoxic effect, via the delivery of drug, and the antivascular effect due to the embolization of the tumour feeding arteries. Although TACE is considered beneficial, local ischemia caused by the treatment causes upregulation of Vascular Endothelial Growth Factor (VEGF), which induces angiogenesis of hepatic residual tumours and eventual relapse. Therefore, combination of TACE with antiangiogenic therapy will be beneficial to the growing number of patients affected by HCC. Aim: In this multidisciplinary research proposal we aimed to develop a new therapeutic platform for hepatocellular carcinoma. Our therapeutic approach encompasses microencapsulation of angiogenesis inhibitors, within biocompatible alginate beads, for their continuous and localised delivery. The overall aim of the project “MicroEncapsDelivery” is the development of alginate microcapsules for the delivery of antiangiogenesis factors, namely sorafenib and cilengitide. Objectives: i) Development of biocompatible alginate microcapsules ii) Successful encapsulation of antiangiogenic therapeutic drugs and investigation of their pharmacokinetic profiles in vitro. iii)Investigation of the antiangiogenic effect in vitro, and iv) Efficiency of the inhibitors in vivo. Approach: Effect of the anti-angiogenic therapeutic drugs in advanced in vitro culture systems, endothelial and tumour cells co-cultures, 3D vascularised tumour models, angiogenesis models and 3D invasion cultures and validation in the chorioallantoic membrane of the chick embryo and in a chemically induced HCC rat model. Results: Alginate beads with tunable size were prepared and used to encapsulate the two angiogenesis inhibitors. Novel 3D vascularised tumour spheroids were developed posing as a promising model for drug-screening and investigation of cell-cell cell-matrix interactions. Effective combination of sorafenib and cilengitide concentrations was identified in in vitro vascularised 3D tumour speroid, organotypic cell culture model, spheroid invasion model, aortic ring assay and 2D cocculture assays and in vivo on the chorioallantoic membrane of the chick embryo. Ongoing experiments will address the role of sorafenib-cilengitide candidate concentrations on chemically induced HCC rat models. Relevance and Impact: Despite the outstanding progress in cancer research, cancer remains one of the world’s most devastating diseases. Sorafenib is the only drug approved by the FDA for the treatment of patients with advanced HCC. Although Sorafenib improves overall survival and time to progression of HCC patients the adverse event rates are still high owing to its toxic side effects. Therefore, the development of microencapsulation-based therapeutic options that allows the localised administration of effective factors to tumours with lower side effects but with higher specificity is of immense societal and economic impact.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз