Abstract
The therapeutic value of various targeted nanomedicines was evaluated in several inflammatory disorders, including cancer, while exploring which nanocarrier may be most suitable for a specific therapeutic application. First, an overview of drug targeting systems presently available for anti-inflammatory therapy was given. Then, the thesis fell apart in three sections:
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two sections diverging the therapeutic scope of several novel and established targeted nanomedicines to various inflammatory diseases and cancer, and a final section to bring these and other efforts together in the quest for the ‘optimal’ nanomedicine for a given application. The first section dealt with the preclinical evaluation of targeted dexamethasone-containing carriers in three different models of inflammatory disease. On the one hand, the therapeutic activity of dexamethasone encapsulated into the aqueous core of long-circulating liposomes was studied in mice with experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), as well as in mice with dextran sodium sulfate (DSS)-induced colitis, a model for inflammatory bowel disease (IBD). Interestingly, the targeted delivery of dexamethasone using long-circulating liposomes was therapeutically efficacious in preclinical models of RA and MS, but not in IBD. On the other hand, a dexamethasone-delivery system based on core-crosslinked polymeric micelles demonstrated strong therapeutic efficacy in two preclinical models of rheumatoid arthritis (RA). The second section focused on the development of new nanomedicines derived from colchicine with vascular disrupting activity. The synthesis, liposomal encapsulation and in vitro characterization of two polymeric prodrugs of colchicine were described, and one of these prodrugs was selected for preclinical evaluation in tumor-bearing mice, to demonstrate a highly efficacious in vivo vascular disrupting activity of this new type of colchicine-derivatives. As part of the third and last section, which addressed the application-oriented search for an optimal nanocarrier system for drug targeting, three different nanocarriers of dexamethasone were evaluated in a comparative study to assess their therapeutic efficacy in two animal models of RA, providing deeper insights in the therapeutic efficacy of each of the systems. Then, to allow for the screening of different nanomedicines without requiring extensive usage of laboratory animals, an in vitro assay for predicting the in vivo circulation kinetics of liposomes was presented. Finally, the thesis concludes with a summarizing discussion regarding the findings presented in this thesis
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