Targeted inhibition of cancer-inflammation

Abstract

The new paradigm in cancer treatment that aims to inhibit the smoldering inflammatory response in tumors is explored to develop new anticancer treatments. It appears that targeted drug delivery is essential in this concept as high local levels of anti-inflammatory agents are needed to observe the beneficial effects of inflammation inhibition. An overview of classes of anti-inflammatory drugs and drug delivery systems that so far have been studied to treat cancer-inflammation is given. This thesis falls apart in two sections: the first section studies and evaluates the antitumor efficacy of targeted glucocorticoids, whereas the second part focuses on the development and preclinical evaluation of antitumor effects of different anti-inflammatory compounds encapsulated in long-circulating liposomes. In the first section, it is shown that the antitumor effects of liposomal prednisolone phosphate are not limited to tumor-graft models since this potent anti-inflammatory nanomedicine also inhibits tumor growth in a spontaneous mouse tumor model (which more closely resembles the slow progressive chronic inflammatory human disease). When the glucocorticoids is targeted to tumors with core-crosslinked polymeric micelles, the observed antitumor effects do not differ substantially compared to long-circulating liposomes, however the versatility of the polymeric system on drug release profile may assist on the optimization of glucocorticoids release for maximal antitumor effect. In the second section of this thesis, liposomal formulations of different natural (resveratrol, caffeic acid, pterostilbene, carvacrol, etc) or synthetic (pravastatin) anti-inflammatory compounds were developed, characterized and evaluated for antitumor efficacy. Interestingly, only targeted nanomedicines of multi-targeted and potent anti-inflammatory compounds seem to induce antitumor effects in experimental tumor models. The targeted delivery of anti-inflammatory drugs to tumors as anticancer strategy is more complex that foreseen at the outset of these studies and involves several critical factors that have been pinpointed with these studies. Finally, the findings presented in this thesis and suggestions for future work are discussed in a final summarizing discussion.