Targeted Delivery of Kinase Inhibitors: A Nanomedicine Approach for Improved Selectivity in Cancer

Isil      Altintas; Raymond      Schiffelers; Robbert      Jan Kok

Abstract

Conventional treatment of cancer is accompanied by severe systemic side effects. As an alternative, targeting only deregulated intracellular pathways that cause proliferation, migration and metastasis are emerging in the field of cancer therapy. Kinase inhibitors are one appealing class of drugs that target specific intracellular pathways. However, kinase inhibitors are not specific in terms of tissue or cellular distribution, and kinase inhibitor therapy can cause serious side effects that are dose-limiting or reason to withdraw the compound from clinical testing. This review will highlight how the selectivity of kinase inhibitors can be improved via a different type of targeted therapy, i.e. by using drug delivery systems that are capable of directing kinase inhibitors specifically to tumor cells. We will explain how so-called nanomedicines obtain specificity for tumor cells and how other mechanisms can contribute to the guiding of the drug delivery system into the tumor tissue. EGFR and VEGFR are two classes of receptor tyrosine kinases that are highly deregulated in almost all cancers, and several effective kinase inhibitors targeted to these pathways have entered the clinic. We will focus on the inhibition of these pathways by analyzing the strategies that combine these kinase inhibitors with drug delivery systems to obtain enhanced tumor-selective effects.

Keywords: Kinase inhibitors, drug targeting, drug delivery systems, intracellular delivery, EGFR, VEGFR, cancer, conjugates, liposomes, microspheres, tyrosine kinase inhibitors, formulation, encapsulation, polymeric particles, nanomedicines, imatinib, erlotinib, wortmannin, curcumin, PTK787, side effects, therapeutic index, coordination chemistry, linker strategies