Drug targeting to tumors using HPMA copolymers

Abstract

Copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer agents. HPMA copolymers circulate for prolonged periods of time, and by means of the Enhance Permeability and Retention (EPR) effect, they localize to tumors both effectively and selectively. As a consequence, the concentrations of attached active agents in tumors can be increased, and their accumulation in healthy organs and tissues can be attenuated, together resulting in a substantial improvement in the balance between the efficacy and the toxicity of chemotherapy. Taking these notions into account, the aim of the present thesis was to investigate, understand, improve and extend drug targeting to tumors using HPMA copolymers. To provide a proper theoretical framework for investigating drug targeting to tumors using HPMA copolymers, in Chapter 2, the basic principles of passive and active drug targeting are summarized, and several clinically relevant examples of tumor-targeted nanomedicines are highlighted. To better understand drug targeting to tumors, in Chapter 3, the circulation kinetics, the biodistribution and the tumor accumulation of thirteen physicochemically different HPMA copolymers are evaluated. In Chapter 4, based on the notion that HPMA copolymers circulate for prolonged periods of time, a gadolinium-containing contrast agent is developed for MR angiography, i.e. for imaging blood vessels. In Chapter 5, to provide some initial indications in favor of the combination of polymeric nanomedicines with surgery, the impact of intratumoral injection on the biodistribution and the therapeutic potential of HPMA copolymer-based drug delivery systems is investigated. To actively improve passive drug targeting, in Chapter 6, the effects of different doses of radiotherapy and hyperthermia on the tumor accumulation of HPMA copolymers are evaluated. In Chapter 7, drug targeting to tumors using HPMA copolymers is extended, showing both for doxorubicin and for gemcitabine that long-circulating and passively tumor-targeted polymeric drug carriers are able to improve the efficacy of (clinically relevant regimens of) radiochemotherapy. In Chapter 8, using an HPMA copolymer co-functionalized both with doxorubicin and with gemcitabine, evidence is provided showing that polymers, as e.g. liposomes, can be used to deliver two different drugs to tumors simultaneously, and to improve the efficacy of chemotherapy combinations. And finally, in Chapter 9, the insights provided and the evidence obtained are summarized and discussed, and several general conclusions are drawn. Together, the work described in this thesis demonstrates that HPMA copolymers are suitable systems for passive drug targeting to tumors, and that long-circulating and passively tumor-targeted polymeric nanomedicines are suitable systems for improving the efficacy of combined modality anticancer therapy.