Stimuli-responsive biodegradable polymeric micelles for targeted cancer therapy

Abstract

Thermosensitive and biodegradable polymeric micelles based on mPEG-b-pHPMAmLacn have shown very promising results during the past years. The results presented in this thesis illustrate the high potential of these micelles for anticancer therapy and imaging and fully justify further pharmaceutical development to reach clinical trials. For the first time for this system, improved in vivo therapeutic efficacy was shown in tumor-bearing mice. This was achieved by 1) covalent instead of physical entrapment of the anticancer drug in the micellar core though a pH-sensitive hydrazone linker, designed to stably retain the drug linked on the polymer at the neutral pH of the circulation, but release it in the acidic environment of the tumor, as well as in the acidic organelles upon cellular uptake and 2) conjugation of an active targeting anti-EGFR nanobody to the micellar surface, which enhanced their binding and uptake by cancer cells. When the nanobody-modified micelles were combined with covalently entrapped doxorubicin, significantly increased therapeutic effect in tumor-bearing mice was observed compared to the free drug and to non targeted micelles. In addition, an alternative covalent linking strategy was developed, in which the drug was conjugated to the polymer through an enzymatically cleavable linker using click chemistry, followed by micelle formation, and demonstrated very promising in vitro results. Last but not least, an MRI contrast agent was successfully encapsulated, giving rise to further research on micelles as image guided drug delivery systems (‘theranostic system’).