STRATEGIES TO OVERCOME BARRIERS FOR CANCER (NANO)MEDICINES
Dwi Lestari Priwitaningrum is a PhD student in the department of Advanced Organ bioengineering and Therapeutics, TechMed Centre. Supervisors are prof.dr. J. Prakash and prof.dr. G. Storm from the faculty of Science and Technology and prof.dr.ir. W.E. Hennink from Utrecht University.
An increasing number of studies have revealed that the tumor microenvironment conveys signals to tumor cells to acquire resistance against chemotherapy. Development of resistance is an intrinsic feature and is induced via multiple mechanisms such as overexpression of membrane drug transporters, altered DNA repair mechanisms and inhibition of pro-apoptotic mechanisms. Furthermore, many solid tumors undergo desmoplasia i.e., formation of fibrotic stromal tissue composed of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) constituents. ECM constituents are fibrous proteins such as collagen, elastin, and reticulin; link proteins such as fibronectin and laminin; as well as space filling molecules (proteoglycans, glycosaminoglycans). CAFs and ECMs together form a dense network that acts as a barrier for penetration of chemotherapeutic drugs and drug-loaded nanoparticles, thereby negatively affecting therapeutic efficacy.
In this thesis, we studied strategies to overcome the above-mentioned barriers that hinder the efficacy of chemotherapeutics either in free form or after encapsulation in nanoparticles. Two crucial barriers studied in this thesis are the following: (i) activation of an anti-apoptotic mechanism in cancer cells; (ii) formation of stroma hindering nanomedicine penetration into tumors. To overcome the resistance towards chemotherapeutics, the anti-apoptosis pathway was inhibited with a peptide delivered intracellularly using nanoparticles and combined with chemotherapeutic agents. Furthermore, a stroma-rich 3D spheroid model was developed and characterized and used to study the penetration and anti-tumor effects of drug-loaded nanoparticles.
