Strategies to overcome barriers for cancer (nano)medicines

Research output: ThesisPhD Thesis - Research UT, graduation UT

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Abstract

An increasing number of studies have revealed that the tumor microenvironment conveys signals to tumor cells to acquire resistance against chemotherapy [1-5]. 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 [6-9]. 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 [1].

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.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Twente
Supervisors/Advisors
  • Prakash, J., Supervisor
  • Storm, G. , Supervisor
  • Hennink, Wim E., Supervisor, External person
Award date24 May 2023
Place of PublicationEnschede
Publisher
Print ISBNs978-90-365-5615-6
Electronic ISBNs978-90-365-5616-3
DOIs
Publication statusPublished - 24 May 2023

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