Microfabrication of an Organ-on-a-chip Device to Model Cardiotoxicity Induced by Chemotherapies for Cancer Nanomedicine Evaluation




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Cancer is the leading cause of death worldwide, and more efficient treatments and pre-clinical tests for the evaluation of novel therapies are in high demand. Chemotherapy, as the most common cancer treatment, is facing severe challenges, including low water solubility of anti-cancer drugs and the cardiotoxicity induced by them. Nanotechnology has made significant contributions to the development of drug delivery systems by reducing the toxicities, which leads to improvement in conventional chemotherapies. Chapter 2 describes a micellar drug delivery system's design using benzyl substituted poly(ε-caprolactone) as the hydrophobic block, and co-loaded doxorubicin anticancer drug and quercetin cardioprotective agent to increase the solubility of the anticancer drug in water and reduce the cardiotoxicity induced by the anticancer drug. Oligo(ethylene) glycol substituted poly(ε-caprolactone)s were used as hydrophilic blocks and make the polymer thermoresponsive. Our proposed biodegradable and thermoresponsive micellar DDS can open the door to developing a more effective platform for cancer treatment. Although many therapeutics have been developed so far, the pharmaceutical industry is still facing challenges for drug discovery, which is mostly attributed to the lack of proper pre-clinical testing. In Chapter 3, we try to model the cardiotoxicity induced by anticancer drugs on an organ-on-achip device to improve conventional pre-clinical cell culture. Organ-on-a-chip devices can mimic the whole-body response to therapeutics by fluidically connecting microscale cell cultures and generating a realistic model of human organs of interest. We described a pumpless heart/liver-ona-chip (HLC) using the HepG2 hepatocellular carcinoma cells and H9c2 rat cardiomyocytes to reproduce the cardiotoxicity induced by Doxorubicin (DOX) in vitro. Our designed HLC device represents a unique approach to assess the off-target toxicity of drugs and their metabolites, which will eventually improve current pre-clinical studies.



Microfabrication, Drugs -- Metabolism, Doxorubicin, Drug delivery systems, Thermoresponsive polymers, Critical micelle concentration, Cancer -- Treatment