Nanoparticles-based Drug Delivery Systems for Resistant Cancer Treatment
Type of DegreePhD Dissertation
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Many FDA-approved drugs have been repurposed as anticancer agents to fulfill the increasing demand for more effective anti-cancer drugs especially for drug-resistant cancers. Disulfiram (DSF) is an FDA-approved drug which has been used for treating alcoholism for several decades. It was recently found to have promising anticancer effects against multiple types of cancers. Copper diethyldithiocarbamate [Cu(DDC)2] complex formed by DSF and copper ions is a major active ingredient for its anticancer activity. However, efficient drug delivery remains a significant challenge for the clinical use of Cu(DDC)2. In this study, we developed a facile stabilized metal ion ligand complex (SMILE) method to prepare Cu(DDC)2 nanoparticles (NPs). The optimized formulations demonstrated excellent drug loading efficiency, high drug concentration, and optimal particle size. Cu(DDC)2 NPs exhibited outstanding stability in serum and in room temperature storage. The anticancer effects of Cu(DDC)2 NPs were determined by multiple in vitro assays and showed excellent activity against drug-resistant prostate cancer cells and other cancer cells. Our study also demonstrated that Cu(DDC)2 NPs induced cell death in drug resistant prostate cancer cells (DU145-TXR) through paraptosis, which is a non-apoptotic cell death. In addition, metal-organic nanoparticles (MONs) are novel nanomaterials with great potential for drug delivery and other biomedical applications. By using SMILE technology, we developed a series of MONs. We extensively explored the effects of three design parameters (i.e., ligands, metal ions, and stabilizers) on the properties of MONs. These MONs can be used as a versatile delivery system for small molecules and macromolecules. We developed multiple loading strategies to prepared MONs loaded with different payloads of various physiochemical properties. Further, we also prepared biomimetic cell membrane camouflaged MONs with cell membrane from natural killer cells and enhanced MON delivery into tumor cells. Reactive oxygen species (ROS) are the byproducts of physiological metabolism of oxygen. ROS plays a critical role in cell signaling and homeostasis within cells. Tumor cells often showed excessive levels of ROS to promote tumor growth, metastasis, drug resistance. ROS also mediate the crosstalk between tumor cells and tumor associated immune cells to establish an immune suppressive microenvironment. A major challenge of cancer therapy is to specifically target the tumor cells or tumor associated cells while spare the normal cells. The elevated ROS levels in tumors can be exploited to design ROS-responsive therapeutics which can preferentially kill the cancer cells and improve the therapeutic efficacy. Osimertinib (OSI) is the first FDA-approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It can be used for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutation and for patients who are resistant to first-generation EGFR TKIs due to T790M resistance mutation. However, patients treated with OSI ultimately develop acquired resistance, which prevents its long-term benefit for patients. Therefore, the development of effective strategies to overcome OSI resistance will address a significant clinical challenge and benefit patients by prolonging their survival time. In this study, we developed nanoparticle (NP) formulations for co-delivery of osimertinib (OSI) and selumetinib (SEL) to treat OSI-resistant NSCLC effectively. We conjugated SEL with PEG through a reactive oxygen species (ROS)-responsive linker to generate polyethylene glycol (PEG)-SEL conjugate prodrug (PEG-S-SEL). Due to the amphiphilic nature of PEG-S-SEL, it can self-assemble in an aqueous solution to form micelle NP and serve as a delivery carrier for OSI. The ROS-responsive linker can facilitate the release of drugs in the tumor microenvironment with elevated ROS levels. OSI and SEL combination NP can overcome OSI resistance by simultaneously inhibiting both EGFR and mitogen-activated protein kinase (MEK), thus effectively inducing apoptosis in OSI-resistant NSCLC cells and inhibiting OSI-resistant tumors in vivo. In conclusion, the OSI+SEL NP combination therapy showed promising anticancer efficacy and demonstrated potential for treating NSCLC patients with OSI acquired resistance.