Multifunctional Drug and Gene Delivery Nanoparticles for Targeted Cancer Therapy

Drug nanocarriers are of great interest for targeted cancer therapy due to their passive (via the enhanced permeability and retention (EPR) effect) and active (via cell-specific ligand conjugation) tumor-targeting capabilities. Conventional polymer micelles, formed by self-assembly of multiple linear block copolymers, are among the most widely studied nanoplatforms. However, one major limitation with self-assembled multi-molecular polymer micelles is their poor in vivo stability due to the dynamic nature of the self-assembly process. Premature rupture of drug nanocarriers during circulation can cause a burst release of payloads into the bloodstream, which can lead to potential systemic toxicity and loss of tumor-targeting ability, thereby limiting their in vivo applications.;Unimolecular micelles---formed by individual multi-arm star amphiphilic block copolymers---have been investigated to overcome this problem. Because of their covalent nature and unique chemical structure, properly engineered unimolecular micelles can possess excellent in vivo stability. In this dissertation, a multifunctional unimolecular micelle was developed for targeted triple negative breast cancer (TNBC) therapy (Chapter 2). The unimolecular micelles were loaded with aminoflavone (AF; an anticancer drug) and conjugated with GE11, a peptide targeting epidermal growth factor receptor (EGFR), frequently overexpressed in TNBC tumors. These AF-loaded and GE11-conjugated unimolecular micelles induced a tumor regression in an orthotropic TNBC xenograft model. In addition, a unique tumor-targeting upconversion nanoparticle (UCNP)-based unimolecular micelle for simultaneous near-infrared (NIR)-controlled combination chemotherapy and PDT, as well as fluorescence imaging, was developed for neuroendocrine (NE) cancer therapy (Chapter 3). NIR-controlled combination chemotherapy and PDT enabled by these unique UCNP-based theranostic unimolecular micelles were very effective in suppressing the tumor growth of NE cancers.;A better understanding of the genes involved in the tumor development and growth has led to new approaches to treat cancers. RNA interference using small-interfering RNAs (siRNA) has emerged as a new therapeutic to treat cancers and many other diseases. A non-viral tumor-targeted pH/redox dual-responsive unimolecular nanoparticle (NP) was developed for efficient siRNA delivery (Chapter 4). These stimuli-responsive siRNA nanocarriers exhibited excellent gene silencing efficiency with no apparent cytotoxicity. Moreover, a simple UCNP-based siRNA nanoplatform was developed for spatiotemporal gene knockdown by selective NIR irradiation (Chapter 5).