Bio-Inspired and Nanotechnology-Enabled Drug Delivery for Diabetes and Brain Cancer

Nanotechnology-enabled drug delivery systems, inspired by biological processes, were developed to overcome current treatment challenges facing diabetes and cancer patients. Two different systems were developed. The first system, an implantable closed-loop insulin delivery device, utilizes pH-responsive nanoparticles embedded within a glucose-sensing matrix to mimic the physiological delivery of insulin. To prolong implant lifetime we developed a formulation of highly concentrated insulin, up to 80 mg/mL, which maintained excellent insulin stability for up to 30 days under physiological conditions. Moreover, a novel device structure was designed comprising of a microporous membrane that hindered leukocyte migration to the functional implant surface and minimized host inflammatory response. Combining the thermostable insulin formulation and the new device design, long-term closed-loop glycemic control was achieved in Type 1 diabetic rats. The second system is a nanoparticle platform capable of delivering imaging agents and drugs across the blood-brain barrier by mimicking low-density lipoprotein uptake in the brain. We developed this system based on a polysorbate 80-containing terpolymer for improving chemotherapy of metastatic breast cancer disease in the central nervous system. Two nanoparticle formulations were developed: doxorubicin-loaded terpolymer nanoparticles and docetaxel-loaded terpolymer-lipid nanoparticles. Both nanoparticle formulations exhibited high drug loading efficiency, colloidal stability and low systemic toxicity. Parenteral administration of the nanoparticle formulations enabled delivery of blood-brain barrier-impermeable compounds to the brain in healthy mice. Systemic administration of the nanoparticles loaded with clinically relevant doses of drug in brain-tumor bearing mice resulted in drug delivery across the blood-brain barrier to brain metastases of breast cancer and significantly enhanced therapeutic efficacy while minimizing side effects compared to free drug. The nanotechnologies and drug formulations developed in this work present significant progress towards improving therapies for the clinical management of Type 1 diabetes and brain metastases of breast cancer.Ph.D