Development of Drug Delivery Vehicles for Biomedical Applications

Abstract

Polymeric nanoparticles have historically been shown to be valuable tools for the solubilization and delivery of small molecule hydrophobic drugs. However, most systems do not address obstacles associated with off-target effects of the encapsulated drug molecule. Here we present a polyester nanoparticle platform that is capable of targeted delivery of a hydrophobic small molecule drug to a precise location. The developed orthogonal chemistry attachment scheme of ligands to the surface of the particles allows for both targeting peptides and imaging agents to be conjugated to the surface. In this work, this targeted delivery system has been shown to have great success in two separate applications. The first application which has shown great success is the targeting of the beta cells located in the Islets of Langerhans in the pancreas. These cells are responsible for insulin production, and as such are a highly attractive drug target for diabetes treatment. Polyester nanoparticles labeled with Exendin4, a GLP1 agonist, are able to successfully target human islet grafts in vivo, making them a very promising delivery system for the treatment of diabetes. A second application for this nanoparticle platform is in the delivery of naphthofluorescein, an MMP14 inhibitor, specifically to degraded collagen present in unstable arterial plaques. Current therapies aimed at preventing plaque rupture usually involve the systemic administration of broad spectrum metalloproteinase inhibitors, which suffer from multiple side effects and therefore a decreased efficacy. Encapsulation of naphthofluorescein into a nanoparticle structure tagged with a peptide that has specific homing ability towards unstable plaques has been shown to increase the efficacy of the drug by almost 2-fold. Recently, it has been demonstrated that multiple treatments could benefit from the administration of a combination of therapeutics, oftentimes with very different physiochemical properties. Therefore, it follows that there is a need for innovative delivery systems that can provide sustained release of both therapies simultaneously. Here we describe the construction of oxime click hydrogels that have tunable properties for use as a delivery matrix for both bone morphogenetic protein 2, and trametinib loaded polyester nanoparticles. This particular combination treatment has been found to be greatly efficacious for the treatment of bone fractures in individuals affected by neurofibromatosis 1. These hydrogels have great potential as a tailorable delivery system for this particular treatment combination. Another common application for delivery of two or more therapeutics is in the treatment of cancer. Particularly for breast cancer, the administration of anthracycline drugs such as doxorubicin, is common. Doxorubicin has been found to have much higher efficacy when co-delivered with the small molecule formaldehyde than it does alone. Using this combination in a clinical setting requires a delivery system that can co-deliver both the doxorubicin and the formaldehyde at a sustained rate. Here we show the creation of two types of polyglycidol based prodrugs capable of delivering a sustained release of formaldehyde from the backbone. These structures show great promise as pieces of a unique dual delivery system for improved cancer treatment.