The primary objective of this work is the formation and examination of tailored targeted nanoparticles consisting of a dendritic exterior that can be tuned to contain a broad distribution of ligand density and cluster size, and a spacious hydrophobic interior region for cancer drug storage. It is proposed that by creating linear-dendritic block copolymers which can act as amphiphiles in solution, much larger nanostructures than traditional dendrimers can be constructed through the formation of micelles containing N chain aggregates of dendritic species, while the high functional density of the dendrimer system is utilized more efficiently. Mixed micelles of varying ligand density will be used to create unique nanoparticles with variable surface ligand cluster size and density, arranged for optimal binding with the target cell receptor. By crosslinking the interior portion of micelles formed from linear-dendritic diblock copolymers, it will be possible to create stable nanoparticles with exterior surfaces that have unusually dense functionality based on the aggregation number and dendron generation, and large, isolated micelle interior regions which can be designed to undergo biodegradation, thus facilitating drug release following encapsulation. These systems will have larger capacities than dendritic homopolymers, but will be smaller than typical liposomes and microparticles, thus making extravasation and drug permeation more facile. In these studies, the three chosen ligands that will be used to investigate ligand-cluster effects in targeted drug delivery will include folate, which can be used to target cancer tumor cells in the ovary via the folate receptor as an initial evaluation of this system, and galactose, a well characterized saccharide which undergoes binding with the ASGPR protein receptor, known to exhibit high sensitivity to cluster ligand presentation and present on hepatocytes. Finally, as an approach to a directly applicable therapeutic system, the RGD peptide sequences which specifically target the endothelial cells of tumors will be used as a means of directing cytotoxic drugs to the vascular system of the tumor via the alpha-v-beta3 integrin receptor, and thus promoting tumor necrosis via anti-angiogenic approaches.
| Wood, Kris C; Azarin, Samira M; Arap, Wadih et al. (2008) Tumor-targeted gene delivery using molecularly engineered hybrid polymers functionalized with a tumor-homing peptide. Bioconjug Chem 19:403-5 |
