The overall goal of our research is to engineer tissue- and cell-specific nanoparticles containing drugs that overcome limitations of existing technologies used to make sub-micron particulate carriers. The specific goal of this 24-month R21 Research Plan is to demonstrate that targeted solid nanoparticles containing relevant drug molecules can be engineered from novel microemulsion precursors (`nanotemplates') using a rapid, reproducible, and economical process and that these engineered nanoparticles can be targeted to specific tissues and cells in-vivo. Tumor-specific nanoparticles containing gadolinium acetylacetonate (GdAcAc) will be engineered to target to solid tumors for neutroncapture therapy (NCT). Brain-specific nanoparticles containing recombinant nerve growth factor (rNGF) and recombinant glial-derived neurotrophic factor (rGDNF) will be engineered to target the blood-brain barrier to treat or prevent diseases of the brain.
The Specific Aims of the R21 are to: 1) demonstrate that three drug molecules, gadolinium acetylacetonate (GdAcAc), recombinant (3-nerve growth factor (NGF), and recombinant glial-derived neurotrophic factor (GDNF) can be entrapped in nanoparticles (< 100 nm) engineered from microemulsion precursors and that these drug molecules remain stable, 2) Incorporate cell-specific ligands on the surface of the engineered solid nanoparticles for targeting solid tumors (folate) and the brain (choline) and demonstrate cell-specific recognition of targeted nanoparticles either in-vitro or in-situ, and 3) perform in-vivo biodistribution and external gamma scintigraphy studies to demonstrate tissue and cell-specific deposition of radiolabeled nanoparticles containing drug in solid tumors (GdAcAc) and brain (NGF and GDNF). The achievement of Milestones in the R21 phase, particularly those relating to percent tumor uptake of Gd and percent brain uptake of NGF and GDNF after systemic administration, will result in therapeutically relevant concentrations of these molecules in these respective tissues. The 36-month R33 phase will be divided into three therapeutic projects as follows: 1) Therapeutic Effect of Brain-Targeted Nanoparticles Containing NGF or GDNF in the MCAO-Rat Model for Stroke, 2) Therapeutic Effect of Brain-Targeted Nanoparticles Containing GDNF in the MPTP-Mouse Model of Parkinson's Disease, and 3) Neutron Capture Therapy using Tumor-Targeted Gadolinium Nanoparticles in a Mouse Tumor Model. Ideally, data from these therapeutic studies may help to advance these innovative nanotechnologies toward clinical investigation.
