New treatments for radiation injury to the GI-tract are desperately needed to ensure survival after exposure to ionizing radiation arising from accident, nuclear warfare, or terrorist attacks (dirty bombs). Radiation-injuries to the hematopoietic system and the GI-tract are fatal, with the latter more acutely fatal. No treatment is available fo the more acute lethality of intestinal dysfunction due to practical and technical challenges in delivering a sustain dose of promising, but unstable, growth factors that can significantly stop the radiation damage-cascade and accelerate recovery of the intestinal cell function. PharmaIN developed a new drug delivery nanotechnology called protected graft co-polymer (PGC) that can be used in a single subcutaneous (s.c.) or intravenous (i.v.) injection of PGC-drug complex that acts as a drug reservoir and releases active drugs when the amount of free drug in the blood decreases, providing an apparent half-life increase of 50- 600 fold. The complex is shielded from elimination by the reticulo-endothelial system and by serum proteases and is large enough to escape from glomerular clearance. The complex also accumulates at sites with increased vascular permeability such as damaged intestine, thus potentially maximizing their efficacy. This application proposes to formulate of two promising agents, FGF-4 and FGF-7, into various PGCs and will test these formulations in vitro. Selected formulations will be tested in vivo for their ability to increase survival when administered 24-72 hours after lethal radiation exposure.
Aim 1 will focus on the design, synthesis, and purification of candidate PGCs for FGF4 and FGF7.
Aim 2 will focus on the determination of complex formulation efficiency (dissociation constant or Kd) between various PGCs and FGFs and to pick the most suitable PGCs.
Aim 3 will focus on the determination of: 3a) the pharmacokinetic profiles of PGC-FGF4 and PGC-FGF7, and 3b) their corresponding maximum tolerated MTD dose in C57BL/6 mice, and the production of sufficient amounts of selected formulations for the animal study in aim 4.
Aim 4 will test the efficacy of PGC-FGFs in extending survival from an LD50/6 radiation dose when administered 24 to 72 hours after the radiation dose. One of the long term goals of PharmaIN is to manufacture a potent self-administered injectable composition for radiation injury that can be used in civil emergency situations. PharmaIN Corp Confidential
This application proposes to formulate of two promising agents into various nanocarriers for in vitro testing. Selected formulations will be tested in vivo for their ability to increase survival hen administered 24-72 hours after a lethal radiation exposure. At the end of the project, we expect to have a working formulation from which data supporting an IND application can be collected. PharmaIN Corp Confidential