This revised competing continuation application proposes a study to evaluate the applicability of the liposome system, using dogs as experimental animals, for the delivery of the two iron chelators: Desferrioxamine (DF), a hydrophilic chelator, and N,N'-bis (2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED), a lipophilic chelator. During the past granting period, we have used large multilamellar liposomes (MLV) of 600 nm in diameter, large unilamellar liposomes (LUV) of 100-160 nm, and small unilamellar liposomes (SUV) of 25-80 nm for in vivo and in vitro studies. We have demonstrated that these liposomes can selectively deliver iron chelators to each of the two major liver cell types, and that liposomes can enhance iron removal from these liver cells. We have also demonstrated that liposomes are an ideal carrier system for lipophilic iron chelators. We now request continued support for further development of the liposome-chelator system.
Our aim i s to find answers to the following specific questions: (1) Can the liposome-chelator system, used as a subcutaneous (s.c.) slow release device, favorably replace the s.c. infusion of the chelator that is currently in clinical use? (2) Does the efficacy of iron removal by the liposome-chelator system require that the chelator be delivered directly into the cells in which iron is stored? In addition, we propose to use mice to continue our in vivo studies on liposome toxicity and in vitro studies on the liposome-cell interactions using the short-term cultures of isolated liver parenchymal cells and macrophages (or Kupffer cells). We also propose to explore the feasibility of using a Superconducting Quantum Interference Device (SQUID) susceptometer to determine the iron content in our experimental samples. The successful application of the liposome system will not only be useful for treatment of iron overload and metal poisonings, but it will also be beneficial for achieving specific delivery of compounds of biological importance into liver cells.
| Ahima, R S; Bjorbaek, C; Osei, S et al. (1999) Regulation of neuronal and glial proteins by leptin: implications for brain development. Endocrinology 140:2755-62 |
| Ahima, R S; Kelly, J; Elmquist, J K et al. (1999) Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia. Endocrinology 140:4923-31 |
