title: The sustained granulopoietic effect of progenipoietin encapsulated in multivesicular liposomes.
abstract: Progenipoietin (ProGP), a dual receptor agonist of fetal liver tyrosine kinase-3 (flt3) and granulocyte colony-stimulating factor (G-CSF) receptors, has been shown to significantly enhance production of both polymorphonuclear leukocytes and dendritic cells (DCs) in the peripheral blood and spleen of mice, when administered as daily s.c. injections for about 10 days. Here, we have successfully designed a sustained-delivery formulation for this novel chimeric protein using multivesicular liposomes (DepoFoam), and studied the effects of changing both the triglyceride and phospholipid composition of the lipid matrix to modulate its delivery profile. Encapsulation of ProGP in these particles led to retention of its structural integrity, and maintenance of its biological activity in vivo. Administration of a single s.c. dose of 1mg/kg of an optimized DepoProGP formulation in rats, led to significant elevation of absolute neutrophil counts (ANC) that were maintained at levels >10,000 microliter(-1) for 9-11 days, in a reproducible manner. In contrast, administration of the unencapsulated ProGP at the same dose, resulted in elevation of neutrophils by day 1, followed by a quick decline to base line levels by day 3. These data suggest the possibility of administering a single dose of DepoFoam-encapsulated ProGP to improve hematopoietic recovery time after chemotherapy, and for other indications that require multiple daily doses of ProGP.
authors.affiliation: SkyePharma Inc., 10450 Science Center Drive, 92121, San Diego, CA, USA. mysore_ramprasad@skyepharma.com
authors.forename: Mysore P
authors.initials: MP
authors.lastname: Ramprasad
authors.forename: Arjang
authors.initials: A
authors.lastname: Amini
authors.forename: Tugrul
authors.initials: T
authors.lastname: Kararli
authors.forename: Nandini V
authors.initials: NV
authors.lastname: Katre
mesh_terms: D000818:Animals; D002210:Caprylates / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003115:Colony-Stimulating Factors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D003692:Delayed-Action Preparations; D004355:Drug Stability; D006801:Humans; D007279:Injections, Subcutaneous; D007958:Leukocyte Count; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D012995:Solubility; D013499:Surface Properties; D014280:Triglycerides / Q000737:chemistry; D014304:Triolein / Q000737:chemistry
chemical_list: D002210:Caprylates; D003115:Colony-Stimulating Factors; D003692:Delayed-Action Preparations; D008081:Liposomes; C437127:O,O-diethylphosphorylcholine iodide; D010713:Phosphatidylcholines; D011994:Recombinant Proteins; D014280:Triglycerides; C434603:progenipoietin-1; D010767:Phosphorylcholine; D014304:Triolein; C003637:tricaprylin; C017251:1,2-oleoylphosphatidylcholine