Binding of proteins to PEGylated liposomes and improvement of G-CSF efficacy in mobilization of hematopoietic stem cells.
We have previously shown that formulation of coagulation factor VIII and activated factor VII with PEGylated liposomes (PEGLip) results in an extension of circulation time and an increase in hemostatic efficacy. Here we identified additional proteins that associate with PEGLip, including granulocyte colony-stimulating factor (G-CSF). Surface plasmon resonance analyses indicated that G-CSF bound noncovalently but with high affinity and specificity to PEGLip. A pharmacokinetic study in mice demonstrated that PEGLip formulation of G-CSF extended its circulation time and resulted in higher G-CSF levels several hours after both subcutaneous and intravenous injection. PEGLip-formulated G-CSF had a significantly improved efficacy in the mobilization of hematopoietic stem cells (HSC) from the bone marrow to the peripheral blood. The results suggest that PEGLip-formulated G-CSF may function as an effective and safe tool for the mobilization of HSC prior to bone marrow transplantation. We also identified an amino acid sequence present in proteins that associate with PEGLip but absent from those that do not. A peptide based on this consensus sequence bound PEGLip. The results suggest that PEGLip formulation may serve as a platform for the delivery of additional short-half-life proteins/peptides having the relevant consensus sequence.
Yatuv
Rivka
R
Omri Laboratories Ltd., Weizmann Science Park, Nes-Ziona, Rehovot, Israel.
Carmel-Goren
Lea
L
Dayan
Inbal
I
Robinson
Micah
M
Baru
Moshe
M
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016384:Consensus Sequence; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011092:Polyethylene Glycols / Q000737:chemistry*; D011485:Protein Binding; D011994:Recombinant Proteins
D008081:Liposomes; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols