Immune response to controlled release of immunomodulating peptides in a murine experimental autoimmune encephalomyelitis (EAE) model.
The effects of controlled release on immune response to an immunomodulating peptide were evaluated in a murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). The peptide, Ac-PLP-BPI-NH(2)-2 (Ac-HSLGKWLGHPDKF-(AcpGAcpGAcp)(2)-ITDGEATDSG-NH(2); Ac = acetyl, Acp = epsilon aminocaproic acid) was designed to suppress T-cell activation in response to PLP(139-151), an antigenic peptide in MS. Poly-lactide-co-glycolide (PLGA) microparticles containing Ac-PLP-BPI-NH(2)-2 (8+/-4 microm, 1.4+/-0.2% (w/w)) were prepared by a powder-in oil-in water emulsion-solvent evaporation method, sterilized and administered subcutaneously (s.c.) to SJL/J (H-2(s)) mice in which EAE had been induced by immunization with PLP(139-151). Treatment groups received Ac-PLP-BPI-NH(2)-2: (i) in solution by repeated i.v. or s.c. injection, (ii) in solution co-administered with blank PLGA microparticles, (iii) in solution co-administered with Ac-PLP-BPI-NH(2)-2 loaded microparticles, and (iv) as Ac-PLP-BPI-NH(2)-2 loaded microparticles. Administration of Ac-PLP-BPI-NH(2)-2 as an s.c. solution produced clinical scores and maintenance of body weight comparable to i.v. solution, but with reduced overall survival, presumably due to anaphylaxis. Administration as s.c. microparticles provided a somewhat less effective reduction in symptoms but with no toxicity during treatment. Thus, the results suggest that s.c. administration of Ac-PLP-BPI-NH(2)-2 microparticles can provide pharmacological efficacy and reduction in dosing frequency without increased toxicity.
Zhao
Hong
H
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
Kiptoo
Paul
P
Williams
Todd D
TD
Siahaan
Teruna J
TJ
Topp
Elizabeth M
EM
D000707:Anaphylaxis / Q000139:chemically induced; D000818:Animals; D001835:Body Weight; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D007155:Immunologic Factors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010316:Particle Size; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012995:Solubility; D013499:Surface Properties; D013997:Time Factors
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007155:Immunologic Factors; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid