Lipa Shah1, Florence Gattacceca, Mansoor M Amiji. 1. Department of Pharmaceutical Sciences, School of Pharmacy Bouvé College of Health Sciences, Northeastern University, Boston, MA, 02115, USA.
Abstract
PURPOSE: Although neuro-active peptides are highly potent as central nervous system (CNS) therapeutics, their systemic delivery across the blood-brain barrier (BBB) is limited due to lack of permeability in the brain and rapid systemic metabolism. In this study, we aimed at enhancing the brain delivery and stability of chemically modified [D-Arg(2), Lys(4)]-dermorphin-(1-4)-amide)] (DALDA) peptide to achieve prolonged analgesic effects. METHODS: The C8-DALDA peptide analog was encapsulated in an oil-in-water nanoemulsion formulation made specifically with oils rich in omega-3 rich polyunsaturated fatty acid (PUFA) to enhance CNS availability. The nanoemulsion formulation was administered systemically in CD-1 mice and qualitative and quantitative biodistribution was evaluated. We have also examined the effect of curcumin, which is known to down-regulate efflux transporters and inhibit systemic metabolism, on the pharmacokinetic properties of the peptide. RESULTS: Qualitative and quantitative biodistribution and pharmacokinetic studies in mice clearly demonstrated improved plasma and brain exposure of modified DALDA when administered in nanoemulsion, thereby providing an exciting opportunity towards improved efficacy and/or lowered dose of the peptide. The various dosing regimens tested for modified DALDA solution and curcumin nanoemulsion directed towards a novel combination strategy for improved systemic delivery of peptides across the BBB. CONCLUSIONS: Encapsulation of the drug in PUFA nanoemulsion is an effective strategy for delivery of peptides. This work provides a novel combination strategy for improved delivery of peptides to the brain.
PURPOSE: Although neuro-active peptides are highly potent as central nervous system (CNS) therapeutics, their systemic delivery across the blood-brain barrier (BBB) is limited due to lack of permeability in the brain and rapid systemic metabolism. In this study, we aimed at enhancing the brain delivery and stability of chemically modified [D-Arg(2), Lys(4)]-dermorphin-(1-4)-amide)] (DALDA) peptide to achieve prolonged analgesic effects. METHODS: The C8-DALDA peptide analog was encapsulated in an oil-in-water nanoemulsion formulation made specifically with oils rich in omega-3 richpolyunsaturated fatty acid (PUFA) to enhance CNS availability. The nanoemulsion formulation was administered systemically in CD-1mice and qualitative and quantitative biodistribution was evaluated. We have also examined the effect of curcumin, which is known to down-regulate efflux transporters and inhibit systemic metabolism, on the pharmacokinetic properties of the peptide. RESULTS: Qualitative and quantitative biodistribution and pharmacokinetic studies in mice clearly demonstrated improved plasma and brain exposure of modified DALDA when administered in nanoemulsion, thereby providing an exciting opportunity towards improved efficacy and/or lowered dose of the peptide. The various dosing regimens tested for modified DALDA solution and curcumin nanoemulsion directed towards a novel combination strategy for improved systemic delivery of peptides across the BBB. CONCLUSIONS: Encapsulation of the drug in PUFA nanoemulsion is an effective strategy for delivery of peptides. This work provides a novel combination strategy for improved delivery of peptides to the brain.
Authors: Guoxiang Shen; Changjiang Xu; Rong Hu; Mohit R Jain; Avantika Gopalkrishnan; Sujit Nair; Mou-Tuan Huang; Jefferson Y Chan; Ah-Ng Tony Kong Journal: Mol Cancer Ther Date: 2006-01 Impact factor: 6.261
Authors: H H Szeto; J L Lovelace; G Fridland; Y Soong; J Fasolo; D Wu; D M Desiderio; P W Schiller Journal: J Pharmacol Exp Ther Date: 2001-07 Impact factor: 4.030