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-Arg2, Lys4]-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.
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ACKNOWLEDGMENTS AND DISCLOSURES
This study was partially supported by a grant (R21-NS066984) from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. We would like to thank Dr. Kevin Cash and Dr. Heather Clark for their assistance with the IVIS imaging studies. We appreciate the help from Seyed Sadjadi and Jenny Wei at Phenomenex with LC/MS/MS analyses. We also thank Ms. Purva Pandya for her assistance with the in vivo studies.
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Shah, L., Gattacceca, F. & Amiji, M.M. CNS Delivery and Pharmacokinetic Evaluations of DALDA Analgesic Peptide Analog Administered in Nano-Sized Oil-in-Water Emulsion Formulation. Pharm Res 31, 1315–1324 (2014). https://doi.org/10.1007/s11095-013-1252-8
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DOI: https://doi.org/10.1007/s11095-013-1252-8