Release of functional dexamethasone by intracellular enzymes: A modular peptide-based strategy for ocular drug delivery

JOURNAL OF CONTROLLED RELEASE

卷:327

Article

Bhattacharya, Madhushree^1,2  Sadeghi, Amir²  Sarkhel, Sanjay¹  Hagstrom, Marja¹  Bahrpeyma, Sina^1,2  Toropainen, Elisa²  Auriola, Seppo²  Urtti, Arto^1,2,3 

[1] Univ Helsinki, Div Pharmaceut Biosci, Drug Res Programme, Helsinki, Finland

[2] Univ Eastern Finland, Sch Pharm, Kuopio, Finland

[3] St Petersburg State Univ, Inst Chem, Peterhoff, Russia

关键词: Peptide;    Conjugate;    Dexamethasone;    Drug delivery;    Retinal pigment epithelium;    Intravitreal;    Pharmacokinetics;   

DOI  :  10.1016/j.jconrel.2020.09.005

来源: Elsevier

【 摘 要 】

Tissue barriers limit drug delivery in the eye. Therefore, retinal diseases are treated with intravitreal injections. Delivery systems with reduced dosing frequency and/or cellular drug delivery properties are needed. We present here a modular peptide-based delivery system for cell targeted release of dexamethasone in the retinal pigment epithelial cells. The peptide-dexamethasone conjugates consist of cell penetrating peptide, enzyme cleavable linker and dexamethasone that is conjugated with hydrazone bond. The conjugates are chemically stable in the vitreous, internalize into the retinal pigment epithelial cells and release dexamethasone intracellularly by enzymatic action of cathepsin D. In vitro binding assay and molecular docking confirm binding of the released dexamethasone fragment to the human glucocorticoid receptor. In vivo rabbit studies show increased vitreal retention of dexamethasone with a peptide conjugate. Modular peptide conjugates are a promising approach for drug delivery into the retinal cells.

【 授权许可】

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