期刊
JOURNAL OF CONTROLLED RELEASE
卷 327, 期 -, 页码 584-594出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2020.09.005
关键词
Peptide; Conjugate; Dexamethasone; Drug delivery; Retinal pigment epithelium; Intravitreal; Pharmacokinetics
资金
- European Union MCSA-ITN programme (OCUTHER project) [722717]
- Business Finland [5734/31/2016]
- Academy of Finland [311122]
- Marie Curie Actions (MSCA) [722717] Funding Source: Marie Curie Actions (MSCA)
- Academy of Finland (AKA) [311122, 311122] Funding Source: Academy of Finland (AKA)
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.
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