title: Penetratin, a potentially powerful absorption enhancer for noninvasive intraocular drug delivery.
abstract: Intraocular drug delivery is extraordinarily hampered by the impermeability of defensive barriers of the eye. In this study, the ocular permeability of fluorophore-labeled cell-penetrating peptides (CPPs), including penetratin, TAT, low molecular weight protamine, and poly(arginine)8, was investigated based on multilevel evaluations. The human conjunctival epithelial cell (NHC) was exposed to various CPPs to determine the cytotoxicity and cellular uptake. Ex vivo studies with rabbit cornea were performed using side-by-side diffusion chambers to evaluate the apparent permeability coefficients and acute tissue tolerance of the CPP candidates. Among all examined CPPs, penetratin shows an outstanding cellular uptake, by increasing more than 16 and 25 times at low and high concentrations, compared to the control peptide poly(serine)8 respectively. Additionally, the permeability of penetratin across excised cornea is 87.5 times higher in comparison with poly(serine)8. More importantly, after instilled in the conjunctival sac of rat eyes, fluorophore-labeled penetratin displayed a rapid and wide distribution in both anterior and posterior segment of the eye, and could be observed in the corneal epithelium and retina lasting for at least 6 h. Interestingly, penetratin showed the lowest ocular cell and tissue toxicities among all examined CPPs. The high ocular permeability of penetratin could be attributed to its amphipathicity and spatial conformation determined by circular dichroism. Taken together, these data demonstrate that penetratin is potentially useful as an absorption enhancer for intraocular drug delivery.
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education; Department of Pharmaceutics, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors: Chang
authors: C
authors: Liu
authors: Lingyu
authors: L
authors: Tai
authors: Wenjian
authors: W
authors: Zhang
authors: Gang
authors: G
authors: Wei
authors: Weisan
authors: W
authors: Pan
authors: Weiyue
authors: W
authors: Lu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D057846:Cell-Penetrating Peptides; D002478:Cells, Cultured; D002942:Circular Dichroism; D003315:Cornea / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D065587:Ocular Absorption / Q000187:drug effects*; D010539:Permeability; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; C414409:penetratin