Faculty Collaboration Database

DenTimol as A Dendrimeric Timolol Analogue for Glaucoma Therapy: Synthesis and Preliminary Efficacy and Safety Assessment. Mol Pharm 2018 Jul 02;15(7):2883-2889

Date

05/17/2018

Pubmed ID

29767982

Pubmed Central ID

PMC6075655

DOI

10.1021/acs.molpharmaceut.8b00401

Scopus ID

2-s2.0-85047385960 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

In this work, we report the synthesis and characterization of DenTimol, a dendrimer-based polymeric timolol analog, as a glaucoma medication. A timolol precursor ( S)-4-[4-(oxiranylmethoxy)-1,2,5-thiadiazol-3-yl]morpholine (OTM) was reacted with the heterobifunctional amine polyethylene glycol acetic acid (amine-PEG-acetic acid, M_n = 2000 g/mol) via a ring opening reaction of an epoxide by an amine to form the OTM-PEG conjugate. OTM-PEG was then coupled to an ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimer G3 to generate DenTimol using the N-(3-(dimethylamino)propyl)- N'-ethylcarbodiimide hydrochloride (EDC)/ N-hydroxysuccinimide (NHS) coupling reaction. MALDI mass spectrometry, ¹H NMR spectroscopy, and HPLC were applied to characterize the intermediate and final products. Ex vivo corneal permeation of DenTimol was assessed using the Franz diffusion cell system mounted with freshly extracted rabbit cornea. The cytotoxicity of DenTimol was assessed using the WST-1 assay. Our results show that DenTimol is nontoxic up to an OTM equivalent concentration of 100 μM. DenTimol is efficient at crossing the cornea. About 8% of the dendrimeric drug permeated through the cornea in 4 h. Its IOP-lowering effect was observed in normotensive adult Brown Norway male rats. Compared to the undosed eye, an IOP reduction by an average of 7.3 mmHg (∼30% reduction from baseline) was observed in the eye topically treated with DenTimol (2 × 5 μL, 0.5% w/v timolol equivalent) in less than 30 min. Daily dosing of DenTimol for a week did not cause any irritation or toxicity as confirmed by the histological examination of ocular tissues, including the cornea, ciliary body, and retina.

Author List

Lancina MG 3rd, Wang J, Williamson GS, Yang H

Author

Hu Yang PhD Chair, Professor in the Biomedical Engineering department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3T3 Cells
Administration, Ophthalmic
Animals
Antihypertensive Agents
Cornea
Dendrimers
Drug Carriers
Drug Compounding
Drug Evaluation, Preclinical
Ethylenediamines
Glaucoma
Intraocular Pressure
Male
Mice
Models, Animal
Ophthalmic Solutions
Permeability
Rabbits
Rats
Rats, Inbred BN
Timolol