DenTimol as A Dendrimeric Timolol Analogue for Glaucoma Therapy: Synthesis and Preliminary Efficacy and Safety Assessment

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 = 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, H 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.

Polymeric Nanoparticles for Drug Delivery: Recent Developments and Future Prospects

“…They demonstrated that these functionalized NPs were present in the ocular posterior segment after more than 12 h of a non-invasive administration. A dendrimer based on a polyamidoamine was also studied by Lancina et al [ 53 ] In this case, the dendrimeric core was derivatized with a timolol analog, a common drug used for the treatment of ocular hypertension. Their results displayed an intraocular pressure reduction of 30% in normotensive adult Brown Norway male rats, after 30 min of topical application, in addition to the absence of irritation or toxicity after one week of daily administration.…”

A Review on Newer Ocular Drug Delivery Systems with an Emphasis on Glaucoma

“… 141 DenTimol as a dendrimeric timolol analogue for glaucoma therapy is developed by Lancina et al A significant decrease in the IOP (approximately 30% reduction from baseline) is observed 30 minutes after the instillation of the drug topically to Brown Norway male rats, without exhibiting any toxicity. 142 …”

“…Dendrimer based targeted intravitreal therapy for attenuation of neuroinflammation and retinal degeneration using polyamidoamine drug conjugate nanodevice is developed by Iezzi et al The drug (fluocinolone) is released for a period of 90 days from the nanodevice and is observed to be better than the free drug solution 141. DenTimol as a dendrimeric timolol analogue for glaucoma therapy is developed by Lancina et al A significant decrease in the IOP (approximately 30% reduction from baseline) is observed 30 minutes after the instillation of the drug topically to Brown Norway male rats, without exhibiting any toxicity 142.…”

Fundamentals, challenges, and nanomedicine‐based solutions for ocular diseases

“…For ophthalmic drug delivery applications, polyamidoamine (PAMAM)-based dendrimers have been widely explored to improve bioavailability in ocular tissues. Upon topical or intraocular administration, dendrimers have the potential to show an enhanced transport of therapeutic molecules across ocular tissues and prolonged ocular retention of the resultant transported drugs (Iezzi et al, 2012;Lancina, Wang, Williamson, & Yang, 2018;Yavuz et al, 2015). In a study conducted by Yavuz et al (2015), PAMAM dendrimers have shown an improved permeation of dexamethasone (DEX) across ocular tissues in vitro (monolayers of RPE cells), ex vivo (isolated cornea and sclera-choroid-retinal layers of rabbit), and in vivo (Sprague-Dawley rats after topical and subconjunctival applications).…”