Engineering triiodothyronine (T3) nanoparticle for use in ischemic brain stroke

Alexander Mdzinarishvili,Vijaykumar Sutariya,Phani K Talasila,Prabodh Sadana,Werner J Geldenhuys

doi:10.1007/s13346-012-0117-8

Alexander Mdzinarishvili, Vijaykumar Sutariya + Show 3 more

Open Access

https://doi.org/10.1007/s13346-012-0117-8

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Abstract

A potential means of pharmacological management of ischemic stroke is rapid intervention using potent neuroprotective agents. Thyroid hormone (T3) has been shown to protect against ischemic damage in middle cerebral artery occlusion (MCAO) model of ischemic brain stroke. While thyroid hormone is permeable across the blood–brain barrier, we hypothesized that efficacy of thyroid hormone in ischemic brain stroke can be enhanced by encapsulation in nanoparticulate delivery vehicles. We tested our hypothesis by generating poly-(lactide-co-glycolide)-polyethyleneglycol (PLGA-b-PEG) nanoparticles that are either coated with glutathione or are not coated. We have previously reported that glutathione coating of PLGA-PEG nanoparticles is an efficient means of brain targeted drug delivery. Encapsulation of T3 in PLGA-PEG delivery vehicle resulted in particles that were in the nano range and exhibited a zeta potential of −6.51 mV (uncoated) or −1.70 mV (coated). We observed that both glutathione-coated and uncoated nanoparticles are taken up in cells wherein they stimulated the expression of thyroid hormone response element driven reporter robustly. In MCAO model of ischemic stroke, significant benefit of administering T3 in nanoparticulate form was observed over injection of a T3 solution. A 34 % decrease in tissue infarction and a 59 % decrease in brain edema were seen upon administration of T3 solution in MCAO stroke model. Corresponding measurements for uncoated T3 nanoparticles were 51 % and 68 %, whereas for the glutathione coated were 58 % and 75 %. Our study demonstrates that using nanoparticle formulations can significantly improve the efficacy of neuroprotective drugs in ischemic brain stroke.

Highlights

Ischemic brain stroke is one of the leading causes of death and disability in major industrialized countries [1]
Visual inspection shows that there is a striking attenuation of the ischemic area in those slices treated with T3 compared with controls
Pre-treatment with T3 resulted in a reduction of focal ischemia by 34 % in comparison to vehicletreated control animals (Fig. 5c)

Summary

Introduction

Ischemic brain stroke is one of the leading causes of death and disability in major industrialized countries [1]. Substantial research efforts are focused on neuroprotective strategies, and a number of neuroprotective agents have been suggested to improve stroke survival and outcome in preclinical studies [3]. A significant impediment to the clinical success of neuroprotective agents has been the efficient delivery of the neuroprotectant agent in high enough local concentrations to exert protective effects [4]. Blood–brain barrier (BBB) poses significant challenges to the permeation of neuroprotective agents that exert their activity at the site of action. Researchers recently have reported success in overcoming BBB using nanoparticle formulations of these drugs. Nanoparticle formulations reported significant improvement of neuroprotective activity of small molecules, endogenous cytokines and proteins [5,6,7]

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