Original Article
Targeted drug delivery to ischemic stroke via chlorotoxin-anchored, lexiscan-loaded nanoparticles

https://doi.org/10.1016/j.nano.2016.03.005Get rights and content

Abstract

Ischemic stroke is a leading cause of disability and death worldwide. Current drug treatment for stroke remains inadequate due to the existence of the blood–brain barrier. We proposed an innovative nanotechnology-based autocatalytic targeting approach, in which the blood–brain barrier modulator lexiscan is encapsulated in nanoparticles to enhance blood–brain barrier permeability and autocatalytically augment the brain stroke-targeting delivery efficiency of chlorotoxin-anchored nanoparticles. The nanoparticles efficiently and specifically accumulated in the brain ischemic microenvironment and the targeting efficiency autocatalytically increased with subsequent administrations. When Nogo-66 receptor antagonist peptide NEP1-40, a potential therapeutic agent for ischemic stroke, was loaded, nanoparticles significantly reduced infarct volumes and enhanced survival. Our findings suggest that the autocatalytic targeting approach is a promising strategy for drug delivery to the ischemic microenvironment inside the brain. Nanoparticles developed in this study may serve as a new approach for the clinical management of stroke.

Section snippets

Synthesis of PLGA–PLL

Synthesis of PLGA–PLL was accomplished via coupling using dicyclohexyl carbodiimide as previously reported.29, 30, 31 In a typical reaction, PLGA (3 g, 50:50 PLGA Acid End Group; i.v. ~ 0.67 dL/g; Absorbable Polymers: Pelham, AL) and 200 mg poly(ε-carbobenzoxyl-L-lysine) (PLL) in 5 M excess (1000-4000 MW) were dissolved in 6 mL dimethlyformamide in a dry round-bottom flask under argon. Dicyclohexyl carbodiimide (58 mg) and 0.31 mg dimethylaminopyridine were dissolved in 2 mL dimethlyformamide under

Design, synthesis and characterization of NPs

The schematic diagram of a typical PLGA-CTX/LEX NP was illustrated in Figure 1, A. NPs were synthesized through double emulsion procedures using PLL-conjugated PLGA as the starting material. The resulting NPs were modified with NHS-PEG-Mal to display PEG and maleimide functional groups. LEX was encapsulated in NPs during the emulsion with an entrapment efficiency of 33.8% and a loading efficiency of 0.8%. CTX was conjugated to the surface of NPs through the maleimide groups at a ratio of 800

Discussion

In the present study, we proposed an innovative approach for drug delivery to the ischemic microenvironment inside the brain through the combination of the traditional ligand-mediated approach, with a novel autocatalysis mechanism, which is designed to augment delivery efficiency. Our results demonstrated that, the resulting NPs synthesized based on this approach, PLGA-CTX/LEX NPs, efficiently crossed the BBB in the ischemic brain with high specificity. In contrast, NPs engineered either

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  • Cited by (0)

    This work was supported by NIHNS095817, NS095147AHA15GRNT25290018, and a Yale Center for Clinical Investigation CTSA Scholar Award (UL1 TR000142). QC, DT, XG and ZC were partially supported by scholarships from the Chinese Scholarship Council.

    Conflict of interest: S.M.S. is a co-founder of Axerion Therapeutics seeking to develop the Nogo-NogoReceptor-based medicines for Neural Repair, and prion protein-based medicines for Alzheimer disease.

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