Retinal neuroprotection by controlled release of a VCP inhibitor from self-assembled nanoparticles

Merve Sen; Md Al-Amin; Eva Kicková; Amir Sadeghi; Jooseppi Puranen; Arto Urtti; Paolo Caliceti; Stefano Salmaso; Blanca Arango-Gonzalez; Marius Ueffing

doi:10.1016/j.jconrel.2021.09.039

Retinal neuroprotection by controlled release of a VCP inhibitor from self-assembled nanoparticles

J Control Release. 2021 Nov 10:339:307-320. doi: 10.1016/j.jconrel.2021.09.039. Epub 2021 Oct 2.

Authors

Affiliations

¹ Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany; Graduate Training Centre of Neuroscience, University of Tübingen, Tübingen, Germany.
² Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
³ School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
⁴ School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland; Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
⁵ Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany. Electronic address: blanca.arango-gonzalez@klinikum.uni-tuebingen.de.
⁶ Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany. Electronic address: mue@klinikum.uni-tuebingen.de.

PMID: 34606936
DOI: 10.1016/j.jconrel.2021.09.039

Abstract

Mutations in rhodopsin lead to its misfolding resulting in autosomal dominant retinitis pigmentosa (adRP). Pharmacological inhibition of the ATP-driven chaperone valosin-containing protein (VCP), a molecular checkpoint for protein quality control, slows down retinal degeneration in animal models. However, poor water-solubility of VCP inhibitors poses a challenge to their clinical translation as intravitreal injections for retinal treatment. In order to enable the delivery of VCP inhibitors, we have developed and investigated two formulations for the VCP inhibitor ML240. Nanoformulations of ML240 were obtained by using amphiphilic polymers methoxy-poly (ethylene glycol)_5kDa-cholane (mPEG_5kDa-cholane) and methoxy-poly (ethylene glycol)_5kDa-cholesterol (mPEG_5kDa-cholesterol). Both formulations increased the water-solubility of ML240 by two orders of magnitude and prolonged the drug released over ten days. In addition, encapsulation of ML240 in mPEG_5kDa-cholane showed superior photoreceptor protection at lower drug concentrations, normalized rhodopsin localization, and alleviated inflammatory microglial responses in an ex vivo rat model of retinal degeneration. The study demonstrates the potential of VCP inhibitor nanoformulations to treat adRP, a pharmacologically orphan disease.

Keywords: Drug delivery; Intravitreal injection; Retinal degeneration; Self-assembling polymers; VCP inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Delayed-Action Preparations
Disease Models, Animal
Nanoparticles*
Neuroprotection*
Rats
Retinitis Pigmentosa / drug therapy*
Valosin Containing Protein / antagonists & inhibitors*

Substances

Delayed-Action Preparations
Valosin Containing Protein