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Polymer-doxycycline conjugates as fibril disrupters: An approach towards the treatment of a rare amyloidotic disease

Conejos-Sanchez, Inmaculada, Cardoso, Isabel, Oteo-Vives, Marta, Romero-Sanz, Eduardo, Paul, Alison, Ruiz Sauri, Amparo, Morcillo, Miguel A., Saraiva, Maria J. and Vicent, María J. 2015. Polymer-doxycycline conjugates as fibril disrupters: An approach towards the treatment of a rare amyloidotic disease. Journal of Controlled Release 198 , pp. 80-90. 10.1016/j.jconrel.2014.12.003

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Abstract

The term amyloidosis describes neurological diseases where an abnormal protein is misfolded and accumulated as deposits in organs and tissues, known as amyloid, disrupting their normal function. In the most common familial amyloid polyneuropathy (FAP), transthyretin (TTR) displays this role primarily affecting the peripheral nervous system (PNS). Advanced stages of this inherited rare amyloidosis, present as fibril deposits that are responsible for disease progression. In order to stop disease progression, herein we designed an efficient family of nanoconjugates as fibril disrupters. These polymer conjugates are based on doxycycline (doxy), already in phase II trials for Alzheimer's disease, covalently linked to poly-l-glutamic acid (PGA). The conjugates were rationally designed, looking at drug loading and drug release rate by adequate linker design, always considering the physiological conditions at the molecular target site. Conjugation of doxycycline exhibited greater potential towards TTR fibril disaggregation in vitro compared to the parent drug. Exhaustive physico-chemical evaluation of these polymer-drug conjugates concluded that drug release was unnecessary for activity, highlighting the importance of an appropriate linker. Furthermore, biodistribution studies through optical imaging (OI) and the use of radiolabelled polymer-drug conjugates demonstrated conjugate safety profile and renal clearance route of the selected PGA-doxy candidate, settling the adequacy of our conjugate for future in vivo evaluation. Furthermore, preliminary studies in an FAP in vivo model at early stages of disease development showed non-organ toxicity evidences. This nanosized-system raises a promising treatment for advanced stages of this rare amyloidotic disease, and also presents a starting point for possible application within other amyloidosis-related diseases, such as Alzheimer's disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Uncontrolled Keywords: Amyloid disrupters; Drug delivery; Polymer therapeutics; Polymer-drug conjugate; Polymeric drug; Rare diseases
Publisher: Elsevier
Date of Acceptance: 2 December 2014
Last Modified: 04 Jun 2017 08:13
URI: http://orca-mwe.cf.ac.uk/id/eprint/74405

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