title: Polymer-doxycycline conjugates as fibril disrupters: an approach towards the treatment of a rare amyloidotic disease.
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.
authors.affiliation: Polymer Therapeutics Lab., Centro de Investigación Príncipe Felipe (CIPF), Av. Eduardo Primo Yúfera 3, Valencia 46012, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Conejos-Sánchez
authors.affiliation: Instituto de Biología Molecular e Celular (IBMC), Rua do Campo Alegre 823, Porto 4150-180, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Cardoso
authors.affiliation: Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT, Av. Complutense 40, Madrid 28040, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Oteo-Vives
authors.affiliation: Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT, Av. Complutense 40, Madrid 28040, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Romero-Sanz
authors.affiliation: School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Paul
authors.affiliation: Pathology Department, University of Valencia, Blasco Ibáñez 15, Valencia 46010, Spain.
authors.forename: Amparo Ruiz
authors.initials: AR
authors.lastname: Sauri
authors.affiliation: Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT, Av. Complutense 40, Madrid 28040, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Morcillo
authors.affiliation: Instituto de Biología Molecular e Celular (IBMC), Rua do Campo Alegre 823, Porto 4150-180, Portugal.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Saraiva
authors.affiliation: Polymer Therapeutics Lab., Centro de Investigación Príncipe Felipe (CIPF), Av. Eduardo Primo Yúfera 3, Valencia 46012, Spain. Electronic address: mjvicent@cipf.es.
authors.forename: María J
authors.initials: MJ
authors.lastname: Vicent
mesh_terms: D000682:Amyloid / Q000187:drug effects; D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy*; D000818:Animals; D004195:Disease Models, Animal; D004318:Doxycycline / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D065546:Drug Liberation; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010949:Plasma / Q000737:chemistry; D011099:Polyglutamic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000682:Amyloid; D011099:Polyglutamic Acid; D004318:Doxycycline
keywords: Amyloid disrupters; Drug delivery; Polymer therapeutics; Polymer-drug conjugate; Polymeric drug; Rare diseases