Well-Defined Star-Shaped Polyglutamates with Improved Pharmacokinetic Profiles As Excellent Candidates for Biomedical Applications.
There is a need to develop new and innovative polymer carriers to be used as drug delivery systems and/or imaging agents owing to the fact that there is no universal polymeric system that can be used in the treatment of all diseases. Additionally, limitations with existing systems, such as a lack of biodegradability and biocompatibility, inevitably lead to side effects and poor patient compliance. New polymer therapeutics based on amino acids are excellent candidates for drug delivery, as they do not suffer from these limitations. This article reports on a simple yet powerful methodology for the synthesis of 3-arm star-shaped polyglutamic acid with well-defined structures, precise molecular weights (MW), and low polydispersity (Đ = <1.3). These were synthesized by ring-opening polymerization (ROP) of N-carboxyanhydrides (NCA) in a divergent method from novel multifunctional initiators. Herein, their exhaustive physicochemical characterization is presented. Furthermore, preliminary in vitro evaluation in selected cell models, and exhaustive in vivo biodistribution and pharmacokinetics, highlighted the advantages of these branched systems when compared with their linear counterparts in terms of cell uptake enhancement and prolonged plasma half-life.
Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe (CIPF) , Av. Eduardo Primo Yúfera 3, Valencia 46012, Spain.
Aroa
A
Duro-Castano
Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe (CIPF) , Av. Eduardo Primo Yúfera 3, Valencia 46012, Spain.
Richard M
RM
England
Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT , Av. Complutense 40, Madrid 28040, Spain.
David
D
Razola
Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT , Av. Complutense 40, Madrid 28040, Spain.
Eduardo
E
Romero
Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT , Av. Complutense 40, Madrid 28040, Spain.
Marta
M
Oteo-Vives
Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT , Av. Complutense 40, Madrid 28040, Spain.
Miguel Angel
MA
Morcillo
Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe (CIPF) , Av. Eduardo Primo Yúfera 3, Valencia 46012, Spain.
María J
MJ
Vicent
D045744:Cell Line, Tumor / Q000378:metabolism; D002942:Circular Dichroism; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D018613:Microscopy, Confocal; D015394:Molecular Structure; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D058105:Polymerization; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
D011099:Polyglutamic Acid
NCA polymerization; drug delivery; polyglutamates; polymer therapeutics; polypeptides; ring-opening polymerization; star-shaped polymers