Anticancer Activity Driven by Drug Linker Modification in a Polyglutamic Acid-Based Combination-Drug Conjugate
Por:
J. ARROYO-CRESPO, C. DELADRIERE, V. NEBOT, D. CHARBONNIER, E. MASIA, A. PAUL, C. JAMES, A. ARMINAN and M. VICENT
Publicada:
30 may 2018
Resumen:
Combination nanotherapies for the treatment of breast cancer permits synergistic drug targeting of multiple pathways. However, poor carrier degradability, poor synergism of the combined drugs, low drug release regulation, and a lack of control on final macromolecule solution conformation (which drives the biological fate) limit the application of this strategy. The present study describes the development of a family of drug delivery systems composed of chemotherapeutic (doxorubicin) and endocrine therapy (aromatase inhibitor aminoglutethimide) agents conjugated to a biodegradable poly-l-glutamic acid backbone via various linking moieties. Data from in vitro cytotoxicity and drug release assessments and animal model validation select a conjugate family member with optimal biological performance. Exhaustive physicochemical characterization in relevant media (including the study of secondary structure, size measurements, and detailed small-angle neutron scattering analysis) correlates biological data with the intrinsic supramolecular characteristics of the conjugate. Overall, this study demonstrates how a small flexible Gly linker can modify the spatial conformation of the entire polymer-drug conjugate, promote the synergistic release of both drugs, and significantly improve biological activity. These findings highlight the need for a deeper understanding of polymer-drug conjugates at supramolecular level to allow the design of more effective polymer-drug conjugates.
Filiaciones:
:
Ctr Invest Principe Felipe, Polymer Therapeut Lab, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
:
Ctr Invest Principe Felipe, Polymer Therapeut Lab, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
PCAS Canada, 725 Trotter St, St Jean, PQ J3B 8J8, Canada
:
Ctr Invest Principe Felipe, Polymer Therapeut Lab, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
:
Ctr Invest Principe Felipe, Polymer Therapeut Lab, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
Ctr Invest Principe Felipe, Screening Platform, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
:
Ctr Invest Principe Felipe, Polymer Therapeut Lab, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
Ctr Invest Principe Felipe, Screening Platform, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
A. PAUL:
Cardiff Univ, Sch Chem, Main Bldg,Pk Pl, Cardiff CF10 3AT, S Glam, Wales
C. JAMES:
Cardiff Univ, Sch Chem, Main Bldg,Pk Pl, Cardiff CF10 3AT, S Glam, Wales
:
Ctr Invest Principe Felipe, Polymer Therapeut Lab, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
:
Ctr Invest Principe Felipe, Polymer Therapeut Lab, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
Ctr Invest Principe Felipe, Screening Platform, Ave Eduardo Primo Yufera 3, Valencia 46012, Spain
Green Accepted, Hybrid Gold
|