FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy.

Abstract

To develop a biodegradable polymeric drug delivery system for the treatment of ovarian cancer with the capacity for non-invasive fate monitoring, we designed and synthesized N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugates. The polymer backbone was labeled with acceptor fluorophore Cy5, while donor fluorophores (Cy3 or EPI) were attached to HPMA copolymer side chains via an enzyme-cleavable GFLG linker. This design allows elucidating separately the fate of the drug and of the polymer backbone using fluorescence resonance energy transfer (FRET). The degradable diblock conjugate (2P-EPI) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization using a bifunctional chain transfer agent (Peptide2CTA). The pharmacokinetics (PK) and therapeutic effect of 2P-EPI (Mw ~100 kDa) were determined in mice bearing human ovarian carcinoma A2780 xenografts. Compared to 1st generation conjugate (P-EPI, Mw <50 kDa), 2P-EPI demonstrated remarkably improved PK such as fourfold terminal half-life (33.22 ± 3.18 h for 2P-EPI vs. 7.55 ± 3.18 h for P-EPI), which is primarily attributed to the increased molecular weight of the polymer carrier. Notably, complete tumor remission and long-term inhibition of tumorigenesis (100 days) were achieved in mice (n=5) treated with 2P-EPI. Moreover, in vitro cell uptake and intracellular drug release were determined via FRET intensity changes. The results establish a solid foundation for future in vivo tracking of drug delivery and chain scission of polymeric conjugates by FRET imaging.

• Authors: Jiyuan Yang, Rui Zhang, D Christopher Radford, Jindřich Kopeček
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 218 Pg. 36-44 (Nov 28 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 26410808 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Carbocyanines
• Fluorescent Dyes
• Methacrylates
• cyanine dye 3
• cyanine dye 5
• Epirubicin
• hydroxypropyl methacrylate

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, chemistry, pharmacology, therapeutic use)
• Carbocyanines (administration & dosage, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Epirubicin (administration & dosage, chemistry, pharmacology, therapeutic use)
• Female
• Fluorescence Resonance Energy Transfer
• Fluorescent Dyes (administration & dosage, chemistry, pharmacology)
• Humans
• Methacrylates (administration & dosage, chemistry, pharmacology, therapeutic use)
• Mice
• Mice, Nude
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Tumor Burden (drug effects)