title: 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.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: D Christopher
authors.initials: DC
authors.lastname: Radford
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: jindrich.kopecek@utah.edu.
authors.forename: Jindřich
authors.initials: J
authors.lastname: Kopeček
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002232:Carbocyanines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015251:Epirubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008689:Methacrylates / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D002232:Carbocyanines; D005456:Fluorescent Dyes; D008689:Methacrylates; C089187:cyanine dye 3; C085321:cyanine dye 5; D015251:Epirubicin; C032802:hydroxypropyl methacrylate
keywords: Epirubicin; FRET; N-(2-hydroxypropyl)methacrylamide (HPMA); Ovarian carcinoma