title: Evaluation of PolyMPC-Dox Prodrugs in a Human Ovarian Tumor Model.
abstract: A polymer prodrug, composed of doxorubicin (Dox) conjugated covalently to poly(methacryloyloxyethyl phosphorylcholine) (polyMPC), was evaluated for the treatment of human ovarian tumors in animals. PolyMPC-Dox prodrugs were prepared using facile conjugation chemistry to yield conjugates soluble in water and injectable saline, with a Dox loading of ∼19 weight percent. Toxicity evaluation showed that polyMPC was well-tolerated in mice at doses up to 800 mg/kg, confirming the biocompatibility of the polymer carrier at a high concentration. Additionally, the polyMPC-Dox prodrug was well-tolerated in animals at a Dox equivalent dose of 10 mg/kg, greater than twice the maximum tolerated dose of free Dox (∼4 mg/kg) in the same mouse strain. In a human ovarian tumor model (SKOV-3), polyMPC-Dox accumulated in tumors at twice the level of free Dox, with no additional off-target organ uptake, a result of improved pharmacokinetics afforded by the prodrug and passive targeting attributed to an enhanced permeability and retention effect. When administered to human ovarian tumor-bearing mice using a recurring dosing regimen comparable to that used clinically, polyMPC-Dox significantly retarded tumor growth relative to treatment with free Dox. Moreover, animals treated with multiple doses of polyMPC-Dox (eight total doses) exhibited enhanced survival, with a notably reduced incidence of toxicity or adverse events relative to mice treated with free Dox. These in vivo results demonstrate advantages of treating human ovarian tumors with polyMPC-Dox, including reduced systemic toxicity, improved drug accumulation in tumors, and enhanced therapeutic efficacy.
authors.affiliation: Pioneer Valley Life Sciences Institute , 3601 Main Street, Springfield, Massachusetts 01199, United States.|Baystate Medical Center , 759 Chestnut Street, Springfield, Massachusetts 01199, United States.
authors.forename: Kaitlyn E
authors.initials: KE
authors.lastname: Wong
authors.affiliation: Pioneer Valley Life Sciences Institute , 3601 Main Street, Springfield, Massachusetts 01199, United States.|Baystate Medical Center , 759 Chestnut Street, Springfield, Massachusetts 01199, United States.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mora
authors.affiliation: Polymer Science & Engineering Department, University of Massachusetts , 120 Governors Drive, Amherst, Massachusetts 01003, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Skinner
authors.affiliation: Polymer Science & Engineering Department, University of Massachusetts , 120 Governors Drive, Amherst, Massachusetts 01003, United States.
authors.forename: Samantha
authors.initials: S
authors.lastname: McRae Page
authors.affiliation: Baystate Medical Center , 759 Chestnut Street, Springfield, Massachusetts 01199, United States.
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Crisi
authors.affiliation: Pioneer Valley Life Sciences Institute , 3601 Main Street, Springfield, Massachusetts 01199, United States.|Baystate Medical Center , 759 Chestnut Street, Springfield, Massachusetts 01199, United States.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Arenas
authors.affiliation: Pioneer Valley Life Sciences Institute , 3601 Main Street, Springfield, Massachusetts 01199, United States.
authors.forename: Sallie S
authors.initials: SS
authors.lastname: Schneider
authors.affiliation: Polymer Science & Engineering Department, University of Massachusetts , 120 Governors Drive, Amherst, Massachusetts 01003, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Emrick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry*; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010767:Phosphorylcholine / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers; D011355:Prodrugs; D010767:Phosphorylcholine; D004317:Doxorubicin
keywords: doxorubicin; drug delivery; ovarian cancer; poly(methacryloyloxyethyl phosphorylcholine); polymer prodrug