title: Drug delivery of anticancer agents: water soluble 4-poly (ethylene glycol) derivatives of the lignan, podophyllotoxin.
abstract: This paper reports on the synthesis and in vivo oncolytic activity of a series of water-soluble acyl derivatives of polyethylene glycol (PEG) conjugated podophyllotoxin. Some analogs of the polymer conjugate showed significantly better activity in a murine leukemia model than native podophyllotoxin suspended in an intralipid emulsion. Additionally, when tested intravenously against a solid lung tumor (A549) model, some conjugated analogs were equivalent to the podophyllotoxin/intralipid emulsion, while those compounds demonstrating slower rates of plasma hydrolysis (in vitro) appeared to cause greater toxicity. There appeared to be an overall correlation between the in vivo antitumor activity of the conjugate and its rate of hydrolysis in vitro, with those showing faster release possessing greater antitumor activity. In conclusion, the solubilization and predictable release of podophyllotoxin from a PEG carrier was achieved and resulted in some derivatives demonstrating, at a minimum, equivalency with podophyllotoxin when administered on an equal molar basis. Further studies may be warranted to assess the PEG-conjugates pharmacokinetics and therapeutic indices in leukemic models.
authors.affiliation: Department of Organic and Medicinal Chemistry, Research and Development, Enzon, Inc., 20 Kingsbridge Road, Piscataway, NJ 08854, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Greenwald
authors.forename: C D
authors.initials: CD
authors.lastname: Conover
authors.forename: A
authors.initials: A
authors.lastname: Pendri
authors.forename: Y H
authors.initials: YH
authors.lastname: Choe
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Guan
authors.forename: Z
authors.initials: Z
authors.lastname: Yao
authors.forename: K L
authors.initials: KL
authors.lastname: Shum
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011034:Podophyllotoxin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014867:Water
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D014867:Water; D011092:Polyethylene Glycols; D011034:Podophyllotoxin