Drug delivery of anticancer agents: water soluble 4-poly (ethylene glycol)derivatives of the lignan, podophyllotoxin

This paper reports on the synthesis and in vivo oncolytic activity of a ser ies of water-soluble acyl derivatives of polyethylene glycol (PEG) conjugat ed podophyllotoxin. Some analogs of the polymer conjugate showed significan tly better activity in a murine leukemia model than native podophyllotoxin suspended in an intralipid emulsion. Additionally, when tested intravenousl y against a solid lung tumor (A549) model, some conjugated analogs were equ ivalent to the podophyllotoxin/intralipid emulsion, while those compounds d emonstrating 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 v itro, with those showing faster release possessing greater antitumor activi ty. In conclusion, the solubilization and predictable release of podophyllo toxin from a PEG carrier was achieved and resulted in some derivatives demo nstrating, at a minimum, equivalency with podophyllotoxin when administered on an equal molar basis. Further studies may be warranted to assess the PE G-conjugates pharmacokinetics and therapeutic indices in leukemic models. ( C) 1999 Elsevier Science B.V. All rights reserved.