Controlled release of 4‐hydroperoxycyclophosphamide from the fatty acid dimer‐sebacic acid copolymer

Kwame G. Buahin, Kevin D. Judy, Carol Hartke, Abraham J. Domb, Manoj Maniar, O. Michael Colvin, Henry Brem

Research output: Contribution to journalArticle

Abstract

Controlled polymeric release of chemotherapeutic agents has shown promise in the management of malignant gliomas. 4‐Hydroperoxycyclophosphamide (4HC), loaded on the fatty acid dimer–sebacic acid copolymer (FAD:SA, 1:1), significantly prolonged survival in rats implanted with F98 and 9L gliomas. Here, we studied the in vitro and in vivo release kinetics in phosphate‐buffered saline and rat brain of 20% 4HC/FAD:SA (wt:wt), the optimal dose for treatment of rat gliomas. In vitro release under infinite sink conditions was steady over the initial 12 hr to a peak of 20–35% of impregnated drug, consistent with early phase control via surface erosion. Release over the next 3 weeks was minimal, consistent with barrier formation around the polymer by an oily fatty acid dimer degradation product and consequent slowing of release. However, the polymer started to disintegrate by day 4, and there were minimal visible remnants by 3 weeks. Thus, a considerable amount of polymer‐carried drug was probably lost in the disintegrating fragments. Also, drug loss is expected from its inherent hydrolytic instability. In vivo release into brain revealed two peak levels of drug at 0–1 hr and 5–20 days. With loaded polymer implanted intraperitoneally or cyclophosphamide injected systemically, peak brain drug levels were measured in 2–8 hr, with substantial decrease by 48 hr without a second peak. Brain levels were substantially higher than blood levels at all time periods. We conclude that FAD:SA (1:1) adequately protects the otherwise labile 4HC, allowing effective and substained drug release in vivo. Furthermore, it should be possible to modify the polymer to adjust the time of peak release for more beneficial therapeutic effects.

Original languageEnglish (US)
Pages (from-to)311-316
Number of pages6
JournalPolymers for Advanced Technologies
Volume3
Issue number6
DOIs
StatePublished - 1992

Keywords

  • Controlled release
  • Cyclophosphamide
  • Drug delivery
  • Malignant glioma
  • Polymeric release

ASJC Scopus subject areas

  • Polymers and Plastics

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