Local controlled delivery of anti-neoplastic RNAse to the brain

Joram Slager, Betty Tyler, Ariella Shikanov, Abraham J. Domb, Kuslima Shogen, David Sidransky, Henry Brem

Research output: Contribution to journalArticle

Abstract

Purpose: Antineoplastic RNAse proteins, also known as Amphibinases, have been shown effective against various solid tumors but were found selectively neurotoxic to Purkinje cells in the cerebellum. This work describes the use of a waxy biodegradable poly(ricinoleic-co-sebacic acid) for the local controlled delivery of cytotoxic amphibinases in the parietal lobe of the brain in an attempt to overcome cerebellar neuronal toxicity while affecting glioma cells. Methods: Amphibinase analogues were encapsulated in poly(ricinoleic-co-sebacic acid) formulations using mix-melt technology and loaded onto surgical foam. In-vitro release was monitored by BCA colorimetry and by RNAse specific bioactivity. The implants were inserted into rat brains bearing 9L glioma to assess toxicity and efficacy. Results: The various formulations showed extended linear release for several weeks with minimal burst effect. Best in-vivo efficacy was obtained with ACC7201 containing implants, resulting in the extension of the median survival from 13 to 18 days with 13% long-term survivors. Conclusion: Antineoplastic proteins were released from a p(SA-RA) polyanhydride implants in a controlled manner, providing efficacy against 9L glioma, while evading neurotoxicity in the cerebellum. The controlled release of Amphibinases forms the potential for a new therapy against brain tumors.

Original languageEnglish (US)
Pages (from-to)1838-1846
Number of pages9
JournalPharmaceutical Research
Volume26
Issue number8
DOIs
StatePublished - Aug 1 2009

Keywords

  • Amphibinase
  • Glioma
  • Polymer
  • RNAse
  • Ranpirnase

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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