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Local Controlled Delivery of Anti-Neoplastic RNAse to the Brain

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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.

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Acknowledgements

We acknowledge Alfacell Inc. for generously providing Ranpirnase. This work was supported in part by NIH NCDDG CA52857.

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Author notes

  1. Joram Slager

    Present address: SurModics, Inc., 9924 West 74th Street, Eden Prairie, Minnesota, 55344, USA

Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University, CRB2-2M41, 1550 Orleans Street, Baltimore, Maryland, 21231, USA

    Joram Slager, Betty Tyler & Henry Brem

  2. Department of Otolaryngology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21231, USA

    David Sidransky

  3. Department of Medicinal Chemistry, School of Pharmacy, Hebrew University, Jerusalem, 91120, Israel

    Ariella Shikanov & Abraham J. Domb

  4. Alfacell Corp., 300 Atrium Drive, Somerset, New Jersey, 08873, USA

    Kuslima Shogen

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  1. Joram Slager
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  2. Betty Tyler
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Correspondence to Joram Slager.

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Slager, J., Tyler, B., Shikanov, A. et al. Local Controlled Delivery of Anti-Neoplastic RNAse to the Brain. Pharm Res 26, 1838–1846 (2009). https://doi.org/10.1007/s11095-009-9893-3

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  • DOI: https://doi.org/10.1007/s11095-009-9893-3

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