Local controlled delivery of anti-neoplastic RNAse to the brain.
OBJECTIVE
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.


CONCLUSIONS
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.
Department of Neurosurgery, Johns Hopkins University, CRB2-2M41, 1550 Orleans Street, Baltimore, Maryland 21231, USA. jslager@surmodics.com
Joram
J
Slager
Betty
B
Tyler
Ariella
A
Shikanov
Abraham J
AJ
Domb
Kuslima
K
Shogen
David
D
Sidransky
Henry
H
Brem
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D012260:Ribonucleases / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity
D000970:Antineoplastic Agents; D012260:Ribonucleases