Local delivery of a synthetic endostatin fragment for the treatment of experimental gliomas.

Abstract

OBJECTIVE:

Endostatin is an anti-angiogenic agent that blocks matrix-metalloproteinase-2 and inhibits endothelial cell proliferation. Currently, endostatin is available through recombinant technology, which limits its broader use. In this study, a synthetic endostatin fragment (EF) was analyzed to determine its anti-angiogenic properties when locally delivered by controlled-release polymers and to establish its effect as a treatment for experimental gliomas.

METHODS:

Cytotoxicity of EF against 9L gliosarcoma and F98 glioma was determined in vitro. EF was loaded into polyanhydride-poly-(bis-[carboxyphenoxy-propane]-sebacic-acid) (pCPP:SA) polymers at increasing concentrations. Pharmacokinetics of the EF/polymer formulations were defined in vitro. Anti-angiogenic properties of the EF/polymer formulations were evaluated in the rat-cornea micropocket assay. Toxicity and efficacy of locally delivered EF polymers either alone or combined with systemic bischloroethylnitrosourea (carmustine) were determined in rats intracranially challenged with 9L gliosarcoma.

RESULTS:

EF showed scarce cytotoxicity against 9L and F98 in vitro. EF/pCPP:SA formulations showed sustained release by day 19. Mean corneal angiogenesis index 20 days after tumor implantation was 4.5 +/- 0.7 for corneas implanted with 40% EF/pCPP:SA compared with controls (8.5 +/- 1.3, P = 0.02). Intracranial efficacy studies showed that EF polymers alone did not prolong animal survival. Combination of 40% EF/pCPP:SA polymers with systemic bischloroethylnitrosourea (carmustine) prolonged survival (median survival of 44 d, P = 0.001) and generated 33% long-term survivors.

CONCLUSION:

Controlled-release polymers can effectively deliver a biologically active EF in a sustained fashion. EF inhibits angiogenesis in vitro and in vivo, and even though EF does not prolong survival as a single agent, it exhibits a synergistic effect when combined with systemic bischloroethylnitrosourea (carmustine) in the intracranial 9L gliosarcoma model.

• Authors: Gustavo Pradilla, Federico G Legnani, Giovanna Petrangolini, Pierangelo Francescato, Francesco Chillemi, Betty M Tyler, Sergio M Gaini, Henry Brem, Alessandro Olivi, Francesco DiMeco
• Journal: Neurosurgery (Neurosurgery) Vol. 57 Issue 5 Pg. 1032-40; discussion 1032-40 (Nov 2005) ISSN: 1524-4040 [Electronic] United States
• PMID: 16284573 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Endostatins

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, therapeutic use)
• Body Weight (drug effects)
• Cornea (pathology)
• Corneal Neovascularization (drug therapy, pathology)
• Cytotoxicity Tests, Immunologic (methods)
• Dose-Response Relationship, Drug
• Drug Delivery Systems
• Endostatins (chemical synthesis, pharmacokinetics, therapeutic use)
• Glioma (drug therapy)
• Neoplasm Transplantation (methods)
• Neoplasms, Experimental (drug therapy)
• Rats
• Rats, Inbred F344
• Time Factors