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


CONCLUSIONS
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.
Pradilla
Gustavo
G
Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Legnani
Federico G
FG
Petrangolini
Giovanna
G
Francescato
Pierangelo
P
Chillemi
Francesco
F
Tyler
Betty M
BM
Gaini
Sergio M
SM
Brem
Henry
H
Olivi
Alessandro
A
DiMeco
Francesco
F
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D003315:Cornea / Q000473:pathology; D016510:Corneal Neovascularization / Q000188:drug therapy / Q000473:pathology; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D043169:Endostatins / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy*; D009368:Neoplasm Transplantation / Q000379:methods; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D000970:Antineoplastic Agents; D043169:Endostatins