Pradilla Gustavo, Legnani Federico G, Petrangolini Giovanna, Francescato Pierangelo, Chillemi Francesco, Tyler Betty M, Gaini Sergio M, Brem Henry, Olivi Alessandro, DiMeco Francesco
Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Neurosurgery. 2005 Nov;57(5):1032-40; discussion 1032-40. doi: 10.1227/01.neu.0000180059.33665.c1.
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.
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.
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.
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.
内皮抑素是一种抗血管生成剂，可阻断基质金属蛋白酶-2并抑制内皮细胞增殖。目前，内皮抑素可通过重组技术获得，这限制了其更广泛的应用。在本研究中，分析了一种合成的内皮抑素片段（EF），以确定其通过控释聚合物局部递送时的抗血管生成特性，并确定其作为实验性胶质瘤治疗方法的效果。
在体外测定EF对9L胶质肉瘤和F98胶质瘤的细胞毒性。将EF以递增浓度加载到聚酸酐-聚（双-[羧基苯氧基丙烷]-癸二酸）（pCPP:SA）聚合物中。在体外确定EF/聚合物制剂的药代动力学。在大鼠角膜微袋试验中评估EF/聚合物制剂的抗血管生成特性。在颅内接种9L胶质肉瘤的大鼠中，确定单独局部递送EF聚合物或与全身双氯乙基亚硝脲（卡莫司汀）联合使用的毒性和疗效。
EF在体外对9L和F98显示出极低的细胞毒性。EF/pCPP:SA制剂在第19天显示出持续释放。与对照组相比，植入40%EF/pCPP:SA的角膜在肿瘤植入后20天的平均角膜血管生成指数为4.5±0.7（对照组为8.5±1.3，P=0.02）。颅内疗效研究表明，单独使用EF聚合物并不能延长动物存活时间。40%EF/pCPP:SA聚合物与全身双氯乙基亚硝脲（卡莫司汀）联合使用可延长存活时间（中位存活时间为44天，P=0.001），并产生33%的长期存活者。
控释聚合物可以有效地以持续方式递送具有生物活性的EF。EF在体外和体内均抑制血管生成，尽管EF作为单一药物不能延长存活时间，但在颅内9L胶质肉瘤模型中与全身双氯乙基亚硝脲（卡莫司汀）联合使用时表现出协同作用。
