Benny Ofra, Duvshani-Eshet Maayan, Cargioli Theresa, Bello Lorenzo, Bikfalvi Andreas, Carroll Rona S, Machluf Marcelle
Laboratory of Cancer Drug Therapeutics and Mammalian Cell Technology, Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):768-76.
There is an urgent need for modalities that can localize and prolong the administration of the antitumor agents, particularly antiangiogenic, to achieve long-term tumor inhibition. However, one of the major obstacles is designing a device in which the biological activity of sensitive endogenous inhibitors is retained. We have designed a biodegradable polymeric device, which provides a unique and practical means of localizing and continuously delivering hemopexin (PEX) or platelet factor 4 fragment (PF-4/CTF) at the tumor site while maintaining their biological activity. The potential and efficacy of this system is shown in vitro and in vivo in a human glioma mouse model.
Polymeric microspheres made of poly(lactic-co-glycolic acid) (PLGA) were loaded with very low amounts of PEX and PF-4/CTF. The release profiles of these factors from PLGA and their biological activity were confirmed in vitro using proliferation assays done on endothelial and tumor cells. Tumor inhibition using this system was studied in nude mice bearing a human s.c. glioma.
PEX and PF-4/CTF released in vitro from PLGA microspheres were biologically active and significantly inhibited the proliferation of human umbilical vein endothelial cells, bovine capillary endothelial cells, and U87-MG cells. A single local s.c. injection of PLGA microspheres loaded with low amounts of PEX or PF-4/CTF resulted in an 88% and 95% reduction in glioma tumor volume 30 days post-treatment. Immunohistochemical analysis of the treated tumors showed a marked decrease in tumor vessel density compared with untreated tumors.
Our findings show that polymeric microspheres are a very promising approach to locally and efficiently deliver endogenous inhibitors to the tumor site leading to a significant inhibition of the tumor.
迫切需要能够定位并延长抗肿瘤药物（尤其是抗血管生成药物）给药时间的方法，以实现长期的肿瘤抑制。然而，主要障碍之一是设计一种能保留敏感内源性抑制剂生物活性的装置。我们设计了一种可生物降解的聚合物装置，它提供了一种独特且实用的方法，可在肿瘤部位定位并持续递送血红素结合蛋白（PEX）或血小板因子4片段（PF-4/CTF），同时保持它们的生物活性。该系统的潜力和功效在人胶质瘤小鼠模型中进行了体外和体内研究。
由聚乳酸-乙醇酸共聚物（PLGA）制成的聚合物微球装载了极少量的PEX和PF-4/CTF。使用针对内皮细胞和肿瘤细胞的增殖测定法在体外确认了这些因子从PLGA中的释放曲线及其生物活性。在携带人皮下胶质瘤的裸鼠中研究了使用该系统的肿瘤抑制情况。
从PLGA微球体外释放的PEX和PF-4/CTF具有生物活性，并显著抑制人脐静脉内皮细胞、牛毛细血管内皮细胞和U87-MG细胞的增殖。单次局部皮下注射装载少量PEX或PF-4/CTF的PLGA微球，在治疗后30天导致胶质瘤肿瘤体积分别减少88%和95%。对治疗后的肿瘤进行免疫组织化学分析显示，与未治疗的肿瘤相比，肿瘤血管密度显著降低。
我们的研究结果表明，聚合物微球是一种非常有前景的方法，可将内源性抑制剂局部且有效地递送至肿瘤部位，从而显著抑制肿瘤。
