Long-term and zero-order release of basic fibroblast growth factor from heparin-conjugated poly(L-lactide-co-glycolide) nanospheres and fibrin gel
Long-term and zero-order release of basic fibroblast growth factor from heparin-conjugated poly(L-lactide-co-glycolide) nanospheres and fibrin gel
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DOI：
10.1016/j.biomaterials.2005.08.030
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发表时间：
2006-03-01
期刊：
影响因子：
14
通讯作者：
Kim, BS
中科院分区：
文献类型：
--
作者：
Jeon, O;Kang, SW;Kim, BS
碱性成纤维细胞生长因子（bFGF）的受控长期递送可用作血管生成疗法。在这项研究中，开发了新型肝素缀合聚（L-丙交酯-乙交酯）（PLGA）纳米球（HCPN），用于长期、零级递送 bFGF。在 1-[3-(二甲基氨基)丙基]-3-乙基碳二亚胺存在下，通过氨基封端的 PLGA 纳米球与肝素之间的偶联反应制备 HCPN。与由较高分子量 PLGA 或线性 PLGA 制成的纳米球相比，使用由较低分子量 PLGA 或星形 PLGA 制成的纳米球，与 PLGA 纳米球缀合的肝素量增加了 29 倍。 HCPN 中 bFGF 的释放持续 3 周，没有最初的爆发释放。使用悬浮在纤维蛋白凝胶中的 HCPN 递送系统，bFGF 释放期延长至 4 周以上。此次发布几乎是零订单。 bFGF 从纤维蛋白凝胶中的 HCPN 释放的速率由纤维蛋白凝胶中的纤维蛋白原浓度控制。随着纤维蛋白原浓度增加，bFGF 释放速率降低。使用人脐静脉内皮细胞 (HUVEC) 培养物评估纤维蛋白凝胶中 HCPN 释放的 bFGF 的生物活性。从纤维蛋白凝胶中的 HCPN 释放的 bFGF 表现出 HUVEC 生长 15 天，与每天添加游离形式的 bFGF 的培养物相似。这表明纤维蛋白凝胶中 HCPN 的递送系统可以长时间释放生物活性形式的 bFGF。在小鼠肢体缺血模型中研究了使用纤维蛋白凝胶中的 HCPN 递送 bFGF 的治疗潜力。小鼠缺血肢体的免疫组织学分析表明，使用纤维蛋白凝胶中的 HCPN 递送 bFGF 治疗的缺血肢体的微血管密度比每天注射 bFGF 或使用纤维蛋白凝胶递送 bFGF 治疗的缺血肢体高得多。这项研究表明，在纤维蛋白凝胶中使用 HCPN 的 bFGF 递送系统表现出可控、长期、零级的 bFGF 释放，并增强了 bFGF 给药的血管生成功效。 (c) 2005 Elsevier Ltd. 保留所有权利。
Controlled long-term delivery of basic fibroblast growth factor (bFGF) could be used as an angiogenesis therapy. In this study, novel heparin-conjugated poly(L-lactide-co-glycolide) (PLGA) nanospheres (HCPNs) were developed for long-term, zero-order delivery of bFGF. HCPNs were prepared by using a coupling reaction between amino-terminated PLGA nanospheres and heparin in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide. The amount of heparin conjugated to the PLGA nanospheres was increased up to 29-fold by using nanospheres made from lower molecular weight PLGA, or star-shaped PLGA, as compared to nanospheres made from higher molecular weight PLGA, or linear PLGA. The release of bFGF from HCPNs was sustained for 3 weeks with no initial burst release. The bFGF release period was increased to more than 4 weeks using a delivery system of HCPNs suspended in fibrin gel. The release was nearly zero order. The rate of bFGF release from HCPNs in fibrin gel was controlled by the fibrinogen concentration in the fibrin gel. As the fibrinogen concentration increased, the bFGF release rate decreased. The bioactivity of bFGF released from HCPNs in fibrin gel was assessed using human umbilical vein endothelial cell (HUVEC) culture. bFGF released from HCPNs in fibrin gel exhibited HUVEC growth for 15 days, similar to that of cultures to which bFGF in free form was added daily.. suggesting that the delivery system of HCPNs in fibrin gel can release bFGF in a bioactive form for a long period. The therapeutic potential of bFGF delivery using HCPNs in fibrin gel was investigated in a mouse limb ischemia model. Immunohistological analysis of mouse ischemic limbs indicated that the microvessel density was much higher in the ischemic limbs treated with bFGF delivery using HCPNs in fibrin gel than in the ischemic limbs treated with daily injections of bFGF or with bFGF delivery using fibrin gel. This study shows that a bFGF delivery system using HCPNs in fibrin gel exhibits controllable, long-term, zero-order release of bFGF and potentiates the angiogenic efficacy of bFGF administration. (c) 2005 Elsevier Ltd. All rights reserved.