Delivery of soluble tumor necrosis factor receptor from in-situ forming PLGA implants:: In-vivo
Delivery of soluble tumor necrosis factor receptor from in-situ forming PLGA implants:: In-vivo
复制标题
DOI：
10.1023/a:1007621512647
复制
发表时间：
2000-12-01
影响因子：
3.7
通讯作者：
Kost, J
中科院分区：
文献类型：
--
作者：
Eliaz, RE;Wallach, D;Kost, J
肿瘤坏死因子 (TNF) 的许多有害影响是由于这种细胞因子在体内某些不同位点的长期形成造成的。可溶形式的 TNF 受体 p55 和 p75 能够通过与细胞表面 TNF 受体竞争来阻断 TNF 的作用 (1-4)，可以防止 TNF 在慢性炎症性疾病中产生有害的病理作用。慢性炎症性疾病与可溶性 TNF 受体内源性形成增加有关，部分原因是 TNF 刺激其合成 (5-12)。这些受体是通过细胞表面 TNF 受体的蛋白水解加工形成的，并对应于其胞外域中富含半胱氨酸的配体结合区域。由于 sp55-R 从血液中清除得相当快，因此重复注射可能无法将它们维持在所需的位点并保持足够高的浓度。由于这种蛋白质在体内的半衰期较短（6 小时），基于乙烯醋酸乙烯酯 (EVAc) 植入物或注射含有人可溶性 p55 TNF 受体的聚乳酸-乙醇酸 (PLGA) 共聚物微球的受控递送系统 (13) 可以增强天然可溶性 TNF 受体在慢性疾病中的治疗潜力。本研究的目的是开发一种药物输送系统，该系统具有植入物的优点，但易于注射到需要的部位。该输送系统涉及简单的准备程序，并且避免了植入或移除过程中的侵入性技术，例如手术。我们开发了一种原位成型植入系统，可以使用标准注射器和针头以液体形式给药。 Dunn 等人最近描述了一种可生物降解的注射给药系统(14)。接触后
Many harmful effects of tumor necrosis factor (TNF) result from chronic formation of this cytokine at certain distinct loci in the body. The soluble forms of the TNF receptors p55 and p75, which have the ability to block TNF action by competing for it with the cell surface TNF receptors (1–4), can protect against harmful pathological effects of TNF in chronic inflammatory diseases. Chronic inflammatory diseases are associated with increased endogenous formation of the soluble TNF receptors, in part resulting from stimulation of their synthesis by TNF (5–12). These receptors are formed by proteolytic processing of the cell surface TNF receptors and correspond to the cysteine-rich ligand-binding regions in their extracellular domains.Since sp55-R are cleared rather rapidly from the blood, repeated injections may not maintain them at the required site, at high enough concentrations. Due to the short half-life (6 hours) of this protein in-vivo, a controlled delivery system based on implants of ethylene vinyl-acetate (EVAc) or injections of microspheres of poly (lactic-co-glycolic) acid (PLGA) copolymers containing human soluble p55 TNF receptors (13), could enhance the therapeutic potential of the natural soluble TNF receptors in chronic diseases. The objective of this study was to develop a drug delivery system with the benefits of an implant but the ease of administration of an injection to the site of need. This delivery system involves simple preparation procedures and avoids an invasive technique such as surgery in its implantation or removal. We have developed an in-situ forming implant system that can be administered as a liquid using standard syringes and needles. A biodegradable injectable delivery system was described recently by Dunn et al.(14). Upon contact with