Water-soluble HPMA copolymer -: prostaglandin E1 conjugates containing a cathepsin K sensitive spacer
Water-soluble HPMA copolymer -: prostaglandin E1 conjugates containing a cathepsin K sensitive spacer
复制标题
DOI：
10.1080/10611860600834219
复制
发表时间：
2006-07-01
影响因子：
4.5
通讯作者：
Kopecek, Jindrich
中科院分区：
文献类型：
--
作者：
Pan, Huaizhong;Kopeckova, Pavla;Kopecek, Jindrich
设计、合成并表征了一种新型的骨靶向前列腺素E1（PGE 1）释药系统--N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物。PGE 1通过间隔基结合到聚合物主链上，间隔基由组织蛋白酶K敏感的四肽（Gly-Gly-Pro-Nle）和自消除的4-氨基苄醇结构组成。HPMA共聚物缀合物通过HPMA、含PGE 1的大分子单体和任选的含有反应性对硝基苯基酯基团的共聚单体的光引发自由基共聚来制备。后一基团用作d-天冬氨酸八肽靶向部分的连接点。含PGE 1的大分子单体和HPMA共聚物-PGE 1缀合物与组织蛋白酶K的孵育导致未修饰的PGE 1的释放。释放速率取决于结合物的组成。缀合物中PGE 1含量越高，PGE 1释放越慢。这似乎是疏水侧链在水性介质中缔合的结果，这使得酶底物复合物的形成更加困难。这些数据似乎表明HPMA共聚物-PGE 1缀合物在治疗骨质疏松症和其它骨疾病中具有潜力。
A novel bone targeting, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer based, prostaglandin E 1 (PGE1) delivery system was designed, synthesized and characterized. PGE 1 was bound to the polymer backbone via a spacer, composed of a cathepsin K sensitive tetrapeptide (Gly-Gly-Pro-Nle) and a self-eliminating 4-aminobenzyl alcohol structure. The HPMA copolymer conjugates were prepared by photo-initiated free radical copolymerization of HPMA, PGE 1-containing macromonomer, and optionally a comonomer containing a reactive p-nitrophenyl ester group. The latter group was used as attachment points for the d-aspartic acid octapeptide targeting moieties. Incubation of the PGE 1-containing macromonomer and HPMA copolymer-PGE 1 conjugates with cathepsin K resulted in release of unmodified PGE 1 . The rate of release depended on the composition of the conjugate. The higher the PGE 1 content in the conjugate, the slower the PGE 1 release. This appeared to be the result of association of hydrophobic side-chains in aqueous media, which rendered the formation of the enzyme substrate complex more difficult. The data seems to indicate that HPMA copolymer-PGE 1 conjugates have a potential in the treatment of osteoporosis and other bone diseases.