腺苷官能化的可生物降解的PLA-b-PEG纳米颗粒可改善大鼠的骨关节炎。,Scientific Reports

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腺苷官能化的可生物降解的PLA-b-PEG纳米颗粒可改善大鼠的骨关节炎。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-05-15 , DOI: 10.1038/s41598-019-43834-y
Xiuling Liu ₁ , Carmen Corciulo ₂ , Stephanie Arabagian ₁ , Abraham Ulman ₁ , Bruce N Cronstein ₂

Affiliation

短的生物学半衰期限制了许多小分子的治疗用途。延长药理活性小分子半衰期的一种方法是偶联至降解性较差的纳米颗粒。在这里，我们报告了用作腺苷受体激动剂的六个靶向聚合物（PEG-b-PLA）纳米颗粒的合成和活性。使用点击化学，PLA-b-PEG400-N3和PLA-b-PEG2000嵌段共聚物在带有乙炔基的3'，4'-OH，5'-OH和6-NH2位置与腺苷键合。通过缀合物刺激RAW264.7鼠巨噬细胞中cAMP增加的能力来测试缀合物作为腺苷受体配体的活性。仅结合了腺苷的纳米颗粒（A-3'，4'-OH-TPN2），其中PEG2000在3'，4'羟基上与腺苷结合，刺激的cAMP增加，这些增加被腺苷A2A和A2B受体的选择性拮抗剂阻断，这与这些受体的连接一致。在创伤后骨关节炎的大鼠模型中体内测试了腺苷纳米颗粒；在该模型中，关节腔内注射腺苷纳米颗粒阻止了骨关节炎的发展。这些研究表明，腺苷与可生物降解的纳米颗粒的结合为实现延长的治疗效果提供了一种新颖的方法。在该模型中，关节腔内注射腺苷纳米颗粒阻止了骨关节炎的发展。这些研究表明，腺苷与可生物降解的纳米颗粒的结合为实现延长的治疗效果提供了一种新颖的方法。在该模型中，关节腔内注射腺苷纳米颗粒阻止了骨关节炎的发展。这些研究表明，腺苷与可生物降解的纳米颗粒的结合为实现延长的治疗效果提供了一种新颖的方法。

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Adenosine-Functionalized Biodegradable PLA-b-PEG Nanoparticles Ameliorate Osteoarthritis in Rats.

Short biologic half-lives limit the therapeutic utility of many small molecules. One approach to extending the half-life of pharmacologically active small molecules is conjugation to less degradable nanoparticles; here we report the synthesis and activity of six targeted polymeric (PEG-b-PLA) nanoparticles for use as adenosine receptor agonists. Using click chemistry, PLA-b-PEG400-N3 and PLA-b-PEG2000 block copolymers were bound to adenosine at the 3',4'-OH, 5'-OH, and 6-NH2 positions with an acetylene group. Activity of the conjugates as adenosine receptor ligands was tested by their capacity to stimulate cAMP increases in RAW264.7 murine macrophage cells. Only adenosine-conjugated nanoparticles (A-3',4'-OH-TPN2), in which PEG2000 was bound to adenosine on the 3',4' hydroxyl groups, stimulated cAMP increases and these increases were blocked by selective antagonists of both adenosine A2A and A2B receptors, consistent with ligation of these receptors. Adenosine nanoparticles were tested in vivo in a rat model of post-traumatic osteoarthritis; intra-articular injection of adenosine nanoparticles prevented the development of osteoarthritis in this model. These studies suggest that attachment of adenosine to biodegradable nanoparticles provides a novel approach to achieving prolonged therapeutic effects.

更新日期：2019-05-16

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