通过可生物降解的聚合物包裹的鞘糖脂抑制剂的递送，改善对动脉粥样硬化和心脏肥大的干预。,Biomaterials

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通过可生物降解的聚合物包裹的鞘糖脂抑制剂的递送，改善对动脉粥样硬化和心脏肥大的干预。
Biomaterials ( IF 12.8 ) Pub Date : 2015 Sep , DOI: 10.1016/j.biomaterials.2015.06.001
S. Mishra , D. Bedja , C. Amuzie , C.A. Foss , M.G. Pomper , R. Bhattacharya , K.J. Yarema , S. Chatterjee

D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol（D-PDMP）是一种糖鞘脂合成抑制剂，有望用于治疗动脉粥样硬化和心脏肥大，但体内清除速度过快严重阻碍了其翻译。诊所。为了克服这一障碍，我们使用了基于材料的输送策略，其中D-PDMP被封装在由聚乙二醇（PEG）和癸二酸（SA）组成的可生物降解的聚合物中。将PEG-SA配制成掺有（125）I标记的PEG的纳米颗粒，以通过D-PDMP的体内生物分布和释放动力学通过伽马闪烁显像法测定，然后通过质谱测定。聚合物封装将D-PDMP在治疗小鼠体内的停留时间从不到一小时增加到至少四小时（最多48小时或更长时间）。由聚合物封装提供的这种体内寿命的显着增加导致了在高脂高胆固醇（HFHC）饮食的apoE-/-小鼠中，动脉粥样硬化和心脏肥大的功效得到了数量级的提高。这些结果表明，与未缀合的D-PDMP相比，可生物降解的聚合物中包封的D-PDMP通过增加胃肠道吸收和增加停留时间而提供了优越的递送方式，从而为这种迅速清除的化合物提供了与治疗动脉粥样硬化，心脏疾病相关的治疗意义肥大，以及可能与异常高糖鞘脂生物合成或分解代谢不足的有害影响有关的其他疾病。

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Improved intervention of atherosclerosis and cardiac hypertrophy through biodegradable polymer-encapsulated delivery of glycosphingolipid inhibitor.

D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glycosphingolipid synthesis inhibitor, holds promise for the treatment of atherosclerosis and cardiac hypertrophy but rapid in vivo clearance has severely hindered translation to the clinic. To overcome this impediment, we used a materials-based delivery strategy wherein D-PDMP was encapsulated within a biodegradable polymer composed of poly ethylene glycol (PEG) and sebacic acid (SA). PEG-SA was formulated into nanoparticles that were doped with (125)I-labeled PEG to allow in vivo bio-distribution and release kinetics of D-PDMP to be determined by using gamma-scintigraphy and subsequently, by mass spectrometry. Polymer-encapsulation increased the residence time of D-PDMP in the body of a treated mouse from less than one hour to at least four hours (and up to 48 h or longer). This substantially increased in vivo longevity provided by polymer encapsulation resulted in an order of magnitude gain in efficacy for interfering with atherosclerosis and cardiac hypertrophy in apoE-/- mice fed a high fat and high cholesterol (HFHC) diet. These results establish that D-PDMP encapsulated in a biodegradable polymer provides a superior mode of delivery compared to unconjugated D-PDMP by way of increased gastrointestinal absorption and increased residence time thus providing this otherwise rapidly cleared compound with therapeutic relevance in interfering with atherosclerosis, cardiac hypertrophy, and probably other diseases associated with the deleterious effects of abnormally high glycosphingolipid biosynthesis or deficient catabolism.

更新日期：2017-01-31

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