<i></i>具有结构不同的缩酮的高分子量多功能酸可降解聚合物药物载体的<i>体内</i>生物学评估,Biomacromolecules

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具有结构不同的缩酮的高分子量多功能酸可降解聚合物药物载体的体内生物学评估
Biomacromolecules ( IF 5.5 ) Pub Date : 2016-10-27 00:00:00 , DOI: 10.1021/acs.biomac.6b01198
Rajesh A. Shenoi ₁ , Srinivas Abbina ₁ , Jayachandran N. Kizhakkedathu ₁

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了解可降解化学部分对体内降解，组织分布和排泄的影响对于设计新型可生物降解药物载体至关重要。聚缩酮由于其在温和的酸性细胞内区室中降解的能力和无毒降解产物的产生而最近已成为有希望的治疗递送平台。然而，缩酮基团的化学结构对体内的影响尚未探索水溶性含缩酮的聚合物的降解，生物分布和药代动力学。在当前的工作中，我们通过将结构不同的缩酮基团掺入高度生物相容性聚甘油的主链中，合成了高分子量，水溶性可生物降解的超支化聚甘油（BHPG）。BHPG在缓冲溶液中显示出pH和缩酮基结构依赖性降解。当在小鼠中静脉内施用聚合物时，观察到了体内降解，生物分布和清除率对缩酮基结构的强烈依赖性。所有BHPG均在体内表现出降解和清除，组织堆积最少。有趣的是，与它们在缓冲溶液中的降解相比，在体内观察到具有结构不同的缩酮基团的BHPG的意外降解行为。具有环己基缩酮（CHK）和环戊基缩酮（CPK）基团的BHPG降解速度更快，并且从循环中清除的速度很快，而带有甘油羟基丁酮缩酮（GHBK）基团的BHPG降解速率要慢得多，并且血浆半衰期与不可降解的HPG。在给药30天后，BHPG-GHBK还显示出比不可降解的HPG明显低的组织蓄积。体内差异降解可能归因于不同含缩酮的聚合物疏水特性的差异，这可能会改变它们与体内蛋白质和细胞的相互作用。这是第一个证明缩酮基团的化学结构对聚合物的体内降解和循环特性的影响的研究，并且通过适当的表面修饰，这些聚合物将用作多功能药物载体。

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In Vivo Biological Evaluation of High Molecular Weight Multifunctional Acid-Degradable Polymeric Drug Carriers with Structurally Different Ketals

Understanding the influence of degradable chemical moieties on in vivo degradation, tissue distribution, and excretion is critical for the design of novel biodegradable drug carriers. Polyketals have recently emerged as a promising therapeutic delivery platform due to their ability to degrade under mild acidic intracellular compartments and generation of nontoxic degradation products. However, the effect of chemical structure of the ketal groups on the in vivo degradation, biodistribution, and pharmacokinetics of water-soluble ketal-containing polymers has not been explored. In the present work, we synthesized high molecular weight, water-soluble biodegradable hyperbranched polyglycerols (BHPGs) through the incorporation of structurally different ketal groups into the main chain of highly biocompatible polyglycerols. BHPGs showed pH and ketal group structure dependent degradation in buffer solutions. When the polymers were intravenously administered in mice, a strong dependence of in vivo degradation, biodistribution, and clearance on the ketal group structure was observed. All the BHPGs demonstrated degradation and clearance in vivo, with minimal tissue accumulation. Interestingly, an unanticipated degradation behavior of BHPGs with structurally different ketal groups was observed in vivo in comparison to their degradation in buffer solutions. BHPGs with cyclohexyl ketal (CHK) and cyclopentyl ketal (CPK) groups degraded much faster and were cleared from circulation much rapidly, while BHPG with glycerol hydroxy butanone ketal (GHBK) group degraded at a much slower rate and exhibited similar plasma half-life as that of nondegradable HPG. BHPG-GHBK also showed significantly lower tissue accumulation than nondegradable HPG after 30 days of administration. The difference in in vivo degradation may be attributed to the difference in hydrophobic characteristics of different ketal containing polymers, which may change their interaction with proteins and cells in vivo. This is the first study that demonstrates the influence of chemical structure of ketal groups on in vivo degradation and circulation profile of polymers, and through proper surface modifications, these polymers would be useful as multifunctional drug carriers.

更新日期：2016-10-27

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