Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza 50009, Spain.
Department of Chemical Engineering, University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain.
ACS Appl Mater Interfaces. 2021 Apr 21;13(15):17220-17235. doi: 10.1021/acsami.1c00894. Epub 2021 Apr 6.
The development of thermoresponsive nanogels loaded with nanocrystals of the local anesthetic bupivacaine nanocrystals (BNCs) for prolonged peripheral nerve pain relief is reported here. BNCs were prepared using the antisolvent precipitation method from the hydrophobic form of bupivacaine (bupivacaine free base). The as-prepared BNCs were used stand-alone or encapsulated in temperature-responsive poly(ethylene glycol) methyl ether methacrylate (OEGMA)-based nanogels, resulting in bupivacaine NC-loaded nanogels (BNC-nanogels) of monodisperse size. The synthesis protocol has rendered high drug loadings (., 93.8 ± 1.5 and 84.8 ± 1.2 wt % for the NC and BNC-nanogels, respectively) and fast drug dissolution kinetics in the resulting composite material. tests demonstrated the efficacy of the formulation along with an extended duration of sciatic nerve block in murine models of more than 8 h with a formulation containing only 2 mg of the local anesthetic thanks to the thermoresponsive character of the polymer, which, at body temperature, becomes hydrophobic and acts as a diffusion barrier for the encapsulated drug nanocrystals. The hydrophobicity of the encapsulated bupivacaine free base probably facilitates its pass through cell membranes and also binds strongly to their hydrophobic lipid bilayer, thereby protecting molecules from diffusion to extracellular media and to the bloodstream, reducing their clearance. When using BNC-nanogels, the duration of the anesthetic blockage lasted twice as long as compared to the effect of just BNCs or a conventional bupivacaine hydrochloride solution both containing equivalent amounts of the free drug. Results of the tests showed enough sensory nerve block to potentially relieve pain, but still having mobility in the limb, which enables motor function when required. The BNC-nanogels presented minimal toxicity in the study due to their sustained drug release and excellent biocompatibility. The encapsulation of nano-sized crystals of bupivacaine provides a prolonged regional anesthesia with reduced toxicity, which could be advantageous in the management of chronic pain.
本文报道了一种载有局部麻醉药布比卡因纳米晶体（BNC）的温敏纳米凝胶的开发，用于缓解慢性周围神经痛。BNC 是通过反溶剂沉淀法从布比卡因的疏水性形式（游离布比卡因）制备的。所制备的 BNC 被单独使用或封装在温度响应的聚（乙二醇）甲基醚甲基丙烯酸酯（OEGMA）基纳米凝胶中，得到单分散尺寸的布比卡因 NC 负载纳米凝胶（BNC-纳米凝胶）。该合成方案实现了高药物负载量（分别为 NC 和 BNC-纳米凝胶的 93.8±1.5%和 84.8±1.2%wt）和在所得复合材料中快速的药物溶解动力学。体内实验证明了该制剂的疗效，并在小鼠模型中延长了坐骨神经阻滞时间超过 8 小时，其中仅包含 2mg 局部麻醉药的制剂就能达到这一效果，这要归功于聚合物的温敏特性，在体温下，聚合物变得疏水，并作为封装药物纳米晶体的扩散屏障。包封的游离布比卡因的疏水性可能有助于其穿过细胞膜，并与它们的疏水性脂质双层强烈结合，从而保护分子免受扩散到细胞外介质和血液中的影响，减少其清除率。与仅使用 BNC 或含有等量游离药物的常规盐酸布比卡因溶液相比，使用 BNC-纳米凝胶时，麻醉阻断的持续时间延长了一倍。体内实验结果表明，这种神经阻滞具有足够的感觉神经阻滞作用，有可能缓解疼痛，但仍能使肢体保持活动能力，在需要时能够发挥运动功能。由于其持续的药物释放和优异的生物相容性，BNC-纳米凝胶在这项研究中表现出最小的毒性。纳米级布比卡因晶体的包封提供了一种延长的区域麻醉，同时降低了毒性，这在慢性疼痛的管理中可能是有利的。
