Sustained release of drugs dispersed in polymer nanoparticles
Sustained release of drugs dispersed in polymer nanoparticles
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DOI：
10.1002/anie.200802260
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Zare, Richard N.
中科院分区：
文献类型：
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作者：
Jacobson, Gunilla B.;Shinde, Rajesh;Zare, Richard N.
制药业使用的产品中约有三分之二是颗粒固体的形式。[1]作为将这些产品输送到靶组织的有效手段，控制释放仍然是一个巨大的挑战。在这里，我们描述了使用超临界二氧化碳作为抗溶剂来形成纳米颗粒，该纳米颗粒包含分散在可生物降解聚合物中的生物活性治疗药物。模型化合物荧光素从聚乳酸颗粒(约250-350 nm)中释放长达40天，药物回收率高达90%。转基因小鼠的体内生物发光成像，[2]转基因小鼠普遍表达荧光素酶，提供了荧光素释放的快速读数，并显示了皮下注射这些颗粒时荧光素的缓慢和持续释放。这项工作表明，我们的方法很容易扩展到千克量，代表了一种具有巨大潜力的新药物传递方法，特别是如果颗粒可以被靶向于部位特定的传递。[3]我们使用D-荧光素作为模拟治疗分子的模型系统。D-荧光素是荧光素酶的底物，在37℃下产生约610 nm的生物发光信号，可以在体内测量。荧光素酶氧化荧光素的过程涉及在一个宽的动态范围内同时发射生物发光。使用这样的模型药物为我们提供了一种快速非侵入性评估体内数据的方法，这反过来又使我们能够优化过程参数。我们使用了转基因小鼠，这些转基因小鼠通过使用修改后的β-肌动蛋白启动子，在体内的许多细胞(如果不是全部细胞)中表达荧光素酶。[4]由于大多数荧光素在30-60分钟内从小鼠体内清除，它代表了一种具有快速药代动力学特征的药物模型。
About two-thirds of the products utilized in the pharmaceutical industry are in the form of particulate solids.[1] Controlled release as an effective means of delivery of these products to target tissues remains a significant challenge. Herein, we describe the use of supercritical carbon dioxide as an antisolvent for the formation of nanoparticles that comprise biologically active therapeutics dispersed in a biodegradable polymer. Release of a model compound, luciferin, from poly (lactic acid)(PLA) particles (approximately 250–350 nm in size) was observed for up to 40 days with up to 90% drug recovery. In vivo bioluminescence imaging of transgenic mice,[2] which were genetically engineered to universally express luciferase, provides a rapid readout for luciferin release and demonstrates a slow and sustained release of luciferin upon subcutaneous injection of these particles. This work demonstrates that our process, which is readily scaled to kilogram quantities, represents a new drug delivery approach with great potential, particularly if particles can be targeted for site-specific delivery.[3]We used D-luciferin as a model system to mimic therapeutic molecules. D-Luciferin is a substrate for the enzyme luciferase that produces a bioluminescent signal at approximately 610 nm at 37 C which can be measured in vivo. Luciferase oxidizes luciferin in a process that involves the simultaneous emission of bioluminescence over a wide dynamic range. Using such a model drug provided us with a rapid method to evaluate in vivo data noninvasively, which in turn allowed us to optimize the process parameters. We used transgenic mice that were engineered to express luciferase in many, if not all, cells of the body by using a modified β-actin promoter.[4] As the majority of luciferin is cleared from the body of the mouse in 30–60 min, it represents a drug model with a rapid pharmacokinetic profile.[5]