Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Biomaterials. 2013 Jul;34(21):5328-35. doi: 10.1016/j.biomaterials.2013.03.059. Epub 2013 Apr 22.
Layer-by-Layer (LbL) nanoparticles are an emerging class of therapeutic carriers that afford precise control over key design parameters that facilitate improved drug and carrier pharmacokinetics, and enhanced molecular-targeting capabilities. This paper advances the development of these systems by establishing them as drug carriers, with the means to control drug release in a systemic environment and retard particle clearance from circulation, promoting improved biodistribution of the drug-containing system. Using dual-fluorescent tracking in vivo, this work establishes a robust means of screening libraries of LbL systems generated, affording simultaneous resolution over persistence and biodistribution of both the drug and carrier following systemic administration of a single particle formulation. Employing a PLGA drug-containing core as a substrate for LbL deposition, a range of coated systems were fabricated to investigate the abilities of these films to stabilize drug for delivery as well as to improve the pharmacokinetics of both the drug and carrier. Significant reductions in liver accumulation were observed for different formulations of the layered architectures within the first 30 min of systemic circulation. LbL architectures diminished liver localization of the surrogate drug, cardiogreen, by 10-25% ID/g relative to native PLGA nanoparticles and modulated carrier accumulation in the liver >50% ID/g. Further, enhanced persistence of the drug was observed with the coated systems, significantly increasing the drug half-life from 2 to 3 min for free drug and 1.87 h for the uncoated core to 4.17 h and 4.54 h for the coated systems. These systems provide an exciting, modular platform that improves the pharmacokinetic properties of the therapeutic, reduces bolus release of drug from nanoparticles, and enhances the safety and circulation half-life of the drug in vivo, proving them to be highly clinically-relevant and a promising approach for future development of molecularly-targeted and combination therapeutics.
层层（LbL）纳米粒子是一类新兴的治疗载体，能够精确控制关键设计参数，从而改善药物和载体的药代动力学，并增强分子靶向能力。本文通过将这些系统确立为药物载体，来推进这些系统的发展，从而实现系统环境中药物释放的控制，并延缓粒子从循环中的清除，促进含药物系统的生物分布改善。通过体内双荧光跟踪，本工作建立了一种强大的筛选库的方法，对系统给药后药物和载体的持久性和生物分布进行同时解析，为单个粒子制剂给药后同时解析药物和载体的持久性和生物分布提供了一种稳健的方法。采用 PLGA 载药核作为 LbL 沉积的基质，制备了一系列涂层体系，以研究这些薄膜稳定药物输送的能力，以及改善药物和载体的药代动力学。在系统循环的前 30 分钟内，观察到不同涂层结构的制剂在肝脏中的积累显著减少。与原生 PLGA 纳米粒子相比，LbL 结构使替代药物心绿的肝定位减少了 10-25% ID/g，并使载体在肝脏中的积累增加了>50% ID/g。此外，涂层体系观察到药物的持久性增强，使游离药物的药物半衰期从 2 到 3 分钟，未涂层核的药物半衰期从 1.87 小时显著增加到 4.17 小时和 4.54 小时。这些系统提供了一个令人兴奋的模块化平台，改善了治疗药物的药代动力学特性，减少了纳米粒子中药物的突释，并提高了药物在体内的安全性和循环半衰期，证明它们具有很高的临床相关性，是未来发展分子靶向和联合治疗的很有前途的方法。
