Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Vascular Biology Program and Dept. of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Biomaterials. 2017 Sep;139:187-194. doi: 10.1016/j.biomaterials.2017.06.003. Epub 2017 Jun 6.
Here we describe injectable, ultrasound (US)-responsive, nanoparticle aggregates (NPAs) that disintegrate into slow-release, nanoscale, drug delivery systems, which can be targeted to selective sites by applying low-energy US locally. We show that, unlike microbubble based drug carriers which may suffer from stability problems, the properties of mechanical activated NPAs, composed of polymer nanoparticles, can be tuned by properly adjusting the polymer molecular weight, the size of the nanoparticle precursors as well as the percentage of excipient utilized to hold the NPA together. We then apply this concept to practice by fabricating NPAs composed of nanoparticles loaded with Doxorubicin (Dox) and tested their ability to treat tumors via ultrasound activation. Mouse studies demonstrated significantly increased efficiency of tumor targeting of the US-activated NPAs compared to PLGA nanoparticle controls (with or without US applied) or intact NPAs. Importantly, when the Dox-loaded NPAs were injected and exposed to US energy locally, this increased ability to concentrate nanoparticles at the tumor site resulted in a significantly greater reduction in tumor volume compared to tumors treated with a 20-fold higher dose of the free drug.
在这里，我们描述了可注射的、对超声（US）有响应的纳米颗粒聚集体（NPAs），它们可以分解成缓慢释放的纳米级药物递送系统，通过局部施加低能量 US 可以将其靶向选择性部位。我们表明，与可能存在稳定性问题的基于微泡的药物载体不同，由聚合物纳米颗粒组成的机械激活 NPAs 的特性可以通过适当调整聚合物分子量、纳米颗粒前体的大小以及用于将 NPA 保持在一起的赋形剂的百分比来进行调节。然后，我们通过制造由载有阿霉素（Dox）的纳米颗粒组成的 NPAs 并通过超声激活来测试它们治疗肿瘤的能力将这一概念付诸实践。小鼠研究表明，与 PLGA 纳米颗粒对照（有或没有施加 US）或完整的 NPAs 相比，超声激活的 NPAs 对肿瘤的靶向效率显著提高。重要的是，当载有 Dox 的 NPAs 被注射并暴露于局部 US 能量时，与用 20 倍高剂量游离药物治疗的肿瘤相比，将纳米颗粒集中在肿瘤部位的能力显著增强，导致肿瘤体积显著减小。
