Department of Chemical Biological Engineering, University of Colorado Boulder, Boulder, CO, 80303, USA.
Department of Mechanical Engineering, University of Colorado Boulder, Boulder, CO, 80309, USA.
Adv Healthc Mater. 2017 Sep;6(18). doi: 10.1002/adhm.201700514. Epub 2017 Jul 12.
The mechanical effects of cavitation can be effective for therapy but difficult to control, thus potentially leading to off-target side effects in patients. While administration of ultrasound active agents such as fluorocarbon microbubbles and nanodroplets can locally enhance the effects of high intensity focused ultrasound (HIFU), it has been challenging to prepare ultrasound active agents that are small and stable enough to accumulate in tumors and internalize into cancer cells. Here, this paper reports the synthesis of 100 nm nanoparticle ultrasound agents based on phospholipid-coated, mesoporous, hydrophobically functionalized silica nanoparticles that can internalize into cancer cells and remain acoustically active. The ultrasound agents produce bubbles when subjected to short HIFU pulses (≈6 µs) with peak negative pressure as low as ≈7 MPa and at particle concentrations down to 12.5 µg mL (7 × 10 particles mL ). Importantly, ultrasound agents are effectively uptaken by cancer cells without cytotoxic effects, but HIFU insonation causes destruction of the cells by the acoustically generated bubbles, as demonstrated by (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) and lactate dehydrogenase assays and flow cytometry. Finally, it is showed that the HIFU dose required to effectively eliminate cancer cells in the presence of ultrasound agents causes only a small temperature increase of ≈3.5 °C.
空化的机械效应可用于治疗，但难以控制，因此可能导致患者出现非靶向副作用。虽然施用超声活性剂（如氟碳微泡和纳米液滴）可局部增强高强度聚焦超声（HIFU）的效果，但制备足够小且稳定以在肿瘤中积累并内化进入癌细胞的超声活性剂一直具有挑战性。本文报道了基于磷脂包覆的介孔、疏水性官能化硅纳米颗粒的 100nm 纳米颗粒超声剂的合成，该超声剂可内化进入癌细胞并保持声学活性。超声剂在短 HIFU 脉冲（≈6µs）下产生气泡，其峰值负压低至 ≈7MPa，颗粒浓度低至 12.5µg mL（7×10 个颗粒 mL ）。重要的是，超声剂可被癌细胞有效摄取而无细胞毒性作用，但 HIFU 照射会导致细胞被声致气泡破坏，这可通过（2,3-双-(2-甲氧基-4-硝基-5-磺苯基)-2H-四唑-5-羧基苯胺（XTT）和乳酸脱氢酶测定和流式细胞术来证明。最后，结果表明，在存在超声剂的情况下有效消除癌细胞所需的 HIFU 剂量仅导致 ≈3.5°C 的小温升。
