Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound

Abstract

Background: As one of the most effective triggers with high tissue-penetrating capability and non-invasive feature, ultrasound shows great potential for controlling the drug release and enhancing the chemotherapeutic efficacy. In this study, we report, for the first time, construction of a phase-changeable drug-delivery nanosystem with programmable low-intensity focused ultrasound (LIFU) that could trigger drug-release and significantly enhance anticancer drug delivery.Methods: Liquid-gas phase-changeable perfluorocarbon (perfluoropentane) and an anticancer drug (doxorubicin) were simultaneously encapsulated in two kinds of nanodroplets. By triggering LIFU, the nanodroplets could be converted into microbubbles locally in tumor tissues for acoustic imaging and the loaded anticancer drug (doxorubicin) was released after the microbubble collapse. Based on the acoustic property of shell materials, such as shell stiffness, two types of nanodroplets (lipid-based nanodroplets and PLGA-based nanodroplets) were activated by different acoustic pressure levels. Ultrasound irradiation duration and power of LIFU were tested and selected to monitor and control the drug release from nanodroplets. Various ultrasound energies were introduced to induce the phase transition and microbubble collapse of nanodroplets in vitro (3 W/3 min for lipid nanodroplets; 8 W/3 min for PLGA nanodroplets).Results: We detected three steps in the drug-releasing profiles exhibiting the programmable patterns. Importantly, the intratumoral accumulation and distribution of the drug with LIFU exposure were significantly enhanced, and tumor proliferation was substantially inhibited. Co-delivery of two drug-loaded nanodroplets could overcome the physical barriers of tumor tissues during chemotherapy.Conclusion: Our study provides a new strategy for the efficient ultrasound-triggered chemotherapy by nanocarriers with programmable LIFU capable of achieving the on-demand drug release.

<p>G250 Antigen-Targeting Drug-Loaded Nanobubbles Combined with Ultrasound Targeted Nanobubble Destruction: A Potential Novel Treatment for Renal Cell Carcinoma</p>

“…EE = amount of TEM encapsulated in NBs/total amount of added TEM × 100%; LE = amount of TEM encapsulated in NBs/total amount of lipids for NB preparation × 100%. 15…”

Ultrasound-Mediated Gene Therapy of Hepatocellular Carcinoma Using Pre-microRNA Plasmid-Loaded Nanodroplets

“…With respect to tumor implantation, 0.15 mL of SMMC-7721 cancer cells (approximately 1 £ 10 7 cells/mL) was subcutaneously injected into the dorsal hindlimb region of the mouse to establish a xenograft HCC model. The tumor volume was calculated as volume = 0.5 £ L £ W 2 , where L and W were the length and width of the tumor, respectively, measured with calipers (Cao et al 2018). Approximately 15 d later, mice with consistent tumor (approximately 5À8 mm long) were selected for further experiments.…”

“…In addition, when exposed to US, the cells secreted much more soluble factors that stimulated proliferation, differentiation and migration of peripheral cells (Vezeridis et al 2006;Fung et al 2014b). However, some studies have reported that US cavitation can inhibit the growth of tumor and cancer cells (Huang et al 2012b;Cao et al 2018). All of the aforementioned effects were obtained under ultrasonic conditions; thus, scientists should try to modulate different important parameters of US, for example, PNP (Li et al 2002), PD (Reher et al 2002), PRF (Wang et al 1994) and axial distance of the focus region (Fung et al 2014a), to exert an optimal effect.…”

Physical‐, chemical‐, and biological‐responsive nanomedicine for cancer therapy

“…Under the first ultrasound exposure, the first phase‐change triggered drug release and significantly enhanced anti‐cancer effect. According to the report (Y. Cao et al, ), the biological barriers of tumors could be temporarily overcome by post‐formed lipid‐based nanoparticles. The cellular uptake of PLGA‐based nanodroplets (PN) was enhanced by the microjets.…”

“…Schematic diagram of the release of nanodroplets complex triggered by low‐intensity focused ultrasound radiation at different stages. (Reprinted with permission from Y. Cao et al (). Copyright 2018 Ivyspring International Publisher)…”