Ultrasound-triggered Drug Delivery Using Acoustic Droplet Vaporization.

[摘要] The goal of targeted drug delivery is the spatial and temporal localization of a therapeutic agent and its associated bioeffects. One method of drug localization is acoustic droplet vaporization (ADV), whereby drug-laden peruorocarbon (PFC)emulsions are vaporized into gas bubbles using ultrasound, thereby releasing drug locally. Transpulmonary droplets are converted into bubbles that occlude capillaries, sequestering the released drug within an organ or tumor. This research investigates the relationship between the ADV and inertial cavitation (IC) thresholds - relevant for drug delivery due to the bioeffects generated by IC - and explores the delivery oflipophilic and hydrophilic compounds using PFC double emulsions.IC can positively and negatively affect ultrasound mediated drug delivery. TheADV and IC thresholds were determined for various bulk fluid, droplet, and acoustic parameters. At 3.5 MHz, the ADV threshold occurred at a lower rarefactional pressure than the IC threshold. The results suggest that ADV is a distinct phenomenon from IC, the ADV nucleus is internal to the droplet, and the IC nucleus is the bubble generated by ADV.The ADV triggered release of a lipophilic chemotherapeutic agent, chlorambucil(CHL), from a PFC-in-oil-in-water emulsion was explored using plated cells. Cells exposed to a CHL-loaded emulsion, without ADV, displayed 44% less growthinhibition than cells exposed to an equal concentration of CHL in solution. Upon ADV of the CHL-loaded emulsion, the growth inhibition increased to the same level as cells exposed to CHL in solution.A triblock copolymer was synthesized which enabled the formulation of stablewater-in-PFC-in-water (W1/PFC/W2) emulsions. The encapsulation of fluorescein in the W1 phase significantly decreased the mass flux of fluorescein; ADV was shown to completely release the fluorescein from the emulsions. ADV was also shown to release thrombin, dissolved in the W1 phase, which could be used in vivo to extend synergistically the duration of ADV-generated, microbubble-based embolizations.Overall, the results suggest that PFC double emulsions can be used as an ultrasound-triggered drug delivery system. Compared to traditional drug delivery systems, ADV could be used to increase the therapeutic efficacy and decrease thesystemic toxicity of drug therapy.

[发布机构] University of Michigan

[效力级别] Emulsion

[关键词] Acoustic Droplet Vaporization;Emulsion;Drug Delivery;Ultrasound;Perfluorocarbon;Cavitation;Biomedical Engineering;Radiology;Physics;Engineering;Health Sciences;Science;Biomedical Engineering