Improving Release of Liposome-Encapsulated Drugs with Focused Ultrasound and Vaporizable Droplet-Liposome Nanoclusters

Abstract

Active targeted delivery of small molecule drugs is becoming increasingly important in personalized therapies, especially in cancer, brain disorders, and a wide variety of other diseases. However, effective means of spatial targeting and delivering high drug payloads in vivo are still lacking. Focused ultrasound combined with superheated phase-shift nanodroplets, which vaporize into microbubbles using heat and sound, are rapidly becoming a popular strategy for targeted drug delivery. Focused ultrasound can target deep tissue with excellent spatial precision and without using ionizing energy, thus can activate nanodroplets in circulation. One of the main limitations of this technology has been poor drug loading in the droplet core or the shell material. To address this need, we have developed a strategy to combine low-boiling point decafluorabutane and octafluoropropane (DFB and OFP) nanodroplets with drug-loaded liposomes, creating phase-changeable droplet-liposome clusters (PDLCs). We demonstrate a facile method of assembling submicron PDLCs with high drug-loading capacity on the droplet surface. Furthermore, we demonstrate that chemical tethering of liposomes in PDLCs enables a rapid release of their encapsulated cargo upon acoustic activation (>60% using OFP-based PDLCs). Rapid uncaging of small molecule drugs would make them immediately bioavailable in target tissue or promote better penetration in local tissue following intravascular release. PDLCs developed in this study can be used to deliver a wide variety of liposome-encapsulated therapeutics or imaging agents for multi-modal imaging applications. We also outline a strategy to deliver a surrogate encapsulated drug, fluorescein, to tumors in vivo using focused ultrasound energy and PDLCs.

Evaluation of Liposome-Loaded Microbubbles as a Theranostic Tool in a Murine Collagen-Induced Arthritis Model

“…Inevitably, microbubble-loaded liposomes are prone to a fast clearance by Kupffer cells in the liver as has been frequently reported before for several types of microbubbles [112][113][114][115]120]. Usage of the previously discussed smaller ultrasound-responsive nanodroplets that can be similarly loaded with liposomes as described by Honari et al [129], will likely enhance both the neovascular penetration and sustain longer circulation times [130,131] as they are less quickly captured in the liver. In this way, they might tackle some of the limits observed using microbubbles in murine arthritis.…”

Acoustically-Activated Liposomal Nanocarriers to Mitigate the Side Effects of Conventional Chemotherapy with a Focus on Emulsion-Liposomes

“…Thus, they have been used as intra-vascular agents to actively target endothelial markers such as VEGFR2 and αvβ3 integrin. The size restriction of microbubbles introduced the use of nano-scale-sized nanobubbles and nanoemulsions that would easily extravasate into the tumor tissues and get endocytosed into the tumor cells [ 100 , 101 , 102 , 103 ].…”

“…Perfluorocarbons (PFCs) are considered excellent candidates for emulsions in drug delivery applications due to their biocompatibility, non-toxicity, and hydrophobic behavior; hence, they have a very low solubility in aqueous solutions or even blood. In medicine, PFCs find their application as ultrasound imaging contrast agents and oxygen carriers in blood substitutes [ 35 , 66 , 102 , 103 ].…”

Targeted Drug Delivery for Cardiovascular Disease: Modeling of Modulated Extracellular Vesicle Release Rates

“…Besides, noninvasive modulation of drug release is a demand for therapy in future healthcare systems. Recently, Honari et al proposed a novel ultrasound-mediated drug delivery system which can target deep tissue precisely and release drugs rapidly [10]. A new approach to combine some special lowboiling point nanodroplets with drug-loaded liposomes known as droplet-liposome nano-clusters was proposed [10].…”

“…Recently, Honari et al proposed a novel ultrasound-mediated drug delivery system which can target deep tissue precisely and release drugs rapidly [10]. A new approach to combine some special lowboiling point nanodroplets with drug-loaded liposomes known as droplet-liposome nano-clusters was proposed [10]. The droplet-liposome nano-clusters can release drugs in vascular network when focused-ultrasound vaporizes the nanodroplets.…”