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

Arvin Honari,Darrah A Merillat,Aditi Bellary,Shashank R Sirsi,Mohammadaref Ghaderi

doi:10.3390/pharmaceutics13050609

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.

Highlights

Active targeting of therapeutic molecules to a diseased tissue has long been an area of interest in pharmaceutical drug delivery
Our initial aim of the study was to demonstrate a facile method of producing phase-changeable droplet-liposome clusters (PDLCs) using a single-step strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) click chemistry approach, motivated by Slagle et al [59]
No qualitative difference in negative control and PDLC sample was observed in brightfield microscopy

Summary

Introduction

Active targeting of therapeutic molecules to a diseased tissue has long been an area of interest in pharmaceutical drug delivery. Researchers have developed and evaluated numerous passive or active targeting approaches in the past few decades [1,2,3]; the lack of a reliable targeting strategy persists in clinical applications. Cancer therapy would benefit from better targeting approaches and more effective drug delivery due to the detrimental side effects of highly toxic chemotherapeutics. The most well-known targeting strategy in cancer therapies is the enhanced permeability and retention (EPR) effect, first introduced in 1986 by Matsumura and Maeda [4]. The pursuit of passive targeting approaches, hinging on the EPR effect for cancer therapy, gave rise to the need for nano-sized drug carriers in the 1990s. Many studies have used circulating nanoparticles to deliver drug payloads, most of which relied on leaky vascular tissue in tumors to accumulate small drugs or drug carriers in the tumor [5,6,7,8]

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