Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions

Abstract

Perfluorocarbon nanoemulsions can deliver lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or 19F MRI. In the first generation of block copolymer stabilized perfluorocarbon nanoemulsions, perfluoropentane (PFP) was used as the droplet forming compound. Although manifesting excellent therapeutic and ultrasound imaging properties, PFP nanoemulsions were unstable at storage, difficult to handle, and underwent hard to control phenomenon of irreversible droplet-to-bubble transition upon injection. To solve the above problems, perfluoro-15-crown-5-ether (PFCE) was used as a core forming compound in the second generation of block copolymer stabilized perfluorocarbon nanoemulsions. PFCE nanodroplets manifest both ultrasound and fluorine (19F) MR contrast properties, which allows using multimodal imaging and 19F MR spectroscopy for monitoring nanodroplet pharmacokinetics and biodistribution. In the present paper, acoustic, imaging, and therapeutic properties of unloaded and paclitaxel (PTX) loaded PFCE nanoemulsions are reported. As manifested by the 19F MR spectroscopy, PFCE nanodroplets are long circulating, with about 50% of the injected dose remaining in circulation two hours after the systemic injection. Sonication with 1-MHz therapeutic ultrasound triggered reversible droplet-to-bubble transition in PFCE nanoemulsions. Microbubbles formed by acoustic vaporization of nanodroplets underwent stable cavitation. The nanodroplet size (200 nm to 350 nm depending on a type of the shell and conditions of emulsification) as well as long residence in circulation favored their passive accumulation in tumor tissue that was confirmed by ultrasonography. In the breast and pancreatic cancer animal models, ultrasound-mediated therapy with paclitaxel-loaded PFCE nanoemulsions showed excellent therapeutic properties characterized by tumor regression and suppression of metastasis. Anticipated mechanisms of the observed effects are discussed.

Polymer-Grafted Mesoporous Silica Nanoparticles as Ultrasound-Responsive Drug Carriers

“…17,18 Ultrasound waves can induce thermal and/or mechanical effects that could trigger the release of the drug from a collection of nanocarriers, such as liposomes, micelles, microbubbles, etc. 16 Moreover, advances in sonochemistry have shown that ultrasound-induced chemical reactions can differ from those carried out by bulk heating, implying mechanical or thermal effects at the nanoscale.…”

Phase-transition Perfluorocarbon Nanoparticles for Ultrasound Molecular Imaging and Therapy

“…Thereby, the traditional therapeutic efficacy are dramatically increased as a result of the enhancement of intracellular uptake on nanoparticles, genes, and drugs [19,29,[102][103][104][105]. …”

“…The phase-transition PFC nanoparticles as effective drug carriers were first reported in this study on account of the regression of tumor growth using PFP droplets to successfully deliver doxorubicin (DOX) into tumor tissues. And then, more valuable work has been explored by Rapoport [12,19,29,103] et al For instance, the PFC nanoemulsions encapsulated paclitaxel (PTX) can enhance the ultrasoundmediated tumor imaging on the ultrasonic therapy of pancreatic cancer and breast cancer in animal models due to the significant therapeutic characterizations based on tumor regression and suppression of metastasis [29].…”

“…One of the most promising examples is the perfluorocarbon (PFC) nanoparticles, because its characters of nontoxic biocompatibility and low solubility in aqueous liquids are extremely essential for medical application [24][25][26][27]. The most important thing is that PFC nanoparticles advance a way to solve the above problem for the reason that they would effectively accumulate in tumor tissues beyond to blood vessels and then convert into microbubbles under ultrasound irradiation to enhance the ultrasound imaging [19,28,29]. In that case, the ability of PFC nanoparticles to combine imaging efficacy and therapeutic capability may remarkably improve the early assessment of response to treatment and considerably promote the development of personalized therapy [21,30,31].…”

Crucial factors and emerging concepts in ultrasound-triggered drug delivery

“…The advantage of the use of liquid perfluorocarbons is that they can be emulsified in water when stabilized by an appropriate surfactant (e.g. pluronic, lipids) [34][35][36]. Such nanodroplets are typically smaller than 200 nm, which allows them to extravasate from the leaky tumor vasculature [37].…”