In vitro evaluation of polymeric nanoparticles with a fluorine core for drug delivery triggered by focused ultrasound

Abstract

Polymeric nanoparticles are being intensively investigated as drug carriers. Their efficiency could be enhanced if the drug release can be triggered using an external stimulus such as ultrasound. This approach is possible using current commercial apparatus that combine focused ultrasound with MRI to perform ultrasonic surgery. In this approach, nanoparticles made of a perfluoro-octyl bromide core and a thick polymeric (PLGA-PEG) shell may represent suitable drug carriers. Indeed, their perfluorocarbon core are detectable by 19 F MRI, while their polymeric shell can encapsulate drugs. However, their applicability in ultrasound-triggered drug delivery remains to be proven. To do so, we used Nile red as a model drug and we measured its release from the polymeric shell by spectrofluorometry. In the absence of ultrasound, only a small amount of Nile red release was measured (<5%). Insonations were performed in a controlled environment using a 1.1 MHz transducer emitting tone bursts for a few minutes, whereas a focused broadband hydrophone was used to detect the occurrence of cavitation. In the absence of detectable inertial cavitation, less than 5% of Nile red was released. In the presence of detectable inertial cavitation, Nile red release was ranging from 10 to 100%, depending of the duty cycle, acoustic pressure, and tank temperature (25 or 37℃). Highest releases were obtained only for duty cycles of 25% at 37℃ and 50% at 25℃ and for a peak-to-peak acoustic pressure above 12.7 MPa. Electron microscopy and light scattering measurements showed a slight modification in the nanoparticle morphology only at high release contents. The occurrence of strong inertial cavitation is thus a prerequisite to induce drug release for these nanoparticles. Since strong inertial cavitation can lead to many unwanted biological effects, these nanoparticles may not be suitable for a therapeutic application using ultrasound-triggered drug delivery.

Targeted drug release from stable and safe ultrasound-sensitive nanocarriers

“…The core has been hypothesized to be a critical factor in governing the effectiveness of ultrasoundbased drug release (Wu et al, 2018; Rapoport et al, 2011; Somaglino et al, 2021). Indeed, our 900 kHz data show (Figure 3, right, red) that at the range of commonly applied ultrasound frequencies (≥ 1 MHz), the core is a key determinant of release effectiveness.…”

“…The in vitro release data presented here contribute to the understanding of the release mechanism. Thus far, the predominant hypothesis of action has been the vaporization of the PFC droplet upon the impact of focused ultrasound (Sheeran et al, 2013; Shpak et al, 2014; Doinikov et al, 2014; Wu et al, 2018; Rapoport et al, 2011; Somaglino et al, 2021). In this mechanism, the thermal and mechanical aspects of propagating ultrasound exceed the vaporization threshold governed by the PFC boiling point and the Laplace pressure.…”

“…Several groups have shown that ultrasound can release drugs from nano-sized structures stabilized with biocompatible shells (Rapoport et al, 2007; Rapoport et al, 2009; Rapoport et al, 2011; Rapoport et al, 2015; Rapoport, 2016; Airan et al, 2017; Boissenot et al, 2017; Airan et al, 2017; Wang et al, 2018; Zhong et al, 2019; Wu et al, 2018; Lea-Banks and Hynynen, 2021; Lea-Banks et al, 2021; Somaglino et al, 2021). These nano-sized structures have been commonly filled with perfluorocarbon (PFC) cores.…”

“…For instance, FDA approvals have been readily granted to PFCs with high boiling points to be administered into humans in large quantities (Castro and Briceno, 2010; Li et al, 2018). Nonetheless, drug-release from such nanoparticles appears to be less effective (Boissenot et al, 2017; Somaglino et al, 2021). In this study, we tested whether such high-boiling-point-based nanoparticles could be activated with ultrasound of particular parameters.…”

Nanotechnology as a Versatile Tool for 19F-MRI Agent’s Formulation: A Glimpse into the Use of Perfluorinated and Fluorinated Compounds in Nanoparticles

“…PEGylation of PLGA polymer is a widely used approach for increasing the half-life of the NPs in the bloodstream, and it was reestablished with PLGA-PEG nanocapsule encapsulated with PFOB [210]. For probing ultrasound-triggered drug release, PFOB loaded PLGA-PEG NPs encapsulated with Nile red had been investigated, which proved that the mentioned NPs are least suitable for the function due to the requirement of robust inertial cavitation [211]. Cruz et al manipulated PEGylated PLGA NPs for the detection and monitoring of ischemic diseases and traumatic brain injury, using optical microscopy and 19 F MRI [212].…”