Converting nanoparticles or monomeric compounds into larger supramolecular structures by endogenous or external stimuli is increasingly popular because these materials are useful for imaging and treating diseases. However, conversion of microstructures to nanostructures is less common. Here, we show the conversion of microbubbles to nanoparticles using low-frequency ultrasound. The microbubble consists of a bacteriochlorophyll-lipid shell around a perfluoropropane gas. The encapsulated gas provides ultrasound imaging contrast and the porphyrins in the shell confer photoacoustic and fluorescent properties. On exposure to ultrasound, the microbubbles burst and form smaller nanoparticles that possess the same optical properties as the original microbubble. We show that this conversion is possible in tumour-bearing mice and could be validated using photoacoustic imaging. With this conversion, our microbubble can potentially be used to bypass the enhanced permeability and retention effect when delivering drugs to tumours.
This study presents a unique approach to understanding the biophysical mechanisms of ultrasound-triggered cell membrane disruption (i.e., sonoporation). We report direct correlations between ultrasound-stimulated encapsulated microbubble oscillation physics and the resulting cellular membrane permeability by simultaneous microscopy of these two processes over their intrinsic physical timescales (microseconds for microbubble dynamics and seconds to minutes for local macromolecule uptake and cell membrane reorganization). We show that there exists a microbubble oscillation-induced shear-stress threshold, on the order of kilopascals, beyond which endothelial cellular membrane permeability increases. The shear-stress threshold exhibits an inverse squareroot relation to the number of oscillation cycles and an approximately linear dependence on ultrasound frequency from 0.5 to 2 MHz. Further, via real-time 3D confocal microscopy measurements, our data provide evidence that a sonoporation event directly results in the immediate generation of membrane pores through both apical and basal cell membrane layers that reseal along their lateral area (resealing time of ∼<2 min). Finally, we demonstrate the potential for sonoporation to indirectly initiate prolonged, intercellular gaps between adjacent, confluent cells (∼>30-60 min). This real-time microscopic approach has provided insight into both the physical, cavitation-based mechanisms of sonoporation and the biophysical, cell-membrane-based mechanisms by which microbubble acoustic behaviors cause acute and sustained enhancement of cellular and vascular permeability.ultrasound therapy | microbubble contrast agent | endothelial membrane | gene delivery | sonoporation D elivery vehicles for therapeutic nucleic acids (e.g., siRNA, mRNA, plasmids, oligonucleotides), including nanoparticles or viruses, are intended to increase the local effectiveness of the therapeutic within a target tissue while reducing off-target effects. A major barrier to the successful delivery of molecular therapeutics in this manner is the endothelial cell membrane. Viral vectors, although able to efficiently deliver genetic material to target cells via their intracellular trafficking machinery, may elicit specific inflammatory and nonspecific antiviral immune responses (1, 2). As an alternative, nonviral vectors--for example, localized needle injection of naked therapeutic nucleic acids or lipofection--use physical forces or compounds, respectively, to deliver a genetic payload into a cell and are generally less toxic and immunogenic than viral vectors (3). However, direct needle injection into the target poses challenges in achieving homogeneous tissue distribution of the payload (4), and clinical implementation is limited by the impractical requirements of repetitive needle injections into sites which may be difficult to access. Systemically injected liposomes face the endothelial barrier, are vulnerable to intravascular destruction and/or renal excretion (depending on size), and, when endocytosed b...
Porphyrin-phospholipid conjugates were used to create photonic microbubbles (MBs) having a porphyrin shell ("porshe"), and their acoustic and photoacoustic properties were investigated. The inclusion of porphyrin-lipid in the MB shell increased the yield, improved the serum stability, and generated a narrow volumetric size distribution with a peak size of 2.7 ± 0.2 μm. Using an acoustic model, we calculated the porshe stiffness to be 3-5 times greater than that of commercial lipid MBs. Porshe MBs were found to be intrinsically suitable for both ultrasound and photoacoustic imaging with a resonance frequency of 9-10 MHz. The distinctive properties of porshe MBs make them potentially advantageous for a broad range of biomedical imaging and therapeutic applications.
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