Ultrasound-enhanced Drug Delivery Research Articles

Physical acoustics lab at the university of oxford

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ID: 329152 A Scoping Review: Focused Ultrasound Enhanced Drug Delivery Across the Blood-Brain Barrier for Brain Tumors

ID: 329152 A Scoping Review: Focused Ultrasound Enhanced Drug Delivery Across the Blood-Brain Barrier for Brain Tumors

A Scoping Review of Focused Ultrasound Enhanced Drug Delivery for Across the Blood-Brain Barrier for Brain Tumors.

Previous mechanisms of opening the blood-brain barrier (BBB) created a hypertonic environment. Focused ultrasound (FUS) has recently been introduced as a means of controlled BBB opening. Here, we performed a scoping review to assess the advances in drug delivery across the BBB for treatment of brain tumors to identify advances and literature gaps. A review of current literature was conducted through a MEDLINE search inclusive of articles on FUS, BBB, and brain tumor barrier, including human, modeling, and animal studies written in English. Using the Rayyan platform, 2 reviewers (J.P and C.Y) identified 967 publications. 224 were chosen to review after a title screen. Ultimately 98 were reviewed. The scoping review was designed to address the following questions: (1) What FUS technology improvements have been made to augment drug delivery for brain tumors? (2) What drug delivery improvements have occurred to ensure better uptake in the target tissue for brain tumors? Microbubbles (MB) with FUS are used for BBB opening (BBBO) through cavitation to increase its permeability. Drug delivery into the central nervous system can be combined with MB to enhance transport of therapeutic agents to target brain tissue resulting in suppression of tumor growth and prolonging survival rate, as well as reducing systemic toxicity and degradation rate. There is accumulating evidence demonstrating that drug delivery through BBBO with FUS-MB improves drug concentrations and provides a better impact on tumor growth and survival rates, compared with drug-only treatments. Here, we review the role of FUS in BBBO. Identified gaps in the literature include impact of tumor microenvironment and extracellular space, improved understanding and control of MB and drug delivery, further work on ideal pharmacologics for delivery, and clinical use.

Nonspherical ultrasound microbubbles

Surface tension provides microbubbles (MB) with a perfect spherical shape. Here, we demonstrate that MB can be engineered to be nonspherical, endowing them with unique features for biomedical applications. Anisotropic MB were generated via one-dimensionally stretching spherical poly(butyl cyanoacrylate) MB above their glass transition temperature. Compared to their spherical counterparts, nonspherical polymeric MB displayed superior performance in multiple ways, including i) increased margination behavior in blood vessel-like flow chambers, ii) reduced macrophage uptake invitro, iii) prolonged circulation time invivo, and iv) enhanced blood-brain barrier(BBB) permeation invivo upon combination with transcranial focused ultrasound (FUS). Our studies identify shape as a design parameter in the MB landscape, and they provide a rational and robust framework for further exploring the application of anisotropic MB for ultrasound-enhanced drug delivery and imaging applications.

The Influence of Nanobubble Size and Stability on Ultrasound Enhanced Drug Delivery.

Lipid-shelled nanobubbles (NBs) are emerging as potential dual diagnostic and therapeutic agents. Similar to their micron-scale counterparts, microbubbles (1-10 μm), they can act as ultrasound contrast agents as well as locally enhance therapeutic uptake. Recently, it has been shown that the reduced size of NBs (<1 μm) promotes increased uptake and accumulation in tumor interstitial space, which can enhance their diagnostic and therapeutic performance. However, accurate characterization of NB size and concentration is challenging and may limit their translation into clinical use. Their submicron nature limits accuracy of conventional microscopy techniques, while common light scattering techniques fail to distinguish between subpopulations present in NB samples (i.e., bubbles and liposomes). Due to the difficulty in the characterization of NBs, relatively little is known about the influence of size on their therapeutic performance. In this study, we describe a novel method of using a commercially available nanoparticle tracking analysis system, to distinguish between NBs and liposomes based on their differing optical properties. We used this technique to characterize three NB populations of varying size, isolated via centrifugation, and subsequently used this to assess their potential for enhancing localized delivery. Confocal fluorescence microscopy and image analysis were used to quantify the ultrasound enhanced uptake of fluorescent dextran into live colorectal cancer cells. Our results showed that the amount of localized uptake did not follow the expected trends, in which larger NB populations out-perform smaller NBs, at matched concentration. To understand this observed behavior, the stability of each NB population was assessed. It was found that dilution of the NB samples from their stock concentration influences their stability, and it is hypothesized that both the total free lipid and interbubble distance play a role in NB lifetime, in agreement with previously proposed theories and models.

Ultrasound-enhanced drug delivery to spinal cord tumors

The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) are major obstacles to the treatment of CNS diseases and disorders as they prevent the passage of most therapeutic agents from the blood pool to the CNS tissue. Transient, reversible opening of the BBB using ultrasound and microbubbles (MBs) has been extensively studied and has reached clinical investigations. Ultrasound and MBs can similarly modify the BSCB, although applications in the spinal cord have received less attention. We have previously demonstrated ultrasound and MB-mediated opening of the BSCB in rodents, as well as in large animals through the intact spine, using a spine-specific pulse scheme called short-burst phase keying (SBPK). In this talk, we will discuss our work evaluating treatment control approaches for controlling SBPK exposures and will present recent results from drug delivery studies in rodent models of primary and metastatic spinal cord tumors.

Gas-stabilizing solid cavitation nuclei for systemic or transdermal ultrasound-enhanced drug and vaccine delivery and immunomodulation

Originally developed for diagnostic purposes and already approved for clinical use, lipid and protein-shelled microbubbles were a natural choice as initial nucleation agents for cavitation-based therapies entering the clinic. However, several emerging therapeutic ultrasound applications require nuclei that: (i) are significantly smaller in size, in order to overcome a particular biological barrier such as the leaky vasculature of tumours or the stratum corneum; (ii) offer greatly increased cavitation persistence, both during a single extended ultrasound pulse and in terms of extended circulation following intravenous administration; (iii) have better resilience to sudden ambient pressure changes in order to enable direct injection without nuclei destruction into tissue targets via a needle and syringe; and (iv) are made of materials or have an increased payload or surface area that can interact beneficially with the relevant tissue target during or following cavitation. Gas-stabilizing solid particles will be reviewed in this context, providing an overview of their known characteristics in terms of size distribution, associated acoustic emissions, cavitation thresholds, cavitation persistence and circulation. The relationship between this acoustic characterization and associated bioeffects including drug and vaccine delivery, and immunomodulation will subsequently be explored.

Targeted ultrasound enhanced drug delivery to foam cell spheroids

Atherosclerosis is a chronic vascular disorder marked by the accumulation of foam cells in the intimal space of the artery. Foam cells are macrophages that reside in the arterial wall after internalizing excessive cholesterol. Though many strategies to remove cholesterol from foam cells have been put forward, delivering these agents at the site of the lesion remains a challenge. Here, we investigated the ability of our previously reported multi-cavity poly-co-lactic-co-glycolic acid microparticles (mc-PLGA MPs) to penetrate into a model for early stage atherosclerosis, a 3D foam cell spheroid, and deliver hydroxyl beta cyclodextrin (HBCD) and sirolimus. HBCD is a polysaccharide that solubilizes cholesterol and promotes cholesterol efflux from foam cells. First, the drug release capability of mcPLGA MPs was tested using DAPI dye as a model drug. Sustained release of DAPI from mcPLGA MPs was observed in foam cell nuclei three days after implantation. We found that DAPI released from mcPLGA MPs distributed evenly throughout the spheroid even though mcPLGA MPs were implanted predominantly at the periphery. FITC conjugated HBCD was co-administered with sirolimus loaded mc-PLGA MPs and was also found to be implanted only under ultrasound exposure. Foam cell viability and the inflammatory response of the ultrasound treatment were also monitored across a week. In conclusion, this study shows the possibility of atherosclerosis treatment with targeted ultrasound enhanced drug delivery.

Remote targeted implantation of sound-sensitive biodegradable multi-cavity microparticles with focused ultrasound

Ultrasound-enhanced drug delivery has shown great promise in providing targeted burst release of drug at the site of the disease. Yet current solid ultrasound-responsive particles are non-degradable with limited potential for drug-loading. Here, we report on an ultrasound-responsive multi-cavity poly(lactic-co-glycolic acid) microparticle (mcPLGA MP) loaded with rhodamine B (RhB) with or without 4′,6-diamidino-2-phenylindole (DAPI) to represent small molecule therapeutics. After exposure to high intensity focused ultrasound (HIFU), these delivery vehicles were remotely implanted into gel and porcine tissue models, where the particles rapidly released their payload within the first day and sustained release for at least seven days. RhB-mcPLGA MPs were implanted with HIFU into and beyond the sub-endothelial space of porcine arteries without observable damage to the artery. HIFU also guided the location of implantation; RhB-mcPLGA MPs were only observed at the focus of the HIFU away from the direction of ultrasound. Once implanted, DAPI co-loaded RhB-mcPLGA MPs released DAPI into the arterial wall, staining the nucleus of the cells. Our work shows the potential for HIFU-guided implantation of drug-loaded particles as a strategy to improve the local and sustained delivery of a therapeutic for up to two weeks.

Ultrasound-Enhanced Drug Delivery for Treatment of Acanthamoeba Keratitis.

Reaching sufficient amounts of therapeutic agents in ocular tissues is a major challenge in ophthalmology. In this study, we examined the effects of ultrasound application for delivery of polyhexamethylene biguanide for treatment of Acanthamoeba keratitis. Ultrasound intensities of 0.5 - 0.8 W/cm2 and frequencies of 400 - 600 kHz were tested with exposure durations of 1 - 5 minutes. Light microscopy was used to determine the ultrasound-induced structural changes in the cornea. All groups showed increases in drug concentration, up to 2.36 times, passing through the cornea, with the 600 kHz treatment groups reaching statistical significance. Structural changes were observed in the epithelial layer of the cornea, but the stroma and endothelium remained mostly unaffected.

Biomedical Applications for Gas-Stabilizing Solid Cavitation Agents.

For over a decade, advancements in ultrasound-enhanced drug delivery strategies have demonstrated remarkable success in providing targeted drug delivery for a broad range of diseases. In order to achieve enhanced drug delivery, these strategies harness the mechanical effects from bubble oscillations (i.e., cavitation) of a variety of exogenous cavitation agents. Recently, solid cavitation agents have emerged due to their capacity for drug-loading and sustained cavitation duration. Unlike other cavitation agents, solid cavitation agents stabilize gaseous bubbles on hydrophobic surface cavities. Thus, the design of these particles is crucial. In this Review, we provide an overview of the different designs for solid cavitation agents such as nanocups, nanocones, and porous structures, as well as the current status of their development. Considering the numerous advantages of solid cavitation agents, we anticipate further innovations for this new type of cavitation agent across a broad range of biomedical applications.

Passive acoustic mapping of extravasation following ultrasound-enhanced drug delivery

The amount and distribution of chemotherapeutic agents delivered to tumours can vary significantly due to tumour heterogeneity, even under focussed ultrasound (FUS) assisted drug delivery regimes. The ability to non-invasively localise cavitation nuclei of a similar size to therapeutic drugs, both within the vasculature and tumour tissue, may provide a useful marker of ultrasound-enhanced drug delivery and extravasation. Solid polymer based nanoscale cavitation nuclei, under FUS excitation, have previously been shown to extravasate into tissue-mimicking phantoms, and to increase drug delivery in murine tumour models in vivo. Here we show in a tissue-mimicking material that these nuclei, once extravasated under FUS excitation, are still acoustically active and can be non-invasively localised using passive acoustic mapping (PAM). By using a high resolution dual linear array setup in conjunction with adaptive beamformers, we demonstrate that the average ‘maximum distance’ of a PAM pixel to an extravasated particle across experiments is mm. Although the primary objective of the paper is to show that extravascular cavitation can be used as evidence of successful drug extravasation in a tissue-mimicking phantom, we also recognise the physical and computational limitations of using a high resolution dual array setup with adaptive beamformers. Thus as a secondary objective, we evaluate tradeoffs between adaptive and non-adaptive beamformers, as well as between dual and single array geometries. When compared to a conventional beamformer, adaptive beamformers reduce the maximum distance of PAM pixels to extravasated particles from an average of mm to mm in the single array case. The distance is further reduced to mm using the dual array configuration, thereby demonstrating that increasing the solid angle spanned by the PAM array aperture significantly improves drug delivery localisation. Future work will test the applicability of PAM-based monitoring of ultrasound-enhanced drug delivery in vivo.

Approximating coupled hyperbolic–parabolic systems arising in enhanced drug delivery

In this paper we study a system of partial differential equations defined by a hyperbolic equation and a parabolic equation. The convective term of the parabolic equation depends on the solution and eventually on the gradient of the solution of the hyperbolic equation. This system arises in the mathematical modeling of several physical processes as for instance ultrasound enhanced drug delivery. In this case the propagation of the acoustic wave, which is described by a hyperbolic equation, induces an active drug transport that depends on the acoustic pressure. Consequently the drug diffusion process is governed by a hyperbolic and a convection–diffusion equation.Here, we propose a numerical method that allows us to compute second-order accurate approximations to the solution of the hyperbolic and the parabolic equation. The method can be seen as a fully discrete piecewise linear finite element method or as a finite difference method. The convergence rates for both approximations are unexpected. In fact we prove that the error for the approximation of the pressure and concentration is of second-order with respect to discrete versions of the H1-norm and L2-norm, respectively. Numerical experiments illustrating the theoretical estimates are also presented. A simplified model for ultrasound enhanced drug transport is also discussed.

Patient-specific large-volume hyperthermia in the liver for ultrasound-enhanced drug delivery from thermosensitive carriers

Ultrasound-mediated mild hyperthermia in the range of 39C to 42C is a promising technique for noninvasive targeted release of thermally sensitive carriers in cancer therapy. The need to sustain a temperature rise of a few degrees evenly throughout a large volume currently limits this therapy to regions with a large accessible acoustic window. Furthermore, the need to continuously scan clinically available highly focused therapeutic ultrasound transducers typically used for ablation limits the volume that can be maintained at this temperature for tens of minutes, and greatly extends treatment time per unit volume. In addition, bone structures, such as the ribs, significantly restrict accessible target locations in areas such as the liver and play a significant role in preventing this therapy from entering into clinical practice. In order to overcome these limitations, we present a combined 3D full wave finite element modelling and experimental approach to design a sectored lens that can be placed on focused transducers to enable direct mild heating of a larger volume in the liver while accounting for patient-specific aberration in the prefocal path. [Work supported by the RCUK Digital Economy Programme, grant number EP/G036861/1 (Oxford Centre for Doctoral Training in Healthcare Innovation).]

Ultrasound-Enhanced Drug Delivery for Treatment of Onychomycosis.

The aim of our study was to determine the effectiveness of using ultrasound (US) to increase the permeability of the nail, with the goal of improving outcomes in the treatment of onychomycosis. Porcine nails were used because of their similarity to human nails. A hydrophilic blue dye was used as a drug-mimicking compound. Two sets of experiments were performed: luminosity experiments to assess the dye levels inside the nail after US and sham treatments and diffusion cell experiments for determination of changes in nail permeability due to US application. In both sets of experiments, planar US transducers were used to sonicate the nails at frequencies of 400, 600, and 800 kHz and 1 MHz, an intensity of 1 W/cm2 , and a duration of 5 min in a continuous mode. Modeling studies were also performed to assess the safety of US application to the human toe for later clinical studies. In the luminosity experiments, application of US at frequencies of 600 and 800 kHz led to statistically significant results (P < .05), with an increase in dye delivery into the nail of up to 95% compared to control values. The diffusion cell results found statistical significance (P < .05) at all applied frequencies, with up to a 70% increase in the nail permeability compared to the control. Safety modeling studies found a maximal temperature increase of 4.4 °C in the bone. Our proposed US method may offer an alternative for improved treatment of onychomycosis. The current maximal temperature increase was found to be at the safety limit, and so pulsing and other alternatives will be investigated to minimize this temperature increase.

Model for Porosity Changes Occurring during Ultrasound-Enhanced Transcorneal Drug Delivery

Ultrasound-enhanced drug delivery through the cornea has considerable therapeutic potential. However, our understanding of how ultrasound enhances drug transport is poor, as is our ability to predict the increased level of transport for given ultrasound parameters. Described here is a computational model for quantifying changes in corneal porosity during ultrasound exposure. The model is calibrated through experiments involving sodium fluorescein transport through rabbit cornea. Validation was performed using nylon filters, for which the properties are known. It was found that exposure to 800-kHz ultrasound at an intensity 2 W/cm2 for 5 min increased the porosity of the epithelium by a factor of 5. The model can be useful for determining the extent to which ultrasound enhances the amount of drug transported through biological barriers, and the time at which a therapeutic dose is achieved at a given location, for different drugs and exposure strategies.

2089953 Ultrasound-Enhanced Drug Delivery for Treatment Of Parasitic Diseases in the Eye

2089953 Ultrasound-Enhanced Drug Delivery for Treatment Of Parasitic Diseases in the Eye

Ultrasound-enhanced drug delivery in prostate cancer xenografts by nanoparticles stabilizing microbubbles

The delivery of nanoparticles to solid tumors is often ineffective due to the lack of specificity towards tumor tissue, limited transportation of the nanoparticles across the vascular wall and poor penetration through the extracellular matrix of the tumor. Ultrasound is a promising tool that can potentially improve several of the transportation steps, and the interaction between sound waves and microbubbles generates biological effects that can be beneficial for the successful delivery of nanocarriers and their contents. In this study, a novel platform consisting of nanoparticle-stabilized microbubbles has been investigated for its potential for ultrasound-enhanced delivery to tumor xenografts. Confocal laser scanning microscopy was used to study the supply of nanoparticles from the vasculature and to evaluate the effect of different ultrasound parameters at a microscopic level. The results demonstrated that although the delivery is heterogeneous within tumors, there is a significant improvement in the delivery and the microscopic distribution of both nanoparticles and a released model drug when the nanoparticles are combined with microbubbles and ultrasound. The mechanisms that underlie the improved delivery are discussed.

Introduction to the special issue on therapeutic ultrasound

In the 1950s, the brothers William and Francis Fry treated a number of patients for Parkinson's disease by focusing high intensity ultrasound on the brains of patients after some part their skull was removed. Local thermal ablations were created in targeted areas of brain and these treatments were shown to be beneficial to the patients. At the same time, in the former USSR, the team of A.K. Burov used high intensity unfocused ultrasound to treat aggressive melanoma cancerous tumors and obtained very promising positive response in a number of patients; similar exposure protocols were used to induce specific immune response in an animal model. However, in those days, imaging systems were in their infancy, no MRI or CT systems were available, and ultrasound technology was not ready to extensively explore the ability of ultrasound to non-invasively induce changes in biological tissue. The advancements in tissue imaging, engineering, and the rapid development of computers that occurred during the last decade have now permitted a new cycle of development of therapeutic ultrasound. Successful medical technologies are already in clinical practice, ranging from tumor treatments to cosmetic applications; clinical studies are under way in ultrasound enhanced drug delivery, sonothrombolysis, and hyperthermia. Recently, a pilot study of the use of focused ultrasound for the treatment of dyskinesia in Parkinson's disease was funded by the Michael J. Fox Foundation bringing back Fry's efforts at a new technological level. Every large acoustics professional meeting, and in particular ASA meetings, include special sessions on therapeutic ultrasound. The annual International Symposium for Therapeutic Ultrasound and the biannual Focused Ultrasound Surgery Foundation Symposium bring world experts together to exchange ideas and accelerate development of this field. Even though therapeutic ultrasound technology is rapidly evolving into clinical practice, basic acoustics still remains an important foundation and a critical component in its successful implementation. This issue represents only a snapshot of the scientific and clinical applications at this moment of time. Many questions are not yet answered. Further progress of the field requires merging new interesting acoustic phenomena with biophysics, engineering solutions, and other exciting interdisciplinary studies. We hope that some of the examples of recent studies presented in this issue will be of general interest to the acoustical community helping to bring a younger generation of acousticians into the field. We also anticipate that some of the results reported in this issue will soon be transitioned into the clinic, resulting in the improvement of health care for our society.

Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound

Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery.