Contrast ultrasound targeted drug and gene delivery: an update on a new therapeutic modality.
01 Jul 2002-Journal of Cardiovascular Pharmacology and Therapeutics (J Cardiovasc Pharmacol Ther)-Vol. 7, Iss: 3, pp 171-180
TL;DR: Recent work in the emerging field of contrast ultrasound-based therapeutics, with particular emphasis on the delivery of drugs and genes to tissue through microvascular networks is reviewed.
Abstract: The effective delivery of intravascular drugs and genes to regions of pathology is dependent on a number of factors that are often difficult to control. Foremost is the site-specific delivery of the payload to the region of pathology and the subsequent transport of the payload across the endothelial barrier. Ultrasound contrast agent microbubbles, which are typically used for image enhancement, are capable of amplifying both the targeting and transport of drugs and genes to tissue. Microbubble targeting can be achieved by the intrinsic binding properties of the microbubble shells or through the attachment of site-specific ligands. Once microbubbles have been targeted to the region of interest, microvessel walls can be permeabilized by destroying the microbubbles with low-frequency, high-power ultrasound. A second level of targeting specificity can be achieved by carefully controlling the ultrasound field and limiting microbubble destruction to the region of interest. When microbubbles are destroyed, drugs or genes that are housed within them or bound to their shells can be released to the blood stream and then delivered to tissue by convective forces through the permeabilized microvessels. An alternative strategy is to increase payload volume by coinjecting drug- or gene-bearing vehicles, such as liposomes, with the microbubbles. In this manifestation, microbubbles are used for creating sites of microvessel permeabilization that facilitate drug or gene vehicle transport. Recent work in the emerging field of contrast ultrasound-based therapeutics, with particular emphasis on the delivery of drugs and genes to tissue through microvascular networks is reviewed.
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Iran University of Medical Sciences1, Sharif University of Technology2, Research Institute of Petroleum Industry3, Shahid Beheshti University4, University of Kerala5, Kharazmi University6, Islamic Azad University7, Tehran University of Medical Sciences8, Boston University9, Harvard University10, University of Tehran11, Massachusetts Institute of Technology12
TL;DR: This review highlights the recent advances of smart MNPs categorized according to their activation stimulus (physical, chemical, or biological) and looks forward to future pharmaceutical applications.
Abstract: New achievements in the realm of nanoscience and innovative techniques of nanomedicine have moved micro/nanoparticles (MNPs) to the point of becoming actually useful for practical applications in the near future. Various differences between the extracellular and intracellular environments of cancerous and normal cells and the particular characteristics of tumors such as physicochemical properties, neovasculature, elasticity, surface electrical charge, and pH have motivated the design and fabrication of inventive “smart” MNPs for stimulus-responsive controlled drug release. These novel MNPs can be tailored to be responsive to pH variations, redox potential, enzymatic activation, thermal gradients, magnetic fields, light, and ultrasound (US), or can even be responsive to dual or multi-combinations of different stimuli. This unparalleled capability has increased their importance as site-specific controlled drug delivery systems (DDSs) and has encouraged their rapid development in recent years. An in-depth understanding of the underlying mechanisms of these DDS approaches is expected to further contribute to this groundbreaking field of nanomedicine. Smart nanocarriers in the form of MNPs that can be triggered by internal or external stimulus are summarized and discussed in the present review, including pH-sensitive peptides and polymers, redox-responsive micelles and nanogels, thermo- or magnetic-responsive nanoparticles (NPs), mechanical- or electrical-responsive MNPs, light or ultrasound-sensitive particles, and multi-responsive MNPs including dual stimuli-sensitive nanosheets of graphene. This review highlights the recent advances of smart MNPs categorized according to their activation stimulus (physical, chemical, or biological) and looks forward to future pharmaceutical applications.
1,072 citations
TL;DR: Therapeutic applications of ultrasound predate its use in imaging, but useful therapeutic effects are now being demonstrated clinically, the mechanisms by which they occur are often not well understood.
Abstract: Therapeutic applications of ultrasound predate its use in imaging. A range of biological effects can be induced by ultrasound, depending on the exposure levels used. At low levels, beneficial, reversible cellular effects may be produced, whereas at high intensities instantaneous cell death is sought. Therapy ultrasound can therefore be broadly divided into "low power" and "high power" applications. The "low power" group includes physiotherapy, fracture repair, sonophoresis, sonoporation and gene therapy, whereas the most common use of "high power" ultrasound in medicine is probably now high intensity focused ultrasound. Therapeutic effect through the intensity spectrum is obtained by both thermal and non-thermal interaction mechanisms. At low intensities, acoustic streaming is likely to be significant, but at higher levels, heating and acoustic cavitation will predominate. While useful therapeutic effects are now being demonstrated clinically, the mechanisms by which they occur are often not well understood.
558 citations
TL;DR: There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has on cells and drug-carrying vesicle and makes cell membranes and capillaries more permeable to drugs.
Abstract: Ultrasound (US) has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Cavitating gas bodies such as microbubbles are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilize cell membranes and disrupt the vesicles that carry drugs. Thus the presence of microbubbles enormously enhances delivery of genetic material, proteins and smaller chemical agents. Delivery of genetic material is greatly enhanced by ultrasound in the presence of microbubbles. Attaching the DNA directly to the microbubbles or to gas-containing liposomes enhances gene uptake even further. US-enhanced gene delivery has been studied in various tissues including cardiac, vascular, skeletal muscle, tumor and even fetal tissue. US-enhanced delivery of proteins has found most application in transdermal delivery of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; it also makes the cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has upon cells and drug-carrying vesicles.
557 citations
Cites background from "Contrast ultrasound targeted drug a..."
...The collapse events appear to permeabilise the vessel walls and provide pathways for extravasation of DNA that is freely floating with the bubbles, or that is associated with the bubble surface [47,52]....
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...1 DNA and gene delivery Gene delivery is a topic of intense interest in targeted drug delivery [43-49]....
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TL;DR: The recent advances of microbubbles as a vehicle for delivery of drugs and genes, and possible therapeutic applications in thrombolysis are reviewed and discussed.
Abstract: The development of ultrasound contrast agents, containing encapsulated microbubbles, has increased the possibilities for diagnostic imaging. Ultrasound contrast agents are currently used to enhance left ventricular opacification, increase Doppler signal intensity, and in myocardial perfusion imaging. Diagnostic imaging with contrast agents is performed with low acoustic pressure using non-linear reflection of ultrasound waves by microbubbles. Ultrasound causes bubble destruction, which lowers the threshold for cavitation, resulting in microstreaming and increased permeability of cell membranes. Interestingly, this mechanism can be used for delivery of drugs or genes into tissue. Microbubbles have been shown to be capable of carrying drugs and genes, and destruction of the bubbles will result in local release of their contents. Recent studies demonstrated the potential of microbubbles and ultrasound in thrombolysis. In this article, we will review the recent advances of microbubbles as a vehicle for delivery of drugs and genes, and discuss possible therapeutic applications in thrombolysis.
396 citations
TL;DR: This research investigated the capacity of acoustically active liposomes for hydrophilic molecule encapsulation and to determine their sensitivity to ultrasound-triggered release, finding that release of contents was highly correlated with the loss of air induced either by ultrasound or rapid pressure reduction.
278 citations
References
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TL;DR: MBF can be quantified with myocardial contrast echocardiography during a venous infusion of microbubbles and has potential for measuring tissue perfusion in any organ accessible to ultrasound.
Abstract: Background—Ultrasound can cause microbubble destruction. If microbubbles are administered as a continuous infusion, then their destruction within the myocardium and measurement of their myocardial ...
1,631 citations
TL;DR: The echo pattern of the aortic root is elicited by locating the typical echo of the mitral valve and then angulating the transducer medially and sometimes cephalically.
Abstract: The echo pattern of the aortic root is elicited by locating the typical echo of the mitral valve and then angulating the transducer medially and sometimes cephalically. The characteristic echo pattern of the aortic root consists of paired undulating signals three to five cm apart. These signals move
908 citations
"Contrast ultrasound targeted drug a..." refers background in this paper
...The ability of microbubbles to generate enhancement of ultrasonic images from within the body has been known for over three decades (1,2)....
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TL;DR: A gas-filled microbubble with anti-ICAM-1 antibody on its shell specifically binds to activated ECs overexpressing ICam-1.
Abstract: Background—Preclinical atherosclerosis is associated with increased endothelial cell (EC) expression of leukocyte adhesion molecules (LAMs), which mediate monocyte adhesion during atherogenesis. Identification of cell-surface LAMs may uniquely allow assessment of endothelial function, but there are no in vivo methods for detecting LAMs. We tested a new microbubble designed to bind to and allow specific ultrasound detection of intercellular adhesion molecule-1 (ICAM-1). Methods and Results—A perfluorobutane gas–filled lipid-derived microsphere with monoclonal antibody to ICAM-1 covalently bound to the bubble shell was synthesized. Bubbles with either nonspecific IgG or no protein on the shell were synthesized as controls. Coverslips of cultured human coronary artery ECs were placed in a parallel-plate perfusion chamber and exposed to 1 of the 3 microbubble species, followed by perfusion with culture medium. Experiments were performed with either normal or interleukin-1β–activated ECs overexpressing ICAM-1,...
816 citations
"Contrast ultrasound targeted drug a..." refers background in this paper
...One of the earliest published studies of microbubble targeting to endothelium was done in vitro (25)....
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TL;DR: The results indicate that monocyte activation plays a major role in angiogenesis and collateral artery growth in rabbits after femoral artery occlusion.
Abstract: We have previously shown that monocytes adhere to the vascular wall during collateral vessel growth (arteriogenesis) and capillary sprouting (angiogenesis). In this study we investigated the association of monocyte accumulation with both the production of the cytokines-basic fibroblast growth factor (bFGF) and TNF-alpha-and vessel proliferation in the rabbit after femoral artery occlusion. In particular, we studied the effects of an increase in monocyte recruitment by LPS on capillary density as well as collateral and peripheral conductance after 7 d of occlusion. Monocytes accumulated around day 3 in collateral arteries when maximal proliferation was observed, and stained strongly for bFGF and TNF-alpha. In the lower limb where angiogenesis was shown to be predominant, macrophage accumulation was also closely associated with maximal proliferation (around day 7). LPS treatment significantly increased capillary density (424+/-26.1 n/mm2 vs. 312+/-20.7 n/mm2; P < 0.05) and peripheral conductance (109+/-33.8 ml/min/100 mmHg vs. 45+/-6.8 ml/min/100 mmHg; P < 0.05) as compared with untreated animals after 7 d of occlusion. These results indicate that monocyte activation plays a major role in angiogenesis and collateral artery growth.
774 citations
"Contrast ultrasound targeted drug a..." refers background in this paper
...we hypothesize that local inflammation created by capillary rupturing is the most likely candidate because, in addition to a number of studies linking TMLR-induced inflammation to neovascularization (31-36), other studies have demonstrated that arteriogenesis may be stimulated either by the systemic injection of monocyte chemoattractant protein-I (38,39) or by the amplification of local monocyte recruitment (40) through the administration of lipopolysaccharide....
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TL;DR: It is suggested that activation of monocytes plays an important role in collateral growth as well as in capillary sprouting in animals with MCP-1 treatment.
Abstract: Monocytes are activated during collateral artery growth in vivo, and monocyte chemotactic protein-1 (MCP-1) has been shown to be upregulated by shear stress in vitro. In order to investigate whether MCP-1 enhances collateral growth after femoral artery occlusion, 12 rabbits were randomly assigned to receive either MCP-1, PBS, or no local infusion via osmotic minipump. Seven days after occlusion, isolated hindlimbs were perfused with autologous blood at different pressures, measuring flows at maximal vasodilation via flow probe and radioactive microspheres, as well as peripheral pressures. This allowed the calculation of collateral (thigh) and peripheral (lower limb) conductances from pressure-flow tracings (slope of the curve). Collateral growth on postmortem angiograms was restricted to the thigh and was markedly enhanced with MCP-1 treatment. Both collateral and peripheral conductances were significantly elevated in animals with MCP-1 treatment compared with the control group, reaching values of nonoccluded hindlimbs after only 1 week of occlusion (collateral conductance, 70.6 +/- 19.23 versus 25.1 +/- 2.59 mL/min per 100 mm Hg; P < .01; peripheral conductance, 119.3 +/- 22.37 versus 45.4 +/- 6.80 mL/min per 100 mm Hg; P < .05). These results suggest that activation of monocytes plays an important role in collateral growth as well as in capillary sprouting.
509 citations
"Contrast ultrasound targeted drug a..." refers background in this paper
...we hypothesize that local inflammation created by capillary rupturing is the most likely candidate because, in addition to a number of studies linking TMLR-induced inflammation to neovascularization (31-36), other studies have demonstrated that arteriogenesis may be stimulated either by the systemic injection of monocyte chemoattractant protein-I (38,39) or by the amplification of local monocyte recruitment (40) through the administration of lipopolysaccharide....
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