Patent Application
20080221382
Embodiments of the invention relate to radiotherapy and, more particularly, to method and system of radiotherapy using ultrasound and microbubbles.
It has been found that microbubble agents exposed to ultrasound can perturb vascular endothelial cells in blood vessels, thereby rendering tissues and tumors more sensitive to the therapeutic effects of radiation. Microbubble contrast agents for ultrasound comprise microspheres of gas, usually air or a perfluorocarbon, stabilized by a thin shell of biocompatible material such as protein or lipid. A number of agents are approved for clinical use: one example is Definity made by Bristol-Myers Squibb of Boston Mass., which is perfluoropropane within a lipid shell. The median bubble diameter is 1-4 μm so that the bubbles can pass to the systemic circulation following peripheral venous injection. Microbubble contrast ultrasound imaging methods such as pulse inversion imaging exploit the nonlinear response of bubbles to an ultrasound field and allow real-time imaging of flowing or stationary bubbles in the vasculature, suppressing echoes from the tissue that surrounds them, and thus allowing perfusion imaging with ultrasound. These methods are widely available on clinical ultrasound scanners.
In addition to allowing visualization of the vasculature, acoustic exposure of bubbles at or near their resonant frequency can perturb the function of nearby cells; with effects including a reversible increase of cell membrane permeability. Phenomena related to acoustic bubble disruption, such as the formation of local microjets and shockwaves are capable of permeabilizing, as well as destroying a cell. Preliminary studies in laboratories have also shown the ability of ultrasound to enhance the uptake of drug analogues in a reversible manner that leaves the cell viable. Stable bubble oscillation and acoustic microstreaming are probably implicated, although there is little direct evidence. Proposed applications for this interaction include permeabilizing the blood-brain barrier for drug delivery, permeabilizing cells to introduce therapeutic agents or genes, and treating intravascular thrombi.
Bubbles can also be created in situ by the combined use of ultrasound and liquid droplets administered intravenously. For example, perfluorocarbon droplets can be vaporized by ultrasound to form gas bubbles. The advantage of such a method is that at the ultrasound exposures below the vaporization threshold the fluid droplets are practically transparent to the propagating ultrasound field and thus the cavitation or vaporization effect can be localized completely at the desired location.
In general, radiation is a major anti-cancer therapy and is currently used to treat a majority of patients with tumors in Europe and North America. Canonical radiobiology recognizes that radiation acts primarily by damaging cancer-cell DNA leading to cell death. However, emerging data indicate that radiation-induced apoptotic effects on blood-vessel cells can lead to vascular destruction and subsequent secondary tumor-cell death. In this view, it is the endothelial cell lining the vasculature that is proposed as the primary target for radiation. It is postulated that this vascular death may be an important mechanism of tumor kill in vivo, so that tumor cells die secondarily to damage caused by radiation to the microvasculature. Though the relative contributions of radiation-induced vascular effects and clonogenic tumor-cell death are not fully understood, efforts to optimize radiation treatment attempt to account for vascular effects, for example, by using drugs that target tumor blood vessels in combination with radiation.
It has been demonstrated that single large doses of radiation preferentially damage gut endothelial cells causing apoptosis and that epithelial stem-cell death is secondary to this. These results have been recapitulated in lung and brain tissue. Conversely, basic fibroblast growth factor (bFGF), a vascular protective agent, enhances epithelial stem-cell survival from whole-body irradiation. Some studies conclude that early phase microvascular endothelial apoptosis is mandatory for tumor cure. Other work has shown that tumors grown in apoptosis resistant mice, with deficiency in asmase (acid-sphingomyelinase) or bax (a pro-apoptotic member of the Bcl-2 family of proteins), were completely resistant to 15-20 Gy single dose irradiation. The same asmase-deficient mice, lacking a gene for acid-sphingomyelinase, an enzyme enriched in endothelial cells and required for apoptosis, were also protected from other radiation effects. Thus it is suggested that radiation-induced lesions in tumor cells were by themselves not lethal but their conversion to lethal damage is connected to the endothelial cell function.
These results lead to the idea of modifying tumor radiosensitivity by inhibiting endothelial-cell protectors and decreasing endothelial cell stimulators, thus increasing radiosensitivity with better treatment outcomes using lower doses of radiation. To date, pharmacological or chemical agents have been used. Among other problems, these methods of administration are not spatially specific in the body, and can create problems of toxicity: for example, histone-deacetylase inhibitors are effective radiosensitizers whose application is limited by high toxicity.
There is, therefore, a need for a method and system to improve effects of radiotherapy on tumorous tissue while minimizing effects on neighboring normal tissue.
An embodiment of the invention is related to a system for providing radiotherapy to a treatment region. The system includes a radiation source and a sound source. The radiation source is positioned to irradiate the treatment region. The sound source is positioned to provide ultrasound to the treatment region so that the treatment region is subject to coincidental treatment by irradiation and ultrasound.
Another embodiment of the invention is related to a method of providing radiotherapy to a treatment region. According to the method, microbubbles are provided within vasculature of the treatment region. The treatment region is exposed to ultrasound to cause perturbation of vascular endothelial cells within the treatment region. The treatment region is also exposed to radiation.
Certain details are set forth below to provide a sufficient understanding of embodiments of the invention. However, it will be clear to one skilled in the art that embodiments of the invention may be practiced without these particular details. Moreover, the particular embodiments of the present invention described herein are provided by way of example and should not be used to limit the scope of the invention to these particular embodiments.
With the system depicted in
When there is a desired or maximal microbubble concentration within the tumor vasculature, the subject may be exposed to ultrasound, directed at the tumor or target area so as to expose the tumor or target area with a predetermined set of parameters, such as mechanical index, frequency, pulse duration and repetition frequency for a preset period of time. This is intended to cause microbubble oscillation and/or disruption to result in perturbation of vascular endothelial cells within the tumor while minimizing effects of the treatment outside of the tumor. The above ultrasound parameters may be controlled through information derived from real time ultrasound imaging. Afterwards, the subject may undergo radiotherapy by being exposed to radiation. Alternatively, the administration of radiation may precede or be carried out simultaneously with the aforementioned procedures of imaging the subject to locate the tumor, administration of intravenous contrast agent or administration of an exogenous material to produce microbubbles in the treatment region, and exposure to ultrasound.
This process may be repeated with every radiation fraction during a course of treatment or with selected fractions. It may be used with fractionated or non-fractionated treatment. It may be used with external beam radiation, brachytherapy (intracavitary, interstitial or other), or targeted radiation treatments (for instance, but not limited to, radioconjugated antibodies). Embodiments of the invention may be used in conjunction with therapeutic agents, such as drugs that are targeted to disrupt or inhibit the vasculature. The ultrasound exposure may be guided by ultrasound imaging, other imaging methods known in the art or yet to be developed, or a combination of imaging methods.
An embodiment of the invention includes a device that provides ultrasound-mediated microbubble cellular perturbation which enhances the response of cells to radiation. Various embodiments of the invention include its use in vivo to enhance tumor responses to radiation by perturbing the vasculature and should permit radioenhancement to be conformally targeted to a tumor, thus minimizing effects on neighboring normal tissue. The method is used prior to, during, or shortly after the delivery of radiation to enhance and localize the therapeutic effects of radiation. Embodiments of the invention are applicable not only to elicit the conformal targeting of radioenhancement prior to or after external beam radiation, but can also be used to conformally target radioenhancement prior to or after brachytherapy or other modes of delivery of radiotherapy.
Embodiments of the invention may include the above process as well as any technology that enables the process or is used in connection with the process or to carry it out. One implementation is by using a stand-alone ultrasound unit or an ultrasound device combined with a radiotherapy device whereby the ultrasound device is used to visualize the tumor. This or a separate ultrasound device may also be used to selectively perturb the vascular endothelial cells within the tumor so as to conformally radiosensitize the tumor.
As will be appreciated by those ordinarily skilled in the art, embodiments of the invention provide a technique to improve effects of radiotherapy on tumorous tissue while minimizing effects on neighboring normal tissue by use of ultrasound and microbubbles. The effect of the ultrasound treatment is to sensitize the target region T to the effects of radiotherapy. The disclosed procedure relies on the fact that microbubble agents exposed to ultrasound can perturb vascular endothelial cells in blood vessels, thereby rendering tissues and tumors more sensitive to the therapeutic effects of radiation. The radiotherapy might be administered by irradiation from an external beam or by the implantation of radioactive sources in the target region, such as in brachytherapy. The radiotherapy may be administered before, during or after the ultrasound treatment. An imaging system can be used to co-localize the ultrasound and radiotherapy treatments.
From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.
This application claims the benefit of U.S. Provisional Application No. 60/906,114, filed Mar. 9, 2007.
| Number | Date | Country | |
|---|---|---|---|
| 60906114 | Mar 2007 | US |
