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Nanobubbles useful as an ultrasonic contrast agent for the lymphatic system

Nanobubbles useful as an ultrasonic contrast agent for the lymphatic system description/claims

This application is a continuation application of application Ser. No. 09/637,516 filed Aug. 11, 2000, which claims benefit under 35 U.S.C. § 119(e) to application Ser. No. 60/148,892, filed Aug. 13, 1999, the disclosures of which are incorporated herein by reference in their entirety.

This invention relates to hollow gas-filled Nanoparticles in a size range optimized for uptake by the lymphatic system and to their method of use in identifying sentinel lymph notes around tumors by means of echographic imaging techniques.

Solid tumor cancers often spread through lymph channels to regional lymph nodes. Because of this tendency, elective lymph node dissection has become a recognized treatment for patients with early stage melanoma, breast, and other cancers. Many surgeons believe that elective lymph node dissection in a patient with micrometastases can prolong the patient's life and, if conducted early enough, cure the disease. Elective lymph node dissection, however, benefits only those patients with micrometastases and is unnecessary in many cases. This is a matter of concern because dissection of the entire lymphatic drainage basin is a major surgical procedure associated with a number of potential short- and long-term complications including increased surgical trauma and scarring, risk of nerve damage, possible reduced immune system function, and lymphedema.

Sentinel lymph node identification and dissection is a relatively new technique wherein the surgeon performs a biopsy of a few of the lymph nodes surrounding the tumor of a cancer patient to determine if the tumor has metastasized to those lymph nodes near the tumor. These so-called “sentinel nodes” are the first nodes that receive drainage from lymph ducts around a tumor. Studies have shown that the pathologic status of the sentinel nodes accurately predicts the status of all the lymph nodes along the drainage path. Thus, if the sentinel nodes are free of metastatic cells, the other subsequent nodes are most likely free of cancer as well and formal lymphadenectomy (and its associated morbidity) can be avoided.

Current techniques for the identification of sentinel lymph nodes involve the subcutaneous injection of visible dyes and/or colloidal radioactive tracers around a tumor. After allowing time for the peripheral uptake of these materials into the lymphatic system and their migration to the sentinel nodes, the nodes are localized visually or with a gamma probe, respectively. The use of radioactive tracers and gamma probes has the added benefit of being non-invasive. Sentinel nodes identified by either method can then be removed entirely or samples of tissue removed for evaluation by a pathologist. In some cases the tissue sample is collected by aspiration with a fine needle using ultrasound to guide the collection.

Other imaging technologies such as computerized tomography (CT) and magnetic resonance imaging (MRI) have historically been used to aid in the examination of lymph nodes and the identification of cancerous nodes that are grossly altered in their size or structure. Lymphatic contrast agents for CT and MRI, such as iodinated nanoparticles, perfluorobromide emulsions, gadolinium diethylenetriaminepentaacetic acid and colloidal magnetite have been used to enhance images with these modalities. These technologies can only detect the presence of a sizeable, well-defined tumor mass and have not been routinely applied to the identification of the sentinel nodes.

Sonography has also been used for imaging cancerous lymph nodes. Intravenous injection of microbubbles derived from the dissolution of galactose has been used as an ultrasound contrast agent to assess the vascular architecture of suspected cancerous lymph nodes. However, application of this imaging modality for sentinel node identification has not heretofore been considered because an ultrasonic contrast agent with the necessary size spectrum and acoustic properties has yet to be described.

It is well known that gas-containing microparticles, sometimes called microbubbles, are efficient backscatterers of ultrasound energy. Thus, microbubbles injected interstitially or into the bloodstream can enhance ultrasonic echographic imaging to aid in the visualization of biological structures such as the internal organs or the cardiovascular system. Contrast is achieved when acoustic impedance between two materials at an interface is different. Thus, the greater the impedance difference between the two materials the greater the intensity of the ultrasound echo. Since there is a large difference between the acoustic impedance between body tissue and gas, microbubbles offer excellent ultrasound contrast to aid in delineating biological structures that otherwise would be difficult to distinguish.

There are a number of commercially available ultrasound systems commonly used for imaging biological tissues. Each of these instruments offer the user the ability to select from a variety of transducers with different acoustic characteristics and provide different imaging modes to detect and process the sound waves. Choice of transducer and imaging mode to be employed depends upon factors influencing the acoustic characteristics of the specific regions to be imaged. These factors include the distance from the transducer, the density or type of the target tissue and adjacent or intervening tissues, use of contrast agent, and blood flow. A detailed description of the principles of ultrasound including the variety of transducer types, the different imaging modes (B-mode, power doppler, pulse inversion, etc.) and the factors influencing their use can be found in Diagnostic Ultrasound by Frederick W. Kremkau.

Most current applications for echographic contrast rely upon the intravascular injection of the agent and its delivery to the area of interest via the bloodstream. These contrast agents must be small enough to traverse the vascular system but should be as large as possible to maximize backscatter for ease and sensitivity of detection. For example, contrast agents used for visualizing cardiac function are typically injected intravenously. Before agent can perfuse the tissues of the heart, it must first pass through the pulmonary capillary network. As a result of these competing demands, the practical size range of vascular contrast agents is approximately 1 to 10 microns in diameter. Larger bubbles, though more easily detected, fail to pass through the capillary network and smaller bubbles, though unrestrained by the capillary network, are detected poorly.

Microbubbles in the 1 to 10 micron size range, however, are not suitable for use in the lymphatic system. Passive entry is constrained by the dimensions of openings of the initial lymphatic vessels. Numerous studies in animals using the interstitial delivery of particles of different sizes have demonstrated that, as particle size increases, accumulation in the lymphatic system decreases. While particulate entry into the lymphatic system is also influenced by other factors such as particle surface characteristics and the physical motion or massage of the tissue at the site of delivery, absolute maximum particle size limits seem to be around one micron in diameter or, more specifically, in the 0.5 to 1 micron range. The increasing clinical use of radioactive tracers for sentinel node identification in humans afflicted with either melanoma or breast cancer provides additional data regarding particulate uptake by the initial lymphatics which is generally consistent with the data generated from animal studies. There are currently three commonly used technetium-99m labeled colloidal tracers used for lymphoscintigraphy. These are albumin, sulfur, and antimony trisulfide. Each are characterized by different physicochemical properties, including size. There is as yet no consensus on the optimal radiopharmaceutical agent for sentinel node identification. It may be that different agents are more or less effective depending upon the location of the tumor or other factors. Nevertheless, a number of studies report improved detection with colloids of larger size (200-1000 nm) relative to smaller colloids (<200 nm) (See for example: Paganelli et al, Q J Nuclear Medicine 42, 49 (1998); De Cicco et al, Semin. Surg. Oncology 15, 268 (1998); De Cicco et al, J. Nuclear Med. 39, 2080 (1998); Linehan et al, J. Am. Coll. Surgery 188, 377 (1999)).

In U.S. Pat. No. 5,496,536, a method of diagnosing disease of the lymph nodes by means of lymphography is disclosed comprising the use of a contrast agent in colloidal or particulate form wherein the mean particle size is between 5 and about 900 nanometers.

Solid and liquid particles, and particularly those less than a micron in diameter, have been shown to be poor backscatterers of ultrasound and hence have not traditionally been useful as echographic contrast agents. Air trapping particles of a size range of less than about 900 nanometers, while potentially superior to solid or liquid nanoparticles, presents special challenges not only in their manufacture but also for optimizing a lymphatic ultrasound contrast agent due to the influence of size on its acoustic properties. Such a gas-filled nanoparticle shall hereafter be referred to as a nanobubble.

Incident signals from the ultrasonic scanner interact with the bubbles and a portion of this energy is remitted back to the sender, which generated the signals initially. The amount of backscatter, IIs, depends upon the bubble's scattering cross-section and the intensity of the emitted signal. Medwin (Medwin, H., “Counting Bubbles Acoustically: a Review”, Ultrasonics 15 January 1977, pp 7-14.) discussed this process and gives,

IIs=Ie*σbs  (1)

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