Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
2001-03-09
2003-06-03
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C549S223000
Reexamination Certificate
active
06572839
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a sensitizer for tumor treatment, which is to be used in the treatment of such a disease as tumor by ultrasound irradiation, and to an ultrasonic treatment system and a modality of ultrasonic therapy, in which that sensitizer is used. More specifically, it relates to a sensitizer given the amphiphilicity (both hydrophilicity and lipophilicity) and thus increased in its accumulation in the tumor tissue as derived from a sensitizer having a xanthene dye structure by modifying that structure, and to an ultrasonic treatment system and a modality of ultrasonic therapy, in which that sensitizer is used.
In recent years, even in cancer treatment, attention has been paid to the quality of life of posttreatment patients and, therefore, treatment modalities by which the region of tumor alone might be treated selectively and which would cause less damage to the body except for the region of tumor have been demanded. To develop such a modality of therapy, sonodynamic therapy which uses ultrasound and a sensitizer therefor (Reference 1: Jpn. J. Cancer Res., 80, 219-222, 1989) has become a target of study.
In this modality, an agent administered in advance is activated locally as an antitumor agent by means of waves and thereby the tumor region alone is treated, like in photodynamic therapy (Reference 2: Cancer Res., 39, 146-151, 1979) which is already in clinical application.
In photodynamic therapy, there is a theoretical problem that since the wavelength of a laser beam, thereof the attenuation coefficient in the living body, is restricted, the target of treatment is limited to superficial tumor located at most several millimeters deep from the surface. On the other hand, in sonodynamic therapy, the relation between the wavelength of an ultrasonic wave and the attenuation coefficient thereof is appropriate to the human body and therefore the therapy is characterized in that ultrasonic waves can be focused not only on superficial tumor but also on tumor located in a deep region. Therefore, sonodynamic therapy, if put to practical use, is expected to play a role in low invasive therapy, along with photodynamic therapy, in the target of therapy where it is preferable.
Referring to the above-mentioned sonodynamic therapy, various techniques have been explored through physical and chemical approaches and new techniques have been developed with respect to both system and agent.
In sonodynamic therapy, acoustic cavitation is thought to play an important role in the mechanisms of that therapy. Acoustic cavitation is a phenomenon of bubbles formed upon ultrasound irradiation growing and collapsing, and biological reactions are produced mechanically and chemically by the very high pressure and temperature temporarily generated on the occasion of the collapse.
Techniques for efficiently introducing this acoustic cavitation have been developed, for example the technique comprising irradiating ultrasound while switching the acoustic fields (Reference 3: JP Kokai H02-126848) and the technique comprising superimposing the second harmonics on the fundamentals (Reference 4: International laid-open Patent Specification WO 94/06380). When these techniques are used, acoustic cavitation can be introduced at a lower level of acoustic intensity.
On the other hand, through the agent side approach, the present inventors previously proposed an acoustic cavitation promoter for lowering the acoustic intensity threshold required for introducing acoustic cavitation in which a sensitizer having a xanthene dye structure is used (Reference 5: International laid-open Patent Specification WO 98/01131).
Further, it is known, as a basic mechanism of sonodynamic tumor treatment, that the use of a substance capable of generating active oxygen due to a chemical effect of ultrasound can increase the sonochemical antitumor effect (Reference 6: JP Kokai H06-29196). It is also known that sensitizers having a xanthene dye structure, which are acoustic cavitation promoters, are active oxygen-producing substances.
BRIEF SUMMARY OF THE INVENTION
In addition to the foregoing, it is important that the agent be capable of being accumulated in tumor tissues. In sonodynamic therapy, the spatial selectivity of the region to be treated is attained principally by the irradiation of focused ultrasound. However, when the treatment of that tumor located in a deep region of a living body or the treatment of a tumor species showing a complicated boundary between normal tissues and tumor tissues, such as infiltrative or disseminated tumor, is taken into consideration, it is essential for realizing safer and more effective therapy that the agent to be administered be itself capable of being accumulated in tumor tissues.
Therefore, for an agent to be ideal for sonodynamic therapy, it is desired that the agent have three characteristics simultaneously, namely (1) acoustic cavitation promoting activity, (2) ability to produce antitumor effects and (3) potential for being accumulated in tumor tissues.
Tumor tissues tend to take up lipoproteins to maintain their vigorous growth and have lymphoid tissues poorly formed, hence lipoproteins once taken up by them can hardly be excreted therefrom. A highly lipophilic agent, which has high affinity for lipoproteins, is thought to migrate with lipoproteins and be readily accumulated in tumor tissues. On the other hand, for an agent to be administered to the living body, it is essential that the agent have hydrophilicity as well.
Therefore, for an agent to be capable of being accumulated in tumor cells, it is desirable that the agent be endowed with a balance between lipophilicity and hydrophilicity and be high in both characteristics, namely be amphiphilic. Sensitizers having a xanthene dye structure are generally very high in hydrophilicity but very low in lipophilicity and, therefore, for improving their accumulation in tumor tissues, it is conceivable that their lipophilicity be increased. For increasing the lipophilicity, it is a common practice to introduce a lipophilic functional group such as an alkyl group. With such type of compound, however, the hydrophilic region is remote from the lipophilic region in the molecule, hence the compound will supposedly take a micelle-like form in body fluids; the possibility that the above characteristics (1) and (2) originally possessed by the compound be adversely affected is high.
Accordingly, it is an object of the present invention to provide a sensitizer containing a xanthene dye structure and endowed with the characteristic (3), namely ability to be accumulated in tumor tissues, without the above characteristics (1) and (2) being impaired.
One of the approaches for obtaining the compound aimed at by the invention is the one previously proposed by the present inventors and described in the above-cited reference 5. This comprises dimerizing a sensitizer having a xanthene dye structure and serving as an acoustic cavitation promoter simultaneously having antitumor activity to thereby render the same lipophilic.
Since, however, such sensitizer dimerization has problems on synthesizes, for example a lot of labor is required for isolation, the inventors made attempts to obtain a desired compound through another approach. The process in which the present invention was created is described below in detail.
When an attempt is made to improve the lipophilicity of an agent by mere introduction of a lipophilic group, in particular when a lipophilic group is introduced while sacrificing a hydrophilic functional group, the hydrophilicity may possibly decrease and the administration to a living body may become difficult. It is conceivable that a hydrophilic group be newly introduced to avoid the decrease in hydrophilicity due to lipophilic group introduction. However, in such a case, too, if the lipophilic group and hydrophilic group introduced are intramolecularly remote from each other, the product agent will become micelle-like in body fluids, as discussed above, and the cavitation promoting effect will expectedly
Kawabata Ken-ichi
Sakata Isao
Sasaki Kazuaki
Sugita Nami
Umemura Shin'ichiro
Antonelli Terry Stout & Kraus LLP
Hitachi , Ltd.
Padmanabhan Sreeni
Wells Lauren Q.
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