Sonodynamic therapy using an ultrasound sensitizer compound

Details Sonodynamic therapy using an ultrasound sensitizer compound Sonodynamic therapy using an ultrasound sensitizer compound

1999-11-08

2002-12-24

Shaw, Shawna J. (Department: 3737)

Surgery

Diagnostic testing

Detecting nuclear, electromagnetic, or ultrasonic radiation

C601S002000, C604S022000, C424S009100, C600S431000

Reexamination Certificate

active

06498945

ABSTRACT:

This invention relates to the use of ultrasound-susceptibility modification agents, e.g. water-soluble polymers such as polyalkylene oxides and derivatives thereof, surfactants, oil-in-water emulsions, stabilized particles and certain chromophoric groups such as sulfonated dyes, in methods of treatment of the human or animal body by sonodynamic therapy.
BACKGROUND OF THE INVENTION
The use of dye compounds in photodynamic therapy (PDT) is well established. In PDT, a dye compound, e.g. a porphyrin, which accumulates at a disease site (e.g. a tumor) is administered to the patient whereafter the disease site is illuminated with light of a wavelength absorbed by the dye compound. The resultant localized presence of singlet oxygen destroys cells at the disease site.
Recently it has been found that certain dye compounds, in particular porphyrins, can achieve a similar cytopathogenic effect when the disease site is subjected to ultrasound irradiation. This technique is referred to as sonodynamic therapy (SDT) and is discussed for example by Jeffers et al. in IEEE Ultrasonics Symposium, 1991, pages 1367-1370, Umemura et al. in Ultrasonics Sonochemistry 3: S187-191 (1996), Yumita et al. in Jpn J. Cancer Res. 80: 219-222 (1989), Umemura et al. in Jpn J. Cancer Res. 81: 962-966 (1990), Umemura et al. in Jpn J. Cancer Res. 84: 582-588 (1993), Yumita et al. in Jpn J. Cancer Res. 87: 310-316 (1996), Yumita et al. in Cancer Letters 112: 79-86 (1997), Miyoshi et al. in Radiation Research 143: 194-202 (1995), Kessel et al. in Int. J. Radiat. Biol 66: 221-228 (1994) and Kessel et al in J. Photochem. and Photobiol. B. Biology 28: 219-221 (1995)
SUMMARY OF THE INVENTION
As used herein, the term “sonodynamic therapy agent” is synonymous with “ultrasound-susceptibility modification agent”. An effective amount of one or more SDT agent of this invention together with an effective amount of ultrasound acoustic energy, when administered to cells in a human or animal body such as diseased cells and cells that cause disease, is cytopathogenic to those cells. In the absence of said effective amount of sonodynamic therapy agent, the effective amount of ultrasound acoustic energy is substantially non-cytopathogenic to the cells, and in the absence of said effective amount of ultrasound acoustic energy, the effective amount of sonodynamic therapy agent is substantially non-cytopathogenic to the cells.
“Cytopathogenic” is herein meant to include the terms cytotoxic, cytolytic, cytocidic, cytoclastic, cytostatic as well as other descriptors which relate to the onset or potentiation or initiation of cell death, cell fragmentation, cell rupture, cell dormancy, or change in one or more cellular function to effect a change from a diseased to a non-diseased state including from infection to non-infection, relative to the human or animal body.
SDT has an advantage over PDT in that ultrasound penetrates more deeply into the body than the light used in PDT which is rapidly diffused by scattering over millimeter distances.
One aspect of the present invention is based on the realization that certain materials, for example water soluble polymers (e.g. hexamers and higher polymers), in particular polyalkyleneoxide compounds, are also effective sensitizer agents in sonodynamic therapy (SDT).
By a sensitizer agent is meant a material which enhances the cytopathogenic efficacy of the SDT procedure. “Sensitizer agent” herein is synonymous with sonodynamic therapy (SDT) agent. Such an agent may be administered on its own or in combination with other sensitizer agents such as the porphyrin compounds discussed in the literature references listed above.
Thus viewed from one aspect the invention provides a method of treatment of the human or animal body (e.g. a vascularized mammalian, avian or reptilian body) by sonodynamic therapy in which a sensitizer agent is administered to said body and said body is exposed to ultrasound to achieve a cytopathogenic effect at a site (e.g. a tumor site) therein, wherein the said sensitizer agent is a physiologically tolerable substance which is capable of enhancing the cytopathogenic efficacy of said sonodynamic therapy.
The sensitizer agent may be selected from water-soluble polymers and derivatives thereof, surfactants, oil-in-water emulsions, stabilized particles and certain chromophoric groups such as sulfonated dyes. Preferably the sensitizer agent is a water-soluble polymer, such as a polyalkylene oxide, or a derivative thereof. Viewed from a further aspect the invention provides the use of a physiologically tolerable water-soluble polymer compound or a conjugate thereof for the manufacture of a sensitizer composition for use in a method of sonodynamic therapy.
In the method of the invention, the target site for SDT is preferably exposed to ultrasound irradiation before commencement of the SDT as this may facilitate uptake of the sensitizer agent at the target site.
The water-soluble polymer compounds useful as sensitizer agents in accordance with the invention conveniently have a molecular weight of 150 to 1000000 (especially 500 to 500000, most preferably 1000 to 50000), and preferably are hexamers or higher polymers. The polymers preferably contain monomer residues contributing 2 to 6 atoms to the polymer backbone, especially 2, 3 or 4 atoms. Optionally the polymers contain groups which can act as free radical precursors or groups susceptible to oxidation to produce such groups. Particularly preferably the polymers contain ether or hydroxyl groups or groups having heteroatom:heteroatom bonds (for example nitrogen-nitrogen, nitrogen-oxygen or oxygen-oxygen bonds, e.g. peroxide bonds). The polymers may conveniently comprise residues of monomers such as alkylene oxides, hydroxyalkyl-acrylates or methacrylates, vinyl alcohol, vinyl pyrrolidone, acrylamide, styrenes, etc. The polymer compounds are optionally partially oxidized, e.g. being hydroperoxides or peroxides, i.e. carrying pendant groups —OOH or —OOR
1
(where R
1
is a linear, branched, and/or cyclic alkyl or alkenyl group containing up to 30 carbons or is a hydroxy residue, such as PEG-). The introduction of such groups may frequently be effected by exposure of the polymer to air or oxygen. Peroxy groups may be introduced by treatment with a hydroperoxide in the presence of a metal catalyst such as a salt of cobalt, magnesium, or copper, e.g. cuprous chloride as described by Sosnovsky and Rawlinson (Organic Peroxides Vol. 2, p.153-268, Interscience, New York 1970). The presence of such groups or bonds leads to the compounds functioning as radical precursors, convertible to free radicals under the action of ultrasound irradiation in SDT.
By a conjugate is meant a composition of matter, e.g. a compound or aggregate, which contains a polymeric moiety, preferably a residue of a polymeric compound as described in the previous paragraph, attached to one or more further moieties, e.g. a chromophore, a targeting vector or a reporter moiety. Thus although the polymeric moiety may be conjugated to a chromophore, the polymeric moiety need not itself be a chromophore and simple non-chromophoric non-conjugate (water soluble) polymers may be used to advantage in the method of the invention.
As used herein, a branched polymer is a polyalkylene oxide moiety which contains at least one branching group to which is attached at least one additional polyalkylene oxidyl group.
In one aspect, a branching group in the backbone of the polyalkylene oxide moiety can be selected from the group consisting of a nitrogen atom and a carbon atom. At least one additional polyalkylene oxidyl group can be attached to the branching group by a chemical bond selected from the group consisting of carbon-carbon, carbon-nitrogen, and carbon-oxygen chemical bonds, or by a linking group.
Preferred linking groups to a nitrogen branching group include:
methylene groups, [—CH
2
—];
poly(methylene) groups, [—(CH
2
)
n
—] wherein n is an integer from 2 to about 16, such as can be formed by reaction between a nitrogen NH group and an alkylenyl group containing

Affiliated with

Also associated with

Rating

Sonodynamic therapy using an ultrasound sensitizer compound does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Sonodynamic therapy using an ultrasound sensitizer compound, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Sonodynamic therapy using an ultrasound sensitizer compound will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2997012