Perylenequinones for use as sonosensitizers

Details Perylenequinones for use as sonosensitizers Perylenequinones for use as sonosensitizers

2001-01-30

2003-09-30

Padmanabhan, Sreeni (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ketone doai

C514S732000, C514S717000

Reexamination Certificate

active

06627664

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention involves compositions and methods for treating diseases and the like by administering compounds that are both photosensitizers and sonosensitizers.
BACKGROUND OF THE INVENTION
Treatment for cancer has traditionally encompassed three main strategies: surgery, chemotherapy, and radiotherapy. Although considerable progress in these areas has been attained, the search for more effective and safe alternative treatments continues. Lipson, et al. were the first to use photodynamic therapy (PDT), in 1966 at the Mayo Clinic [
Proc. IX Internat. Cancer Congress
, page 393 (1966)].
Since the advent of PDT, problems have been associated with photosensitizer use, including prolonged cutaneous phototsensitivity; the compositions are oligomeric mixtures of lipophilic molecules prone to molecular aggregation (with concomitant loss of photopotentiation); complicated pharmacokinetics; poor absorption and photoactivation in the “therapeutic window” (600 nm to 850 nm, i.e., visible red light). Furthermore, batch reproducibility, even in the clinical compositions, has been poor.
The photosensitizing properties of perylenequinonoid pigments (PQPs), such as hypocrellins, in biological systems have been recognized during the past two decades. See Diwu, et al.,
J. Photochem. Photobiol. A: Chem.,
64:273 (1992); Zhang et al., (1989); and Wan, et al., “Hypocrellin A, a new drug for photochemotherapy,” Kexue Tongbao (English edition) 26:1040 (1981).
Perylenequinones comprise a growing and highly diverse group of natural pigments, and they posses some unique chemical and biological properties. The natural perylenequinonoid pigments (PQP) identified to date include hypocrellins, cercosporin, phleichrome, cladochrome, elsinochromes, erythroaphins, and calphostins. Most of them are produced by a wide variety of molds. For their general chemical properties [see Weiss, et al.,
Prog. Chem. Org. Nat. Prod.,
52:1 (1987) and Diwu, et al.,
Photochem
&
Photobiol.,
52:609-616 (1990)]. PQP's general photophysical and photochemical properties have been reviewed in Diwu, et al.,
Pharmac. Ther.,
63:1 (1994). Hypocrellins belong to the general class of perylenequinonoid pigments, and include hypocrellin A (HA) and hypocrellin B (HB).
Because of the difficulty of collecting sufficient activated photosensitizer at the site of action, none of the previously known photosensitizers have gained widespread use as therapeutics.
The importance of sonodynamic therapy (SDT) lies ultimately in its similarity to PDT, an elegant and effective tumor treatment whose success is due to the use of light and drug in combination, i.e., two treatment elements, neither of which has toxic effects by itself (Marcus, 1992). PDT has mild side effects, destroys relatively little healthy tissue, and new photosensitizers with better therapeutic indices and improved clinical properties are being developed. The principal impetus for the development of SDT has been improvement upon PDT's dosimetric shortcomings. PDT is currently restricted to use with superficial tumors. Its use on tumors deep within the body requires interstitial irradiation that increases the complexity of the treatment and compromises its noninvasive nature. SDT provides a means to reach such tumors, since ultrasound propagates easily through several centimeters of tissue, and like light, can be focused principally on the tumor mass where it activates the sonosensitizing compound. Targeted SDT offers the possibility of improving the tolerance of this therapy by further restricting its effects to the target tissue.
While these discoveries represent significant advances, two serious deficiencies remain in the development of experimental SDT. A substantial problem is the lack of sonodynamic agents with favorable clinical properties. Porphyrins are known to cause significant cutaneous photosensitivity (Estey et al., 1996), doxorubicin is cardiotoxic (Myers et al., 1976), and DMSO, DMF and MMF are hepatotoxic (Misik and Riesz, 1996). New sensitizers with better sonodynamic properties, which have milder side effects and which are rapidly cleared, would greatly improve the clinical application of SDT. A further problem is the lack of standardization in the conditions used for evaluating sonodynamic agents.
Potential sonodynamic agents have been tested following exposure to ultrasound intensities ranging from 0.25W/cm
2
to 40W/cm
2
, and frequencies from 500 MHz to 1 MHz (Harrison et al., 1991; Sasaki et al., 1998). Though in vivo use would seem to require greater energies due to roughly isotropic dissipation of the ultrasonic energy, little effort has been made to compare experimental conditions in vitro with those in vivo. Where one group will find evidence of sonodynamic effect, different investigators do not under apparently similar conditions. Development of standard insonation and assay systems compatible with clinical use will permit a more rigorous assessment of the sonodynamic effects of current and future sonosensitizers.
Sonodynamic activation of sensitizers has been found to be useful since ultrasound has the appropriate tissue attenuation coefficient for penetrating intervening tissues to reach desired treatment volumes, while retaining the ability to focus energy on reasonably small volumes. Diagnostic ultrasound is a well accepted, non-invasive procedure widely used in the developed world, and is considered safe even for fetal imaging. The frequency range of diagnostic ultrasound lies between 100 kHz-12 MHz, while 50 kHz sound provides enough energy to effect cellular destruction through microregional cavitation.
Sonodynamic therapy provides treatment strategies unavailable in standard photodynamic therapy, due to the limited tissue penetration of visible light. One example would be the treatment of newly diagnosed breast cancer, where local and regional spread of micrometastatic disease remains clinically undetectable. Using immunoconjugates (anti-breast cancer Mab—sonosensitizer hybrids), it would be theoretically possible to selectively eradicate micrometastases in the absence of normal tissue damage.
Beyond these basic properties shared with other waves, ultrasound exhibits unique properties when propagating through water. Above a certain threshold intensity, propagation of ultrasound waves through water elicits an effect termed ‘cavitation’ (Rayleigh, 1917; Connolly and Fox, 1954). Cavitation involves the formation of small bubbles or ‘cavities’ in the water during the rarefaction half of the wave cycle, followed by the collapse of these bubbles during the compression half of the cycle (Putterman, 1995). Cavities focus the energy of the incident ultrasonic radiation by many orders of magnitude (Hiller et al., 1992). The consequence is that regions of cavitation in water are sites of extremely high temperature and pressure. Estimates of the temperatures generated in a collapsing cavity range from 5000K to 10
6
K (Suslick et al. 1986; Flint and Suslick, 1991; Misik and Riesz, 1995; Kaiser, 1995).
The biological effects of exposure to ultrasound are the result of its physical and chemical effects. The most obvious biological effects of ultrasound treatment stem from heating of the medium through which it passes. Such heating is exploited during physiotherapy to help heal injured tissues. (Lehmann et al., 1967; Patrick, 1966), and has been investigated as a possible modality for tumor treatment. This is due to the sensitivity of many tumours to hyperthermia, a state in which tissue temperatures are elevated above 42° C. (Doss and McCabe, 1976; Marmor et al., 1979; Sculier and Klastersky, 1981; Bleehen, 1982; Hynynen and Lulu, 1990). Ultrasound has also been used in combination with radiation therapy to improve treatment response in vivo compared to radiotherapy alone (Clarke et al., 1970; Repacholi et al., 1971; Mitsumori et al., 1996). A principal danger in the use of ultrasound for therapeutic purposes is the formation of ‘hotspots’ due to regions of constructive interference and preferen

Affiliated with

Also associated with

Rating

Perylenequinones for use as sonosensitizers does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Perylenequinones for use as sonosensitizers, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Perylenequinones for use as sonosensitizers will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3091788