BACKGROUND OF THE INVENTION

Field of Invention

The invention relates to methods and systems for treating cell proliferation disorders, that provide better distinction between normal, healthy cells and those cells suffering a cell proliferation and preferably that can be performed using non-invasive or minimally invasive techniques.

Discussion of the Background

Light modulation from a deeply penetrating radiation like X-ray opens the possibility for activating bio-therapeutic agents of various kinds within mammalian bodies. As an example, the binding of psoralen to DNA through the formation of monoadducts is well known to engender an immune response if done properly. Psoralen under the correct light activation gains the aptitude to bind to DNA. Psoralen has been reported to react to other sites that have a suitable reactivity including and not limited to cell walls. If this reaction is of the correct kind, as is the case for psoralen-DNA monoadducts formation, the binding leads to a programmable cell death referred to as Apoptosis. Such programmable cell death, if accomplished over a cell population, can signal the body to mount an immune response permitting target specific cell kill throughout the body. Such immune response is of importance for various medical treatments including cancer treatment.

Psoralens are naturally occurring compounds found in plants (furocoumarin family) with anti-cancer and immunogenic properties. They freely penetrate the phospholipid cellular bilayer membranes and intercalate into DNA between nucleic acid pyrimidines, where they are biologically inert (unless photo-activated) and ultimately excreted within 24 hours. However psoralens are photo-reactive, acquiring potent cytotoxicity after ‘activation’ by ultra-violet (UVA) light. When photo-activated, psoralens form mono-adducts and di-adducts with DNA leading to marked tumor cytotoxicity and apoptosis. Cell signaling events in response to DNA damage include up-regulation of p21wal/Cipand p53 activation, with mitochondrial induced cytochrome c release and consequent cell death. Photo-activated psoralen can also induce apoptosis by blocking oncogenic receptor tyrosine kinase signaling, and can affect immunogenicity and photochemical modification of a range of cellular proteins in treated cells.

Importantly, psoralen can promote a strong long-term clinical response, as observed in the treatment of cutaneous T Cell Lymphoma utilizing extracorporeal photopheresis (ECP). fir ECP malignant CTCL cells are irradiated with ultraviolet A (UVA) light in the presence of psoralen, and then re-administered to the patient. Remarkably, complete long term responses over many decades have been observed in a sub-set of patients, even though only a small fraction of malignant cells were treated. In addition to ECP, psoralens have also found wide clinical application through PUVA treatment of proliferative skin disorders and cancer including psoriasis, vitiligo, mycosis fungoides, and melanoma.

The cytotoxic and immunogenic effects of psoralen are often attributed to psoralen mediated photoadduct DNA damage. A principle mechanism underlying the long-term immunogenic clinical response likely derives from psoralen induced tumor cell cytotoxicity and uptake of the apoptotic cells by immature dendritic cells, in the presence of inflammatory cytokines. However, photochemical modification of proteins and other cellular components can also impact the antigenicity and potential immunogenicity of treated cells. The diversity and potency of psoralen application is further illustrated by recent success using psoralen in the development of virus vaccines.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a phosphor-containing drug activator comprising an admixture of two or more phosphors, which include Zn2SiO4:Mn2°and (3Ca3(PO4)2Ca(F, Cl)2: Sb3+, Mn2+) at a ratio from 1:10 to 10:1, wherein each of the two phosphors have at least one coating selected from the group consisting of an ethylene cellulose coating and a diamond-like carbon coating. The admixture is preferably in dry solid/powder form.

In one embodiment, there is provided a suspension of the phosphor-containing drug activator. The suspension at least includes two or more phosphors capable of emitting ultraviolet and visible light upon interaction with x-rays. The two or more phosphors include Zn2SiO4:Mn2+and (3Ca3(PO4)2Ca(F, Cl)2: Sb3+, Mn2+) at a ratio from 1:10 to 10:1, and each of the two phosphors have at least one coating selected from the group consisting of an ethylene cellulose coating and a diamond-like carbon coating. The suspension further includes a pharmaceutically acceptable carrier.

In one embodiment, there is provided a system for treating a disease in a subject in need thereof The system includes a) the above-noted suspension, b) a photoactivatable drug comprising 8 MOP or UV ALEX untethered from the two or more phosphors, c) one or more devices which infuse the photoactivatable drug and the suspension including the pharmaceutically acceptable carrier into a diseased site in the subject, and d) an x-ray source which is controlled to deliver a dose of x-rays to the subject for production of the ultraviolet and visible light inside the subject to activate the photoactivatable drug and induce a persistent therapeutic response, said dose comprising a pulsed sequence of x-rays delivering from 0.5-2 Gy to the tumor.

In further embodiments, there are provided methods for treating a disease in a subject in need thereof using the phosphor-containing drug activator, either in its dry admixture form or its suspension form. One method includes a) infusing the photoactivatable drug and the suspension including the pharmaceutically acceptable carrier into a diseased site in the subject, and b) delivering a dose of x-rays to the subject for production of the ultraviolet and visible light inside the subject to activate the photoactivatable drug and induce a persistent therapeutic response, said dose comprising a pulsed sequence of x-rays delivering from 0.5-2 Gy to the tumor. A further method includes a) hydrating the dry admixture of the phosphor-containing drug activator, b) combining the hydrated form of the phosphor-containing drug activator with the photoactivatable drug, with the combining either being subsequent to the hydrating or simultaneously with the hydrating, and c) delivering a dose of x-rays to the subject for production of the ultraviolet and visible light inside the subject to activate the photoactivatable drug and induce a persistent therapeutic response, said dose comprising a pulsed sequence of x-rays delivering from 0.5-2 Gy to the tumor.

It is to be understood that both the foregoing general description of the invention and the following detailed description are exemplary, but are not restrictive of the invention.

