Surgery: light – thermal – and electrical application – Light – thermal – and electrical application – Light application
Reexamination Certificate
2003-03-25
2004-11-23
Gibson, Roy D. (Department: 3739)
Surgery: light, thermal, and electrical application
Light, thermal, and electrical application
Light application
C128S898000
Reexamination Certificate
active
06821289
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to photodynamic therapy of malignant tumors or diseased tissue with enhanced cellular proliferation using photosensitizing agents that accumulate selectively in the diseased tissue. In particular, the present invention relates to time-separated, multiple administrations of photosensitizer to enhance accumulation of the photosensitizer in diseased tissue to improve light sensitivity in the diseased tissue (efficacy) and to enhance the safety for normal tissue.
2. Information Disclosure Statement
Photodynamic therapy (PDT) is a well-known method for treatment of cancer and other hyperproliferative diseases. Such other hyperproliferative diseases comprise the skin disease psoriasis, as well as arthritis, a chronic inflammatory disease of the joints.
In PDT, a photosensitizer (PS) is applied to the organism and is expected to accumulate in diseased hyperproliferative tissue to a greater extent than in normal tissue. This differential accumulation is due to several factors. In the blood, the PS is bound to plasma proteins to a varied extent. One of these plasma proteins is low density lipoprotein (LDL). LDL can be taken up by tumor cells, or other cells in hyperproliferative diseases to a higher extent than by normal cells. Therefore, a higher amount of PS is delivered to tumor cells or other hyperproliferating tissue. A further factor may be the altered capillary architecture in malignant tissue, leading to enhanced permeability of the capillaries. Furthermore, tumor tissue can have a lower pH than normal tissue. Low pH favors accumulation of PS with carboxylic groups, because these groups bind protons, thus leading to uncharged PS molecules that can penetrate biomembranes easier than charged PS. Another factor is decreased metabolism of the PS in malignant cells.
Differential accumulation of PS is a highly desirable goal in developing methods for PDT, because it helps to protect normal cells and tissues from damage inflicted by irradiation during PDT or, especially in case of the skin, by normal daylight or indoor artificial lighting. So far all known PS, when activated, cause damage to both healthy and diseased cells in their proximity. Thus, the ability of PS to preferentially accumulate in diseased tissue versus normal tissue is an important element of a beneficial treatment by PDT. Ideally, only malignant cells should be destroyed during PDT. The unaltered function of the surrounding normal, healthy cells and the continued presence of intact connective tissue fibers is the basis for good functional and structural (and in many cases good cosmetic) results with PDT. Absence of differential PS accumulation would result in the need for selective irradiation of the malignant cells. This is, however, generally not possible for a satisfactory treatment. Irradiation of tumors in PDT must include a safety margin around the tumor to ensure that all peripheral cancerous cells are destroyed. Furthermore, it is not possible to limit PDT effects in tissue depth exactly to the tumor. There, a safety margin is also necessary.
U.S. Pat. No. 4,957,481 describes single or multiple local administrations of a PS directly into a tumor mass for covering a larger tumor area. For multiple administrations, each administration is spatially separated, so that a specific volume of tissue is exposed to photosensitizers. This patent uses near simultaneous, spatially-separated, multiple administrations to establish and maintain a desired level of photosensitizer across a large volume of diseased tissue to achieve effective PDT treatment. It does not, however provide guidance to increase sensitivity in diseased tissue while maintaining or improving safety for normal tissue.
Another method involving repeated administrations of PS is described in U.S. Pat. No. 5,298,018, which describes the use of Photodynamic Therapy (PDT) as an adjunctive or stand alone procedure for the treatment of cardiovascular disease, specifically to prevent restenosis by blocking access of growth factor to binding sites in smooth muscle cells. The method relies on a pharmacokinetic therapy with or without light therapy, using physical or chemical interactions between the photosensitizers and muscle cells to block the binding sites independent of any light therapy. In this method, a photosensitizer is administered prior to the surgical or interventional procedure and then readministered after the procedure to replace photosensitizer which is cleared or washed out from the cells over time, thus maintaining a photosensitizer concentration in a level sufficient to block the binding sites. This method does not address how to improve efficacy of PDT treatments while maintaining or improving safety for normal tissue.
A method related to U.S. Pat. No. 5,298,018 is described in U.S. Pat. No. 5,422,362 to inhibit the development of intimal hyperplasia following angioplasty procedures. The method consists essentially of administering a green porphyrin to the subject concurrent with and following the angioplasty. Radiation activation of the green porphyrin is not a part of the method. This method therefore does not address PhotoDynamic Therapy treatments. It thus does not deal with how to improve efficacy of PDT treatments while maintaining or improving the safety for normal tissue.
A study of tissue absorption of the photosensitizer Foscan® was performed that features a double photosensitizer administration protocol. [Cramers et al, “Optimisation of photodynamic therapy: the influence of photosensitizer uptake and distribution on tumour respopse”, SPIE Vol. 4156 (2001), p. 63-67; Cramers et al, “Foscan® uptake and tissue distribution in relation to photodynamic efficiency”, British Journal of Cancer (2003) 88, 283-290)] This study is restricted to meta-tetrahydroxyphenylchlorin (mTHPC), known as Foscan®, and relates the “pharmacokinetic and pharmacodynamic parameters for the photosensitiser Foscan to the extent of PDT damage.” The distribution of Foscan in mice was measured after single and double injections of Foscan and the PDT response of tumor and cancer cells was measured. It was determined that the change in concentration in plasma was not significantly different for single and double injections, nor was the relative concentration in skin and tumor tissue significantly different after single or double injections. Thus, these articles demonstrate that essentially multiple administrations of the photosensitizer Foscan does not change the PDT effect of Foscan as compared to single administrations.
There is a need for a method to increase the concentration and selectivity of accumulation of photosensitizers in hyperproliferative or otherwise diseased tissue, both to increase the effectiveness of the treatment and more effectively protect healthy tissue from damage. The present invention addresses this need.
OBJECTIVES AND BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to provide a photodynamic therapy treatment for diseased, hyperproliferative tissues including cancer, psoriasis, arthritis and pre-cancerous lesions, with improved efficacy and safety.
It is a further object of the present invention to provide a photodynamic therapy treatment method that produces higher and more selective concentrations of PS in diseased tissue than is possible with prior art methods.
Briefly stated, the present invention provides a safer, improved method for treating diseased, hyperproliferative tissue, including cancer, psoriasis, and arthritis, using multiple, sequential administrations of a photosensitizer (PS) prior to irradiation. Preferred photosensitizers are characterized by being retained in the diseased tissue for a longer time than in normal tissue. The interval between administrations is chosen to be of sufficient duration to allow the PS content of normal tissues to drop to a basal or negligible level before the next administration and before irradiation. At that time, the PS content of the diseased tissue is still high, not less than ha
Albrecht Volker
Bode Hans-Peter
BJ Associates
CeramOptec Industries Inc.
Gibson Roy D.
Johnson, III Henry M
Skutnik Bolesh J.
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