Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy

Abstract

Metallotetrapyrrolic compounds having photherapeutic properties useful in photodetection and phototherapy of target issues, particularly porphyrins and azaporphyrins that including gallium in the central pyrrolic core. Also disclosed are methods of using metallotetrapyrrolic compounds for the treatment or detection of cardiovascular disease.

Description

DESCRIPTION OF THE INVENTION [0001] 1. Field of the Invention [0002] This invention relates to metallotetrapyrrolic compounds having phototherapeutic properties utilizable in photodynamic therapy for photodetection and phototherapy of target tissues. [0003] 2. Background of the Invention [0004] Photodynamic therapy (“PDT”) is a new modality for the treatment of malignancies, diseased tissue, hyperproliferating tissues, normal tissues or pathogens. PDT involves a localized or systemic administration of a photosensitizing compound followed by exposure of target tissue to photoactivating light. The photoactivating light excites the photosensitizer which, in turn, interacts with singlet oxygen causing the production of cytotoxic oxygen species. The interaction of the cytotoxic oxygen species with tissues in which the photosensitizer is localized causes a modification of the tissue, resulting in a desired clinical effect. The tissue specificity of the resultant phototoxic damage is deter...

AI Technical Summary

Problems solved by technology

In addition, the biological factors that result in the preferential uptake of some photosensitizers in certain tissue types compared to others is not well understood either.

The occlusion of vessel lumen caused by the plaque leads to reduced blood flow, higher blood pressure and ultimately ischemic heart disease, if untreated.

Unfortunately, in some cases drug therapy can have side effects and does not control progressive or acute atherosclerosis.

Although bypass surgery has become an accepted surgical procedure, it can present substantial morbidity risks, is expensive and generally requires extended hospital care.

Moreover, the procedure is often limited to proximal vessels to the heart and the long-term prognosis is less than satisfactory.

The exact mechanisms responsible for the restenotic process are not fully understood and thus it is not surprising that at present there are no proven clinical therapies to prevent it.

Nevertheless, recent studies in man and animals have shown that two events, intimal thickening and abnormal geometric remodeling, occur following PTA.

However, while stents hold an artery open and significantly reduce acute closure—restenosis rates have been reduced with stents from 40% to 20-35%—it is clear that stents have not eliminated the problem.

Neointimal hyperplasia, i.e., new tissue growth through the sides of the stents, has created a new problem, in-stent restenosis.

Interventional cardiologists have tried to remove this proliferative tissue with rotational and directional atherectomy, cutting balloons, eximer lasers, and deployment of another stent (stent sandwich), but none of these has shown to be effective.

Poor delivery of the gene therapy to the target vessel and immune reactions to some delivery vectors, however, have been major drawbacks for this method.

However, a study recently failed to show the effectiveness of beta radiation (Beta-Cath system clinical trial; Novoste, 2001, Kuntz, et al, J. American College of Cardiology, Feb, 2001) in preventing renarrowing of de novo coronary lesions, i.e., lesions that have not yet been treated with either PTA or stenting.

Moreover, in animal and human studies it has been found that if the dose of radiation is too high, there is no healing of the lumenal endothelial lining of the intima resulting in an increased risk of late-onset thrombosis.

These products all have technical challenges.

The efficacy in animal models to date has been unimpressive and each is still far from commercialization.

While several of the photosensitizers described above have been used to treat atheromatous plaques and some are able to display some inhibition of intimal hyperplasia in animal models, many if not all have characteristics that will limit the usefulness of these drugs in a clinical setting.

A photosensitizer delivered systemically with a long half-life (CASPc, Photofrin, SnET2) may have phototoxic side effects if exposed to direct light, within days of the procedure.

Experiments that we have performed in pig arteries with new photosensitizer candidates at light activation >600 nm have resulted in unacceptable levels of damage to myocardial or cardiac muscle tissue surrounding the treatment area.

Attempts to lower the light dosimetry in order to limit treatments to the target tissue (media / intima) leads to long treatment times and less efficacy.

In addition, long treatment times in the artery exposes the patient to additional risks with inflation and deflation of the balloon devices.

Thus, in our opinion, long wavelength absorbing molecules (>600 nm), unless highly selective to target myocardial and intimal tissues (which has not to date been reported with any photosensitizer in cardiovascular tissues), may cause unacceptable normal cardiac tissue damage.

In addition, protoporphyrin IX and photofrin do not display absorption maximas at 532 nm, thus they may be inefficient at absorbing treatment light at this wavelength and have very low molar extinction coefficients at 575 nm (˜7000 cm−1 / M−1).

Furthermore, because long wavelength photosensitizers by design have red absorption peaks, operating room lighting in an emergency situation may cause serious photosensitivity in light exposed tissues.

Attempts to use red light filters on operating room lights to minimize tissue damage due to the red light penetration results in poor tissue contrast and sub-optimal lighting conditions, making surgical procedures under these conditions extremely difficult, if not impossible.

Blue lasers are available, and even though most of the photosensitizers that have been used in cardiovascular diseases have blue absorptions, the light output of these devices currently limits their applicability to high power light treatments.

Thus, photosensitizers being activated in the blue region may suffer larger therapeutic inconsistancies if small amounts of blood are present within the vessel treatment area.

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