Multifunctional Treatment And Diagnostic Compositions And Methods

Abstract

Multifunctional compositions and methods are provided for therapeutic treatment of bacteria and cancers and for fluorescence diagnosis. Systems generate in situ reactive oxygen species such as singlet oxygen (1O2), hydroxyl radical (OH) and Juglone, and other chemotherapeutic agents. Methods provided selectively produce greater amounts of one reactive oxygen species over others. Variations are effective in aerobic, anaerobic or H2O2 rich environments and in presence of, or absence of, light. In H2O2 rich environment in absence of light, variations decompose H2O2 into O2 gas to remove excess H2O2 for elimination of hypoxic environment. Variations are formed of porphyrins, naphthalene derivatives, and metal ions, for illustration, free base tetrakis Ar substituted porphyrine core without metal or halide substitution but having hydroxyphenyl and alkyl pyridyl substituents at meso positions combined with dihydroxynaphthalene and +3 hydrated metal ions.

Description

GOVERNMENT RIGHTS IN INVENTION[0001]This invention was made with support from Research and Creative Activity grant by Texas' Stephen F. Austin State University Research Enhancement Program (RCA) and Texas Research Grant Funding pursuant to The Welch Foundation (AN-0008 Departmental Grant). While neither support source is directly Federally Sponsored Research or Development, the government may have indirect rights in this invention for research, educational, and clinical purposes.BACKGROUND OF THE INVENTION1. Field of the Invention[0002]This invention relates to methods and compositions for therapeutic treatment to slow or stop the progression of bacteria and cancers and for fluorescence diagnosis. In one aspect, this invention relates to multifunctional treatment compositions and methods effective in aerobic, anaerobic or H2O2 rich environments in presence of, or absence of, light.[0003]In another aspect, this invention relates to in situ generation of one or more reactive oxygen sp...

AI Technical Summary

Benefits of technology

[0049]Most surprisingly, in a H2O2 rich environment, treatment compositions of this invention effectively produce {dot over (O)}H and Juglone or derivatives of Juglone by reacting with H2O2 via Fenton-like reaction in absence of light in aerobic conditions. In addition to {dot over (O)}H's formation from H2O2, the composition decomposes H2O2 into O2 gas providing an ability to remove excess toxic H2O2 as well as ability to eliminate hypoxic environment by produced O2 gas.

[0052]Thus, the compositions of this invention have characteristics which slow or stop the progression of bacteria and other cells such as cancers. Treatment can be by a single dose of composition and in other variations, repeated doses are tolerated.

[0054]It is important that I have discovered treatment compositions that can easily be prepared from commercially available chemicals, and without special equipment, skills or training required, allowing potential for them to be readily available at lower cost in developing and developed countries.

Problems solved by technology

Prior art traditional cancer treatments such as surgery, radiation, and traditional chemotherapy have limitations.

In general, such treatments lack selectivity for removing or killing malignant tumor tissues and are costly or highly invasive or administer toxic treatments.

However such metal-based drugs are reported to lack selectivity and have poor water solubility, pharmacological deficiencies, and serious side effects such as kidney and nerve damage, hearing loss, vomiting and others.

In addition, prior art treatments are not easily synthesized or readily available to the poor in developing or developed countries.

Prior art photodynamic therapy (PDT) methods for cancer treatment are an alternative to the traditional methods but also have limitations.

Upon illumination with visible light or other irradiation with excitation light, photosensitizers transfer energy to ground or lower state oxygen and generate highly reactive singlet oxygen (1O2), as a critical intermediate by reacting with cells of targeted adjacent tissues and result in death of cancer cells.

However, tumor hypoxia at a target tumor cell site is a significant problem for prior art PDT compositions and methods.

Tumor hypoxia limits prior art clinical utility because PDT photochemistry highly depends on the presence of oxygen (O2) for producing cancer lethal singlet oxygen (1O2).

Since every photosensitization reaction uses light to sensitize dissolved oxygen (O2) to singlet oxygen (1O2), PDT methods are completely ineffective in the absence of light.

PDT is also currently significantly limited by the insufficient generation of singlet oxygen.

Insufficient generation of singlet oxygen, at least in part, at the target site is due to (i) insufficient photosensitizers localized at the target site, (ii) not enough visible light at the target site, and (iii) photosensitizer not having favorable or suitable triplet excited states.

After much prior art work, issues remain for finding a suitable low-lying triplet porphyrin for efficient singlet oxygen formation with desired phosphorescence emissions (triplet quantum yield of energy at least 94 KJ / mol).

Other significant existing problems with prior art PDT treatments limit their singlet oxygen reactive oxygen species and effectiveness to narrow ranges.

These other limitations include (1) poor solubility of hydrophobic photosensitizers in bodily tissue or injectable solvent, for illustration, hydrophobic porphyrins may form aggregates in aqueous environment leading to insufficient tumor localization; (2) limited penetration of light into fatty and deeper tissues; (3) preparation involves complex organic / inorganic synthesis and difficult purification procedures for obtaining chemically pure PDT effective compounds; (4) need for lower toxicity and rapid clearance from the body; and (5) lack of dual or multiple functionality to address changes in conditions at site of application.

However, the use of these dual photosensitizers was found to be ineffective in the absence of dissolved oxygen and light and are ineffective in an aqueous environment.

However, prior art synthesis of iron-based therapeutics for use in Fenton reaction is expensive and time-consuming and involves complex purification procedures.

Moreover, in some instances, resulting compositions do not pass toxicity tests due to the inherent toxic nature of the associated ligands.

Furthermore, Fenton reactions from prior art iron-based therapeutics form iron-containing sludge (Fe(OH)3) during the course of reaction, which reduce capability for hydroxyl radical production.

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