Photosensitizers with ligand targeting properties for tumor therapy

Abstract

The present invention provides a drug delivery system wherein a "parachute" structure is coupled to a therapeutic compound. The "parachute" structure comprises hydrophilic branched molecular fragments, or a cyclodextrin moiety, with a defined action diameter. The complex (a parachute structure coupled with a therapeutic compound) is either fixed at a cell membrane or delivered to a defined distance from the membrane within the cell. The membrane-anchoring / localizing effect of the parachute is achieved by hydrophilic structures linked with a branching unit of desired therapeutic compounds. Furthermore, the parachute structures can be connected by a spacer (e.g. beta-amino acids, gamma-amino butyric acid, or poly-amino acids) instead of directly binding to the therapeutic compound, so that the therapeutic compounds can be localized within the cells at a defined distance from the cell membrane. A spacer containing a breaking point can determine the time span, during which the drug exhibits its therapeutic activity. The hydrophilic residues can also carry signals for targeting the parachute-therapeutic complex to a defined tissue type. This can be mediated by an antibody which is specific for a tumor marker. Alternatively, a biotin can be attached at C6 position of the sugar and then react with an avidin-labeled tumor-specific antibody. The parachute function may also be achieved by other, more bulky hydrophilic structures such as oligosaccharides connected to the branching unit. Such sugar oligomers have specific attachment points to cell selecting, and therefore do not need additional molecular structures to target a specific tumor tissue. The use of the parachute structure gives the advantages of being able to localize a photosensitizer or chemotherapeutic drug at the site within a cell where it can destroy the tumor cell most effectively. This reduces the level of necessary systemic doses of the drugs, promotes drug excretion, and therefore considerably reduces side effects of the therapy.

Description

REFERENCE TO RELATED CASE[0001] This application is a continuation-in-part of co-pending U.S. patent application Ser. No. 09 / 599,660 filed on Jun. 22, 2000 by Jorg G. Moser, inventor, entitled "PHOTOSENSITIZERS WITH LIGAND TARGETING PROPERTIES FOR TUMOR THERAPY", and incorporated by reference herein.[0002] 1. Field of the Invention[0003] The present invention relates to photodynamic therapy and chemotherapy, wherein a "parachute" structure is used to deliver a therapeutic agent to a defined subcellular location, and therefore the action of the therapeutic agent, such as destroying tumor cells, is achieved more effectively.[0004] 2. Invention Disclosure Statement[0005] During the last two decades, there has been an increasing interest in utilizing photosensitizers for cancer therapy, where the technique is known as Photodynamic Therapy (PDT). Dougherty T J, Photosensitizers: Therapy and detection of malignant tumors, Photochem. Photobiol, 45(6): 879-889, (1987) and Dougherty T J, Pho...

AI Technical Summary

Benefits of technology

[0013] It is an object of the present invention to provide a system for and method of localizing therapeutic compounds at the most sensitive sites in a cell, thereby reducing therapeutic doses of the drug and in turn reducing the side effects of the therapy.

[0014] It is another object of the present invention to localize therapeutic compounds at cell membranes which results in a reduction of the dosage needed by a factor of 10-100 or more while achieving the same therapeutic effect.

[0017] Briefly stated, the present invention provides a drug delivery system wherein a "parachute" structure is coupled to a therapeutic compound. The "parachute" structure comprises hydrophilic branched molecules with a defined action diameter, where action diameter is the distance between the hydrophilic moieties that is necessary to localize the complex in the cell membrane. The complex (a parachute structure coupled with a therapeutic compound) is either fixed at a cell membrane or delivered to a defined distance from the membrane within the cell. The membrane-anchoring / localizing effect of the parachute is achieved by hydrophilic structures linked with a branching unit of desired therapeutic compounds (such as photosensitizers and chemotherapeutics). For example, di-glucosamine, a hydrophilic structure of a defined action diameter, functions to retard the molecules at the cell membrane, and thus avoids or slows deeper penetration of the therapeutic compounds into the cell during the short time span before irradiation. The defined action diameter can be achieved by using a branching unit, which can be triazine trichloride or trimesinic acid trichloride, to connect the therapeutic compound such as porphyrin over a diamide spacer bridge with two glucosamine residues. The hydrophilic moiety can also consist of a cyclodextrin attached to the drug. The attached cyclodextrin renders the complex water soluble and is bulky and hydrophilic enough to retain the complex in the membrane. Furthermore, the parachute structures can be connected by a spacer (e.g. .beta.-amino acids, .gamma.-amino butyric acid, poly-amino acids, aliphatic, aromatic or heterocyclic molecules) instead of directly binding to the therapeutic compound, so that the therapeutic compounds can be localized within the cells at a defined distance from the cell membrane. A spacer containing a breaking point (for example, it can be cleaved by the action of cellular enzymes) can determine the time span, during which the drug exhibits its therapeutic activity. The hydrophilic residues can also carry signals for targeting the parachute-therapeutic complex to a defined tissue type. This can be mediated by an antibody which is specific for a tumor marker. Alternatively, a biotin can be attached at C6 position of the sugar and then react with an avidin-labeled tumor-specific antibody. The biotin-avidin system has the advantage of minimizing the size of the delivery structure so that it will not be recognized by the reticuloendothelial system and get destroyed. The parachute function may also be achieved by other, more bulky hydrophilic structures such as oligosaccharides connected to the branching unit. Such sugar oligomers have specific attachment points to cell selecting, and therefore do not need additional molecular structures to target a specific tumor tissue. The use of the parachute structure gives the advantage of being able to localize a photosensitizer or chemotherapeutic drug at the site within a cell where it can destroy the tumor cell most effectively. This reduces the level of necessary systemic doses of the drugs, promotes drug excretion, and therefore considerably reduces side effects of the therapy.

Problems solved by technology

The technique utilizes non-toxic, photosensitizing drugs in combination with non-hazardous irradiation, and has the potential of being more selective yet no less effective when compared with the commonly used chemotherapy or radiotherapy.

Although remarkable results have been obtained in some PDT trials, several problems remain.

The low solubility of some of the sensitizers reduces their usefulness for intravascular administration because it can provoke thromboembolic events.

The use of liposomes as transport vehicles can overcome the problem of the solubility, but there still remains the difficulty of directing the sensitizers to specific target sites.

Moreover, liposomes administered intravenously to subjects are rapidly accumulated in the reticuloendothelial system often inducing several severe allergic reactions.

Liposomal systems can be effective in treating tumors that infiltrate these organs (such as hematological malignancies), but have been less useful in treating targeted tumors in other anatomical locations.

As the amount of the applied photosensitizer increases, the chances of its accumulation in normal tissues and the accompanying risk of damaging non-malignant sites profoundly increases.

However, in vivo this method failed due to the recognition of the vast complex by the reticuloendothelial system, subsequent accumulation in the liver, and digestion of the compound before it reached the target site.

But even if the targeting of the dye to the tumor would be successful, still an amount of at least 10.sup.7 photosensitizer molecules per cell has to be reached for the effective destruction of the tumor, which none of the described techniques have successfully achieved.

However, both localizations are not very deleterious for cancer cells since these cells obtain their energy from cytoplasmic basal metabolism.

However, no satisfying solution to this problem has been presented so far.

Images