The present invention provides a method of inhibiting growth of lung metastases in an individual comprising the steps of administering a dose of a lipid-drug enhancer liposomal complex and, in sequence, administering a dose of a lipid-anticancer drug liposomal complex. Furthermore, the lipid-drug enhancer liposomal complex may be administered in a continuing dose with the lipid-anticancer drug liposomal complex whereby both liposomal complexes are mixed in the nebulizer. Methods of inhibiting growth of lung metastases in an individual by the sequential administration via aerosolization of a dilauroylphosphatidylcholine-cyclosporin A liposomal complex and a dilauroylphosphatidylcholine-paclitaxel liposomal complex are also provided.

SUMMARY OF THE INVENTION

The present invention is directed to method of inhibiting growth of lung metastases in an individual. A dose of a lipid-drug enhancer liposomal complex is administered to the individual and, in sequence, a dose of a lipid-anticancer drug liposomal complex is administered to the individual. Both of the liposomal complexes are delivered via aerosolization from a nebulizer whereby the drug enhancer and the anticancer drug inhibit growth of lung metastases in the individual.

The present invention also is directed to the method of inhibiting growth of lung metastases in an individual described supra where a dilauroylphosphatidylcholine-cyclosporin A liposomal complex is the lipid-drug enhancer liposomal complex and a dilauroylphosphatidylcholine-paclitaxel liposomal complex is the lipid-anticancer drug complex.

The present invention is directed further to another method of inhibiting growth of lung metastases in an individual. First a dose of a dilauroylphosphatidylcholine-cyclosporin A liposomal complex is administered to the individual via aerosolization from a nebulizer. Then, in sequence, a dose of a dilauroylphosphatidylcholine-paclitaxel liposomal complex is administered while concurrently administering a continuing dose of the dilauroylphosphatidylcholine-cyclosporin A liposomal complex via aerosolization from a nebulizer where the dilauroylphosphatidylcholine-cyclosporin A liposomal complex is mixed with the dilauroylphosphatidylcholine-paclitaxel liposomal complex in the nebulizer. The drug enhancer and of the anticancer drug inhibit growth of lung metastases in the individual.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention there is provided a method of inhibiting growth of lung metastases in an individual comprising the steps of administering a dose of a lipid-drug enhancer liposomal complex and, in sequence, administering a dose of a lipid-anticancer drug liposomal complex where both of the liposomal complexes are delivered via aerosolization from a nebulizer whereby the drug enhancer and the anticancer drug inhibit growth of lung metastases in the individual. The administration sequence steps maybe repeated at least once.

In all aspects of this embodiment the drug enhancing agents may be cyclosporin A, cyclosporin D, verapamil, ketoconazole, PCS 833, erythromycin, nifedipine, rapamycin or mibefradil. Representative examples of the anticancer drugs are paclitaxel, doxirubicin, etoposide, vinblastine, camptothecins, cisplatinum, carboplatinum, daunorubicin, or adriamycin. The liposome may have a transition temperature of less than about 17.degree. C. A representative example of such a liposome is dilauroylphosphatidylcholine. The aerosol may comprise about 5% to about 10% carbon dioxide in air.

In one aspect the dose of the lipid-drug enhancer complex is a dose of dilauroylphosphatidylcholine-cyclosporin A liposomal complex. Cyclosporin A may be administered in a dose comprising a concentration of about 5.0 mg cyclosporin A/ml solution in the nebulizer at a cyclosporin A: dilauroylphosphatidylcholine weight ratio of about 1:7.5. In a related aspect the dose of the lipid-anticancer drug liposomal complex is a dose of dilauroyl phosphatidylcholine-paclitaxel liposomal complex. Paclitaxel may be administered in a dose comprising about 10.0 mg paclitaxel/ml solution in the nebulizer at a paclitaxel:dilauroylphosphatidylcholine weight ratio of about 1:10.

This embodiment further comprises the step of concurrently administering a continuing dose of the lipid-drug enhancer liposomal complex with the lipid-anticancer drug complex via aerosolization from a nebulizer where the lipid-drug enhancer liposomal complex is mixed with the lipid-anticancer drug complex in the nebulizer. As stated supra the dose of lipid-drug enhancer complex is a dose of a dilauroylphosphatidylcholine-cyclosporin A liposomal complex. Prior to mixing in the nebulizer the concentration of cyclosporin A and the liposomal complex weight ratio in the dose administered are as described supra. Again, as stated supra, the dose of lipid-anticancer drug complex is a dose of a dilauroylphosphatidylcholine-paclitaxel liposomal complex. Prior to mixing in the nebulizer the concentration of paclitaxel and the liposomal complex weight ratio in the dose administered are as described supra.

In another embodiment of the present invention, there is provided a method of inhibiting growth of lung metastases in an individual comprising the steps of administering a dose of a dilauroylphosphatidylcholine-cyclosporin A liposomal complex; and, in sequence, administering a dose of a dilauroylphosphatidylcholine-paclitaxel liposomal complex where both of the liposomal complexes are delivered via aerosolization from a nebulizer whereby cyclosporin A and paclitaxel inhibit growth of lung metastases in the individual. The administration sequence steps may be repeated at least once. In this embodiment the dose concentration and the weight ratios of the liposomal complexes of the cyclosporin A and paclitaxel in the nebulizer are as disclosed supra.

In yet another embodiment of the present invention there is provided a method of inhibiting growth of lung metastases in an individual comprising the steps of administering a dose of a dilauroylphosphatidylcholine-cyclosporin A liposomal complex via aerosolization from a nebulizer and, in sequence, administering a dose of a dilauroylphosphatidylcholine-paclitaxel liposomal complex while concurrently administering a continuing dose of the dilauroylphosphatidylcholine-cyclosporin A liposomal complex via aerosolization from a nebulizer where the dilauroylphosphatidylcholine-cyclosporin A liposomal complex is mixed with said dilauroylphosphatidylcholine-paclitaxel liposomal complex in the nebulizer whereby cyclosporin A and paclitaxel inhibit growth of lung metastases in the individual.

In this embodiment the sequential and concurrent administration steps may be repeated at least once. Furthermore the dose concentration and the weight ratio of the liposomal complexes, of cyclosporin A in the nebulizer for the first adminstration of the dilauroylphosphatidylcholine-cyclosporin A liposomal complex and prior to mixing in the nebulizer for the continuing adminstration with the dilauroylphosphatidylcholine-paclitaxel liposomal complex are as disclosed supra. Also, the dose concentration and the weight ratio of the liposomal complex of paclitaxel in the nebulizer are as disclosed supra.

The following definitions are given for the purpose of facilitating understanding of the inventions disclosed herein. Any terms not specifically defined should be interpreted according to the common meaning of the term in the art.

As used herein, the term "individual" shall refer to animals and humans.

As used herein, the term "anti-cancer drug" shall refer to those drugs with a high probability of causing multidrug-type related resistance during therapy for pulmonary malignancies.

As used herein, the term "drug-enhancer" shall refer to those therapeutic agents that when delivered in combination with the anticancer drug via aerosol enhance or increase the therapeutic effectiveness of the anticancer drug.

The following abbreviations may be used herein:

Cyclosporin A: CsA; paclitaxel: PTX; multiple drug resistance: MDR; cytochrome P450-mediated: CYP; plasma membrane glycoprotein; P-glycoprotein or P-gp.

The present invention provides a method of aerosol co-administration of an anticancer drug, preferably paclitaxel, with a drug-enhancing agent such as cyclosporin A for lung cancer therapy in vivo. Both the drug and the drug-enhancing agent are encapsulated into liposomal formulations and administered via aerosol to BALB/c mice bearing pulmonary renal carcinoma metastases. The lipid in the liposome may be a lipid having a transition temperature of 17.degree. C. or less, for example dilauroylphosphatidylcholine. The liposomal complex may also be delivered via an aerosol comprising about 5% to about 10% carbon dioxide in air.

Particularly, two regimens of combination treatment are provided. In the first combination group cyclosporin A is administered as a liposome aerosol for one half hour before starting one half hour treatment with PTX liposome aerosol (CsA/PTX). In the second group cyclosporin A liposome aerosol is administered for one half hour prior to paclitaxel and then a cyclosporin A liposomal aerosol is concurrently administered with a paclitaxel liposomal aerosol for an additional hour (CsA/PTX+CsA). Animals receiving no treatment or being treated with aerosolized paclitaxel only are used as controls.

In the CsA/PTX+CsA combination, aerosolization of PTX+CsA is accomplished by mixing the liposomal paclitaxel with the liposomal CsA in the nebulizer prior to aerosolization of the combination. Cyclosporin A may be administered in a dose comprising, although not limited to, about 5.0 mg cyclosporin A/ml of solution in suspension prior to nebulization. Paclitaxel may be administered in a dose comprising, although not limited to, about 10.0 mg paclitaxel/ml solution in suspension prior to nebulization at a paclitaxel:dilauroylphosphatidylcholine weight ratio of about 1:10.

For concurrent CsA+paclitaxel administration the nebulizer volume is doubled, so the concentrations of CsA and paclitaxel per total solution volume in the nebulizer is halved, i.e. about 5.0 mg CsA/ml and about 2.5 mg paclitaxel/ml, respectively. However, administration time is doubled so the amount of aerosolized dose is the same as if the CsA and paclitaxel liposomal complexes were aerosolized individually. The total dose of paclitaxel remains the same in all groups whereas the cyclosporin A dose doubles in the cyclosporin A/paclitaxel-cyclosporin A group. These doses may be reduced if toxicity is detected for either drug. One of ordinary skill in the art can determine an appropriate lower dose without undue experimentation.

Both combination aerosol treatments were more effective compared with single-agent paclitaxel aerosol treatment. The dose escalation of cyclosporin A increased inhibitory activity of paclitaxel on lung cancer growth in mice. The most effective regimen was that for mice that inhaled cyclosporin A prior to paclitaxel administration and continued to inhale cyclosporin A during paclitaxel treatment (CsA/paclitaxel-CSA). In this group the number of tumor lesions and the size of the tumors were significantly reduced compared with the group receiving CsA/paclitaxel treatment or paclitaxel only.

In the CsA/PTX-CSA group, escalation of the cyclosporin A dose caused increased toxicity, as demonstrated by a .about.15% whole body weight loss, after 2 weeks of treatment compared with other treated groups, where total body weight was decreased by 6%. The toxicity was quickly reversed after the treatment had been stopped. Histopathology analysis of lung tissues obtained from mice receiving a single dose of cyclosporin A prior to paclitaxel 3 times per week for 3 weeks did not show a significant pulmonary inflammatory response to the treatment. This indicates that the observed toxicity evaluated by the whole body weight loss was systemic.

It is contemplated that liposomal aerosol cyclosporin A can be used as an adjuvant with other MDR-related anticancer drugs having a high probability of causing the multidrug-type resistance, e.g., doxorubicin, etoposide vinblastine, camptothecins, cisplatinum, carboplatinum, daunorubicin, and adriamycin, for the therapy of pulmonary malignancies. As systemic toxicity may be a consideration in using cyclosporin A in such combinations for aerosol therapeutic treatment, it is further contemplated that the P-glycoprotein inhibitors having a lower toxicity index may be used for alternative combinations. A liposomal complex comprising an anti-cancer drug and a drug enhancing agent such as verapamil, ketoconazole, PCS 833, erythromycin, nifedipine, cyclosporin D, rapamycin or mibefradil may be used. These drugs have similar effects on the P450 cytochrome family enzymes and P-glycoprotein which all participate in metabolism.
 

Claim 1 of 26 Claims

1. A method of inhibiting growth of lung metastases in an individual comprising the steps of: administering a dose of a lipid-drug enhancer liposomal complex; and, in sequence, administering a dose of a lipid-anticancer drug liposomal complex, both of said liposomal complexes delivered via aerosolization from a nebulizer; whereby said drug enhancer and said anticancer drug inhibit growth of lung metastases in the individual.

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