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Liposome targeted chemotherapy to treat lung cancer

Institution: University of California, San Francisco
Investigator(s): Francis Szoka, Ph.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8IT-0138 Award: $75,000
Subject Area: Pulmonary Disease
Award Type: Inno Dev & Exp Awards (IDEAS)
Abstracts

Initial Award Abstract
Lung cancers resulting from cigarette smoke are a major killer of Californians. Due to the importance of the lung for life it is often not possible to remove the cancer tumors without dramatically reducing lung function. Thus lung tumors are treated by radiation therapy or chemotherapy. Both types of treatments cause painful toxicityís to the patient that may require that the therapy be halted even though the tumor cells are being killed. This is because all cytotoxic drugs used in humans to treat cancers, kill normal cells as well as cancerous cells. Furthermore, because of the blood circulation in the body only a small fraction of the drug gets to the target tumor; most of drug acts on normal tissues or is rapidly eliminated. Therefore, to obtain a therapeutic effect, a relatively high dose of drug must be administered and usual formulations are a balance between killing the tumor (efficacy) and killing the patient (toxicity).

One way to reduce the toxicity of the drug to the normal tissue is to direct the drug to the tumor cells with a drug delivery system. This is similar in concept to the use of a cruise missile to only destroy a military target. Targeting drug delivery to lung tumors may prove to be the most efficacious and economical means by which to treat lung cancer since groups of tumor cells that have spread away from the main tumor and are too few in number to be detected can be exposed to a high level of drug by these ësmart bombsí. The bomb in this research is called a liposome. The liposome is a microscopic balloon, smaller than a red blood cell, formed from lipids. Cytotoxic drugs can be carried inside the liposome where they do not come into contact with the cells. The lipids can be broken down by metabolism inside the body and the drug is then released. The technology for encapsulating drugs in liposomes has been thoroughly worked out by many laboratories around the world including those of Dr. Szoka. Liposomes are now used in human patients to treat solid tumors but they are not effective for treating lung tumors because the currently available liposomes do not stick to lung tumors.

We propose to turn the liposome into a 'smart bomb' by attaching a carbohydrate molecule (a sugar) to a lipid and including this sugar-lipid in the liposome. The sugar will target the liposome to the tumor. We show that the sugar modified liposomes target lung tumor cells when tested in cell culture. This is a very promising finding because for the first time we can selectively target tumor cells but not normal cells by a simple molecule attached to a liposome. After the formulations are optimized in the cultured lung tumor cells, they will be tested in mice that have developed lung tumors. We will determine if the sugar targeted liposomes go to the lung tumors in mice. We will then determine if the anticancer drug encapsulated in the sugar targeted liposomes is better at killing the lung tumors and curing the mice from the cancer then is the anticancer drug encapsulated in liposomes lacking the sugar or injections of the non-encapsulated anticancer drug. These studies will potentially lead to safe and effective targeted liposomal drug formulations to treat lung cancer in patients.

Final Report
Lung cancers resulting from cigarette smoke are a major killer of Californians. Due to the importance of the lung for life it is often not possible to remove the cancer tumors without dramatically reducing lung function. Thus lung tumors are treated by radiation therapy or chemotherapy. Both types of treatments cause painful toxicity's to the patient that may require that the therapy be halted even though the tumor cells are being killed. This is because all cytotoxic drugs used in humans to treat cancers, kill normal cells as well as cancerous cells. Furthermore, because of the blood circulation in the body only a small fraction of the drug gets to the target tumor; most of drug acts on normal tissues or is rapidly eliminated. Therefore, to obtain a therapeutic effect, a relatively high dose of drug must be administered and usual formulations are a balance between killing the tumor (efficacy) and killing the patient (toxicity).

One way to reduce the toxicity of the drug to the normal tissue is to direct the drug to the tumor cells with a drug delivery system. This is similar in concept to the use of a cruise missile to only destroy a military target. Targeting drug delivery to lung tumors may prove to be the most efficacious and economical means by which to treat lung cancer since groups of tumor cells that have spread away from the main tumor and are too few in number to be detected can be exposed to a high level of drug by these `smart bombs'. The bomb in this research is a called a liposome. The liposome is a microscopic balloon, smaller than a red blood cell, formed from lipids. Cytotoxic drugs can be carried inside the liposome where they do not come in contact with the cells. The lipids can be broken down by metabolism inside the body and the drug is then released. The technology for encapsulating drugs in liposomes has been thoroughly worked out by many laboratories around the world including those of Dr. Szoka. Liposomes are now used in human patients to treat solid tumors but they are not effective for treating lung tumors because the currently available liposomes do not stick to the lung tumors.

We propose to turn the liposome into a `smart bomb' by attaching a carbohydrate molecule to a lipid and including this in the liposome. The carbohydrate would be exposed on the outside of the liposome and provide an address to the lung tumor cell. The novel address we will use is called a hyaluronan carbohydrate. Lung tumor cells often have a receptor on their surface, designated the CD44 receptor that sticks (binds) to the hyaluronan carbohydrate polymer. The problem for using this hyaluronan to target the tumor is that it is a very large molecule and the large molecule form of hyaluronan is quickly removed from circulation by cells in the liver. Thus the hyaluronan polymer cannot be used to target the liposome exclusively to the tumor cells. We have cut the hyaluronan polymer into much smaller fragments and have worked out the chemistry for attaching these short fragments to the lipid. We show in the preliminary results that liposomes that expose this short hyaluronan on their surface can still bind to tumor cells, the B 16F 10 melanoma cell line, but not to normal cells. Furthermore liposomes with the short hyaluronan attached to their surface are not rapidly removed from circulation into the liver after they are injected into mice. This is a very promising finding because for the first time we have the possibility to target the lung tumor cells but not normal cells with a simple molecule. We will optimize the hyaluronan liposomes to target to lung tumors in mice. We will alter the hyaluronan length and the amount that is exposed on the surface of the liposomes to optimize targeting to the B16F10 cells that are grown in culture dishes. We will compare the cytotoxicity of a commonly used anti cancer drug, doxorubicin, in the targeted liposome to the tumor cells in culture to the non-encapsulated drug or the drug encapsulated in non-targeted liposomes. After the formulations are optimized in the cultured lung tumor cells, they will be tested in mice that have developed lung tumors. We will determine if the targeted liposomes go to the lung tumors in mice. We will then determine if doxorubicin encapsulated in the targeted liposomes is better at killing the lung tumors and curing the mice from the cancer then is doxorubicin encapsulated in liposomes lacking the hyaluronan or injections of non-encapsulated doxorubicin. These studies will potentially lead to a safe and effective targeted liposomal drug formulations to treat lung cancer in patients.
Publications

Liposome encapsulated doxorubicin targeted to CD44: A strategy to kill CD44 overexpressing tumor cells
Periodical: Cancer Research Index Medicus:
Authors: Eliaz RE, Szoka Jr FC ART
Yr: 2001 Vol: 61 Nbr: Abs: Pg: 2592-2601