Multifunctional nanodevice platform

Details Multifunctional nanodevice platform Multifunctional nanodevice platform

2000-05-12

2002-10-29

McGarry, Sean (Department: 1635)

Drug, bio-affecting and body treating compositions

Nonspecific immunoeffector, per se ; or nonspecific...

Synthetic polymer or copolymer

C424S001110, C424S277100, C424S094100, C424S130100, C514S04400A, C536S023100, C536S024100, C536S024500

Reexamination Certificate

active

06471968

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel therapeutic and diagnostic systems. More particularly, the present invention is directed to dendrimer based multifunctional compositions and systems for use in disease diagnosis and therapy (e.g. cancer diagnosis and therapy). The compositions and systems generally comprise two or more separate components for targeting, imaging, sensing, and/or triggering release of a therapeutic or diagnostic material and monitoring the response to therapy of a cell or tissue (e.g., a tumor).
BACKGROUND OF THE INVENTION
New initiatives in chemotherapeutics and radiopharmaceutics have improved the survival of patients with many forms of neoplasm. Several cancers now have five year survival rates greater than 80 percent. However, despite these successes, many problems still exist concerning cancer therapy. For example, many common neoplasms, such as colon cancer, respond poorly to available therapies.
For tumor types that are responsive to current methods, only a fraction of cancers respond well to the therapies. In addition, despite the improvements in therapy for many cancers, most currently used therapeutic agents have severe side effects. These side effects often limit the usefulness of chemotherapeutic agents and result in a significant portion of cancer patients without any therapeutic options. Other types of therapeutic initiatives, such as gene therapy or immunotherapy, may prove to be more specific and have fewer side effects than chemotherapy. However, while showing some progress in a few clinical trials, the practical use of these approaches remains somewhat limited at this time.
Despite the limited success of existing therapies, the understanding of the underlying biology of neoplastic cells has advanced. The cellular events involved in neoplastic transformation and altered cell growth are now identified and the multiple steps in carcinogenesis of several human tumors have been documented (See e.g., Isaacs, Cancer 70:1810 [1992]). Oncogenes that cause unregulated cell growth have been identified and characterized as to genetic origin and function. Specific pathways that regulate the cell replication cycle have been characterized in detail and the proteins involved in this regulation have been cloned and characterized. Also, molecules that mediate apoptosis and negatively regulate cell growth have been clarified in detail (Kerr et al., Cancer 73:2013 [1994]). It has now been demonstrated that manipulation of these cell regulatory pathways has been able to stop growth and induce apoptosis in neoplastic cells (See e.g., Cohen and Tohoku, Exp. Med., 168:351 [1992] and Fujiwara et al., J. Natl. Cancer Inst., 86:458 [1994]). The metabolic pathways that control cell growth and replication in neoplastic cells are important therapeutic targets.
Despite these impressive accomplishments, many obstacles still exist before these therapies can be used to treat cancer cells in vivo. For example, these therapies require the identification of specific pathophysiologic changes in an individual's particular tumor cells. This requires mechanical invasion (biopsy) of a tumor and diagnosis typically by in vitro cell culture and testing. The tumor phenotype then has to be analyzed before a therapy can be selected and implemented. Such steps are time consuming, complex, and expensive.
There is a need for treatment methods that are selective for tumor cells compared to normal cells. Current therapies are only relatively specific for tumor cells. Although tumor targeting addresses this selectivity issue, it is not adequate, as most tumors do not have unique antigens. Further, the therapy ideally should have several, different mechanisms of action that work in parallel to prevent the selection of resistant neoplasms, and should be releasable by the physician after verification of the location and type of tumor. Finally, the therapy ideally should allow the physician to identify residual or minimal disease before and immediately after treatment, and to monitor the response to therapy. This is crucial since a few remaining cells may result in re-growth, or worse, lead to a tumor that is resistant to therapy. Identifying residual disease at the end of therapy (i.e., rather than after tumor regrowth) would facilitate eradication of the few remaining tumor cells.
Thus, an ideal therapy should have the ability to target a tumor, image the extent of the tumor and identify the presence of the therapeutic agent in the tumor cells. It ideally allows the physician to determine why cells transformed to a neoplasm, to select therapeutic molecules based on the pathophysiologic abnormalities in the tumor cells, to activate the therapeutic agents only in abnormal cells, to document the response to the therapy, and to identify residual disease.
SUMMARY OF THE INVENTION
The present invention relates to novel therapeutic and diagnostic systems. More particularly, the present invention is directed to dendrimer based multifunctional compositions and systems for use in disease diagnosis and therapy (e.g., cancer diagnosis and therapy). The compositions and systems generally comprise two or more distinct components for targeting, imaging, sensing, and/or triggering release of a therapeutic or diagnostic material and monitoring the response to therapy of a cell or tissue (e.g., a tumor).
For example, the present invention provides a composition comprising a dendrimer complex, said dendrimer complex comprising first and second dendrimers, the first dendrimer comprising a first agent and the second dendrimer comprising a second agent, wherein the first agent is different than the second agent. In preferred embodiments, the first and said second agents are selected from the group consisting of therapeutic agents, biological monitoring agents, biological imaging agents, targeting agents, and agents capable of identifying a specific signature of cellular abnormality. In some embodiments, the first dendrimer is covalently linked to the second dendrimer. In certain embodiments, the dendrimer complex includes additional dendrimers. For example, in some embodiments, the complex comprises a third dendrimer (e.g., a third-dendrimer covalently linked to the first and second dendrimers). In yet other embodiments, the dendrimer complex comprises fourth, fifth, or additional dendrimers. Each of the dendrimers may comprise an agent.
In some embodiments, the present invention provides a composition comprising: a first dendrimer comprising a first agent; and a second dendrimer comprising a second agent, wherein the first and second dendrimers are complexed (e.g., covalently attached) with at least one dendrimer (e.g., to each other, to a common third dendrimer, or each individually to a third and fourth dendrimers respectively), and wherein the first agent is different than the second agent, and wherein the first and the second agents are selected from the group consisting of therapeutic agents, biological monitoring agents (i.e., agents capable of monitoring biological materials or events), biological imaging agents (i.e., agents capable of imaging biological materials or events), targeting agents (i.e., agents capable of targeting a biological material—i.e., specifically interacting with the biological material), and agents capable of identifying a specific signature of cellular identity (i.e., capable of identifying a characteristic of a cell that helps differentiate the cell from other cell types—e.g., a cellular proteins specific for a particular cellular abnormality). The present invention is not limited by the nature of the dendrimers. Dendrimers suitable for use with the present invention include, but are not limited to, polyamidoamine (PAMAM), polypropylamine (POPAM), polyethylenimine, iptycene, aliphatic poly(ether), and/or aromatic polyether dendrimers. Each dendrimer of the dendrimer complex may be of similar or different chemical nature than the other dendrimers (e.g., the first dendrimer may comprises a PAMAM dendrimer, while the

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