THERAPEUTIC NANOPARTICLES FOR THE TREATMENT OF NEUROBLASTOMA AND OTHER CANCERS

Abstract

A therapeutic nanoparticle comprising: at least one oncologic drug; and taurolidine, whereby to provide the simultaneous delivery of the at least one oncologic drug and taurolidine, thereby harnessing the synergistic effect of taurolidine on the at least one oncologic drug.

Claims

1.-70. (canceled)

71. A therapeutic nanoparticle comprising: at least one oncologic drug; and taurolidine, whereby to provide the simultaneous delivery of the at least one oncologic drug and taurolidine, thereby harnessing the synergistic effect of taurolidine on the at least one oncologic drug; and further comprising a coating, which is configured to release the at least one oncologic drug and taurolidine locally to the site of a cancer, wherein the coating comprises an absorbable polymer and wherein the coating is created from combinations of copolymers and multimers derived from polymers structured from at least one from the group consisting of l-lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate.

72. A therapeutic nanoparticle according to claim 71, wherein the at least one oncologic drug comprises at least one from the group consisting of tumor necrosis factor (TNF), an anti neoplastic drug, a cytotoxic drug, vincristine and doxorubicin.

73. A therapeutic nanoparticle according to claim 71, wherein the therapeutic nanoparticle further comprises at least one excipient.

74. A therapeutic nanoparticle according to claim 73, wherein the at least one excipient comprises a buffer so as to provide enhanced hydrolytic stability of the taurolidine and/or the at least one oncologic drug and the taurolidine.

75. A therapeutic nanoparticle according to claim 71, wherein the coating further comprises glycols.

76. A therapeutic nanoparticle according to claim 71, wherein the coating comprises binding molecules which are configured to target delivery of the nanoparticle to specific tissue.

77. A therapeutic nanoparticle according to claim 76, wherein the binding molecules comprise a fragment antigen-binding (Fab) fragment of a monoclonal antibody.

78. A therapeutic nanoparticle according to claim 76, wherein the binding molecules are configured to target neural tissue.

79. A therapeutic nanoparticle according to claim 78, wherein the binding molecules are configured to target at least one from the group consisting of neuroblastoma N-type calcium channels, glycine receptor channels and voltage gated potassium channels.

80. A therapeutic nanoparticle according to claim 76, wherein the binding molecules are embedded in or covalently bound to the surface of the nanoparticle.

81. A method of treating cancer, the method comprising: providing a therapeutic nanoparticle, the therapeutic nanoparticle comprising: at least one oncologic drug; and taurolidine, whereby to provide the simultaneous delivery of the at least one oncologic drug and taurolidine, thereby harnessing the synergistic effect of taurolidine on the at least one oncologic drug; and further comprising a coating, which is configured to release the at least one oncologic drug and taurolidine locally to the site of a cancer, wherein the coating comprises an absorbable polymer and wherein the coating is created from combinations of copolymers and multimers derived from polymers structured from at least one from the group consisting of l-lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate; and delivering said therapeutic nanoparticle to a body so as to provide the simultaneuous delivery of the at least one oncologic drug and tarurolidine.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0091] This invention takes advantage of the synergistic properties of taurolidine with various oncologic drugs. More particularly, this invention comprises the provision and use of nanoparticles comprising one or more oncologic drugs and taurolidine, with or without additional excipients (e.g., a buffer so as to provide enhanced hydrolytic stability of the taurolidine and/or the one or more oncologic drugs and the taurolidine), whereby to provide the simultaneous delivery of the one or more oncologic drugs and taurolidine, thereby harnessing the synergistic effect of taurolidine on these oncologic drugs.

[0092] In one preferred form of the invention, the nanoparticles comprise one or more oncologic drugs and taurolidine, with or without additional excipients (e.g., a buffer so as to provide enhanced hydrolytic stability of the taurolidine and/or the one or more oncologic drugs and the taurolidine), and further comprise a coating which is configured to release the one or more oncologic drugs and taurolidine locally to the site of a cancer, e.g., a tumor. In one preferred form of the invention, the coating is configured to prevent premature exposure of the one or more oncologic drugs and taurolidine to the body prior to delivery to the site of the cancer, e.g., a tumor. This can be important in order to prevent undesirable side effects from the one or more oncologic drugs, the premature hydrolization of the taurolidine, etc. In one preferred form of the invention, the coating comprises an absorbable polymer or lipid.

[0093] And in one preferred form of the invention, the nanoparticles comprise one or more oncologic drugs and taurolidine, with or without additional excipients (e.g., a buffer so as to provide enhanced hydrolytic stability of the taurolidine and/or the one or more oncologic drugs and the taurolidine), and further comprise a coating, wherein the coating is configured to target the nanoparticle to the site of a cancer (e.g., a tumor) so as to improve the efficacy of the one or more oncologic drugs and taurolidine for treatment of the cancer. In one preferred form of the invention, the coating comprises binding molecules which are configured to target delivery of the nanoparticle to specific tissue.

[0094] And in one preferred form of the invention, the nanoparticles are specifically configured for the treatment of neuroblastoma and/or other specific cancers.

[0095] More particularly, this invention takes advantage of the synergistic properties of taurolidine with various oncologic drugs by encapsulating the taurolidine and various oncologic drugs in specific nanoparticle systems that are designed to release the oncologic drug and taurolidine locally to the site of the cancer, e.g., a tumor.

[0096] A number of absorbable polymer systems can be used to optimize the release properties of the oncological drug(s) and taurolidine, especially those created from combinations of copolymers and multimers derived from polymers structured from l-lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate. These may also be associated with glycols such as polyethylene glycols (PEGs), which can either be linear or multi-arm structures.

[0097] Optimization of the systems containing taurolidine, the oncologic drug(s) and the polymers in a nanoparticle yields an improved treatment for cancer in general, and neuroblastoma in particular.

[0098] Additionally, research has shown cannabinoid activity on neuroblastoma N-type calcium channels, glycine receptor channels and voltage gated potassium channels. Each of these is believed to be specific for neural tissue and is not believed to be present in reticuloendothelial system (RES) cells. Therefore, providing the nanoparticle with binding molecules to target neural tissue (e.g., neuroblastoma N-type calcium channels, glycine receptor channels and voltage gated potassium channels) enhances the targeted delivery of the nanoparticle to neural tissue and hence enhances the effectiveness of the oncologic drug(s) (which is further enhanced by the presence of the synergistic taurolidine).

[0099] It is generally important that the binding molecules of the nanoparticle have no other significant biologic activity. To achieve specific binding with no other significant biologic activity, a fragment antigen-binding (Fab) fragment of a monoclonal antibody (which is a region on an antibody that binds to antigens) is utilized. However, since there is a recently described syndrome of severe autoimmune encephalitis resulting from anti-voltage gated potassium channel antibodies, anti-voltage gated potassium channel antibodies (e.g., KvR) are preferably not used as a target. Other targets are also reporting cases of autoimmune encephalitis as the etiology of paraneoplastic syndromes. So far none of these targets are as severe as KvR disease, but this may be due to random chance. Therefore, care must be taken in selecting the binding molecules used to target neural tissue.

[0100] In one preferred form of the present invention, the coating for the nanoparticle comprises a monoclonal antibody against N-type calcium channels (e.g., an anti-N-type calcium channel exofacial Fab fragment) for causing the nanoparticle to bind to neural tissue (e.g., to a neuroblastoma tumor), such that the one or more oncologic drugs and the taurolidine are simultaneously delivered (via the targeted nanoparticle) to the neural tissue, with the taurolidine providing a synergistic effect for the one or more oncologic drugs, whereby to provide enhanced efficacy for the one or more oncologic drugs against the targeted neural tissue.

[0101] In one particularly preferred form of the present invention, the anti-N-type calcium channel exofacial Fab fragment incorporated in the coating for the nanoparticle comprises Ca.sub.v2.2, or a binding equivalent thereof.

[0102] Thus, in one form of the invention, there is provided a nanoparticle containing cytotoxic chemotherapeutic drug(s) and synergistic taurolidine in an appropriate buffer in order to provide enhanced hydrolytic stability of the taurolidine and/or the one or more oncologic drugs and the taurolidine. The surface of the nanoparticle is a lipid envelope or polymer which regulates the release properties of the chemotherapeutic drug(s) and synergistic taurolidine. The surface of the nanoparticle preferably includes binding molecules to target neural tissue.

[0103] It will be appreciated that the present invention provides a nanoparticle which may be used to treat neuroblastoma in a patient, wherein the nanoparticle comprises a chemotherapeutic drug(s) and a synergistic quantity of taurolidine, with the chemotherapeutic drug(s) and taurolidine being encapsulated in a polymer which regulates the release properties of the chemotherapeutic drug and taurolidine.

Modifications of the Preferred Embodiments

[0104] It should be understood that many additional changes in the details, materials, steps and arrangements of parts, which have been herein described and illustrated in order to explain the nature of the present invention, may be made by those skilled in the art while still remaining within the principles and scope of the invention.

REFERENCES

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