Methods for permeabilizing the blood-brain barrier

Abstract

To provide a pharmaceutical composition that permeabilizes the blood brain barrier, for use in the treatment of cancer in the central nervous system of a mammal.SOLUTION: A pharmaceutical composition includes a treatment agent and a monoterpene. The monoterpene is perillyl alcohol. The treatment agent is an antibody or antibody fragment.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention uses monoterpenes or sesquiterpenes to permeabilize the blood-brain barrier. Related to doing. [Background technology]

[0002] The blood-brain barrier (BBB) ​​is the barrier between blood, interstitial fluid (IF), and the cerebrospinal fluid (CSF) of the brain. The blood-brain barrier (BBB) ​​is a continuous boundary between the brain and the brain. It is composed of an effective barrier against the penetration of high and low molecular weight serum components into brain tissue. The restriction to the entry of such substances into the brain and CSF is due to the presence of brain hairs. This is due to the unique structure of the endothelium of small blood vessels. In other organs, the cells of the endothelial layer are connected by gallbladder cells that penetrate the layer. The cells have intercellular anatomical tight junctions with loops and channels between them. Brain hairs are unique in their structure and in the rarity of pinocytic vesicles, which may be frequently found in other endothelia. No such channels exist in the endothelium of small blood vessels.

[0003] Under normal (healthy) conditions, only substances that can cross the BBB can enter the brain. Such substances tend to be relatively hydrophobic (lipid-like). Substances have little or no effect on penetrating the BBB. The range of highly permeable substances is from molecules as large as albumin to molecules as small as sodium. A full range of molecules, from small ions to chemotherapeutic agents, drugs, and diagnostic imaging compounds Some therapeutic agents penetrate the BBB. Although it has sufficient lipid solubility for most drugs (e.g., penicillin) and other Many therapeutically useful substances have limited lipid solubility and therefore are unable to fully penetrate the BBB. This low permeability of the BBB by many potentially useful drugs is due to the lack of brain tissue and C Therefore, it is necessary to "open" the BBB and treat brain disorders. Although it is known to be effective in immunotherapy or diagnostics, it cannot cross the BBB by itself. Develop products and methods that allow access to brain tissue and CSF by drugs that are not readily accessible It is of utmost clinical importance to

[0004] Malignant gliomas, the most common form of central nervous system (CNS) cancer, are currently essentially untreated. Among various malignant gliomas, malignant astrocytoma (grade II I) and glioblastoma multiforme (GBM, grade IV) due to their invasive growth, and They have a particularly poor prognosis due to their resistance to currently available treatments. The standard treatment for rheumatoid arthritis consists of surgery, ionizing radiation, and chemotherapy. However, there has been no significant improvement in the prognosis of malignant gliomas over the past 50 years. al.Malignant gliomas in adults. New England and J Med. 359:492-507,2008.Stupp et al.R adiotherapy plus concomitant and adjuvan t temozolomide for glioblastoma. New England and J Med. 352:987-996,2005. The main reason for the poor prognosis of malignant glioma is the difficulty in delivering sufficient amounts of chemotherapy to the brain. Drug access to the brain is limited by the blood-brain barrier (BBB). The final drug concentration is further reduced by first-pass metabolism in the liver and urinary excretion. Therefore, it is suitable for tumor resection, stereotactic injection of antitumor drugs, or convection-enhanced delivery of drugs. Invasive surgery, such as the placement of a catheter, is often required.

[0005] Intranasal drug delivery is a novel approach that bypasses the blood-brain barrier and rapidly delivers drugs directly to the CNS. It provides a novel non-invasive treatment. Intranasally administered drugs are delivered to the brain parenchyma, spinal cord and / or or cerebrospinal fluid (CSF) within minutes. In addition to delivery via the olfactory tract and trigeminal nerve, Animal studies have shown that therapeutic agents can also be delivered systemically via the nasal vasculature. hizume et al.New therapeutic approach fo r brain tumors: intranasal delivery of te Isomericinase inhibitor GRN163. Neuro-oncology 10:112-120,2008.Thorne et al.Delivery o f insulin-like growth factor-1 to the ra t brain and spinal cord along olfactory and trigeminal pathways following intra asal administration. Neuroscience 127:481 -496, 2004. Intranasal delivery of therapeutic agents has been shown to be effective in treating, for example, lung cancer, prostate cancer (prostatitis), and other cancers. e cancer, breast cancer, hematopoietic cancer and ovarian cancer and providing a systemic approach to treat other types of cancer, such as varicella-infectious cancer. It is possible.

[0006] Despite decades of attempts, curative immunotherapy for cancer remains a fundamentally anti-cancer therapy. The ability to recognize an antigen either by the body or by T cells (via the T cell receptor) It is very difficult to do so (Cousin-Frankel, Science (2013) )342:1432). Antibody-based immunotherapy targets specific molecules in tumor cells compared to normal cells. when the antigen is upregulated (e.g., Her-2 in Her-2-amplified breast cancer), or If the tumor cells express an antigen that can be recognized by an antibody or antibody-toxin conjugate (e.g., For example, rituximab against CD20) is widely used in cancer treatment (Baseline lga et al., Annals Oncology (2001) 12:S35). Clinical trials using antibody-based immunotherapies have focused on a limited number of cancer types (usually standard It has been shown to improve patient survival (when used in combination with chemotherapy), but these effects are associated with safety There are often serious concerns about efficacy and safety (Cousin-Frankel Cancer,Science(2013)342:1432).

[0007] Effective T cell therapy for cancer has been even more difficult to achieve clinically (Schm itt et al.,Hum.Gene Ther.(2009)20(11):12 40) Effective T cell therapy for cancer requires T cells that bind with high affinity to antigens on cancer cells. Chimeric antigen receptor T cells (CAR T cells) are designed to "present" peptides. It has both high affinity and specificity without the need for auxiliary recognition molecules such as HLA antigens. CAR T cells are widely used to recognize antigens on cells. The receptors are "swapped" for antigen-binding heavy and light chains, eliminating the need for HLA accessory molecules. Recombinant CAR T receptors are fused with signaling domains and bind to target antigens. When combined, they activate T cells.

[0008] Perillyl alcohol (POH), a naturally occurring monoterpene, has been shown to be associated with CNS cancer, breast cancer, and anticancer), and its effects on various cancers, including pancreatic cancer, lung cancer, melanoma, and colon cancer It has been suggested that this drug is effective. Gould, M. Cancer chemoprevention event and therapy by monoterpenes.Env iron Health Perspect.1997,105(Suppl 4):9 77-979. A hybrid molecule containing both perillyl alcohol and a retinoid is It was prepared to enhance apoptosis-inducing activity. and synthesis of potential new apoptosis agents:hybrid compounds containing peri llyl alcohol and new constrained retinoi ds.Tetrahedron Letters 2010,51,1462-1466 . Cancers such as malignant gliomas, and other brain diseases such as Parkinson's and Alzheimer's In the treatment of disorders, there remains a need to permeabilize the blood-brain barrier to deliver various therapeutic agents. It exists as. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Wen et al.Malignant gliomas in adults.New England J Med.359:492-507,2008 [Non-licensed document 2] Stupp et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England J Med. 352:987-996, 2005 [Non-licensed document 3] Hashizume et al. New therapeutic approach for brain tumors: intranasal delivery of telomerase inhibitor GRN163. Neuro-oncology 10:112-120, 2008

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[0010] The present invention provides a method of administering a therapeutic agent to the central nervous system of a mammal (e.g., a human), comprising: The method includes administering a monoterpene before, after, or simultaneously with the therapeutic agent.

[0011] The central nervous system may be the brain.

[0012] The monoterpene may be perillyl alcohol.

[0013] Monoterpenes (e.g., perillyl alcohol) can be administered intra-arterially (e.g., by injection into an artery) , may be administered to the vascular system of a mammal. Monoterpenes (e.g., perillyl alcohol) It may be administered by inhalation, intranasally, orally, or intravenously. The drug may be administered intravenously, subcutaneously, or intramuscularly.

[0014] Monoterpenes (e.g., perillyl alcohol) range from about 0.050 mg / kg body weight to about 5 It may be administered at a dose ranging from 0.00 mg / kg body weight.

[0015] The monoterpene (e.g., perillyl alcohol) may be administered from about 0.2 minutes to about 1 minute after the therapeutic agent is administered. It may be administered 60 minutes before, or about 1 minute to about 15 minutes before.

[0016] The monoterpene and the therapeutic agent may be administered separately.

[0017] The monoterpene and the therapeutic agent may be administered simultaneously. In one embodiment, the monoterpene and The therapeutic agents are administered together in a pharmaceutical composition (eg, a solution).

[0018] The therapeutic agent may be a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents include DNA alkylating agents. agents, topoisomerase inhibitors, endoplasmic reticulum stress inducers, platinum compounds, antimetabolites, enzyme inhibitors These include agonists, receptor antagonists, therapeutic antibodies, and combinations thereof.

[0019] The chemotherapy drugs are dimethylcelecoxib (DMC), irinotecan (CPT-11), and tetanus. It may be mozolomide or rolipram.

[0020] The therapeutic agent may be an antibody or antibody fragment.

[0021] The therapeutic agent may be an immune cell that expresses a chimeric antigen receptor. The immune cell may be a T cell. In one embodiment, the therapeutic agent is a CAR-T cell.

[0022] The mammal may have a cancer, such as a tumor of the nervous system (eg, a glioblastoma).

[0023] The method may further comprise treating the mammal with radiation. [Brief explanation of the drawings]

[0024] [Figure 1]Schematic diagrams of Lym-1 and CD19 (FMC 63) CAR constructs are shown. [Figure 2A] Figure 2A shows the accumulation of human CAR T cells within brain tumors. Immunohistochemistry (IHC) staining to detect the penetration of human CAR T cells within the brain and the formed tumor (GL261 mouse glioma). Human-derived CD3-positive cells were identified using a primary antibody, anti-human CD3 antibody (CD3ε (D7A6E™) XP® Rabbit mAb (#85061) (Cell Signaling, Boston, MA). [Figure 2B] 1 shows CD3 expression on cultured human CAR T cells. [Figure 2C] CD3 staining in normal C57 BL / 6 brain sections is shown. [Figure 2D] Shows CD3 expression in the brain of GL261 mice bearing glioma upon administration of Lym-1 human CAR T cells by intravenous (IV) injection. [Figure 2E] Shows CD3 expression in GL261 mouse glioma-bearing brains upon IC injection of 3% NEO100 followed by IV injection of Lym-1 human CAR T cells. [Figure 2F] Shows CD3 expression in the brain of GL261 mice bearing glioma upon administration of anti-CD19 human CAR T cells by intravenous (IV) injection. [Figure 2G] 1 shows CD3 expression in GL261 mouse glioma-bearing brains upon IC injection of 3% NEO100 followed by IV injection of anti-CD19 human CAR T cells. [Figure 2H] A comparison of CD3 positive cells between normal parts of the brain and GL261 tumors is shown. [Figure 3] Figure 1 shows survival rates reflecting the efficacy of anti-mouse PD-1 antibody-mediated treatment in C57 BL / 6 bearing syngeneic murine GBM (GL261) in the absence or presence of perillyl alcohol. [Figure 4A] FIG. 4A shows an in vitro brain barrier tight junction model. [Figure 4B]Figure 4B shows that increasing concentrations enhance penetration of fluorescently labeled antibodies into the upper chamber. [Figure 4C] FIG. 4C shows the decrease in TEER after administration of NEO100 at a concentration of 2 mM. [Figure 4D] FIG. 4D shows the recovery time of TEER after administration of NEO100. [Figure 5A] Intracardiac injection (IC) of a mixture of NEO100 (various concentrations) and 2% Evans Blue (EB) is shown. [Figure 5B] EB penetration into the brain after administration of NEO100 by IC (intracardiac injection) or IV injection is shown. [Figure 6] This shows that NEO100 disrupted tight junctions in the brain. [Figure 7] 1 shows NEO100-mediated dopamine delivery through a disrupted blood-brain barrier. [Figure 8] Measurement of BBB opening and closing times is shown. [Figure 9] 1 shows anti-mouse IgG antibody delivery in the absence or presence of perillyl alcohol. [Figure 10] 1 shows anti-PD-1 antibody delivery in the absence or presence of perillyl alcohol. [Figure 11] Kaplan-Meier survival curves after NEO100-mediated human CAR T cell (Lym-1 CAR) delivery in the treatment of intracranial Raji lymphoma xenografts in NSG mice.

[0025] As used herein, the term "NEO100" refers to perillyl alcohol. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention relates to monoterpenes or sesquiterpenes or derivatives thereof (e.g., periterpenes, Perillyl alcohol, i.e., POH, isoperillyl alcohol, or perillyl alcohol derivative Thus, monoterpenes provide a method for permeabilizing the blood-brain barrier. and delivering at least one therapeutic agent across the BBB using a terpenoid or sesquiterpene. It is possible.

[0027] Monoterpenes (or sesquiterpenes) are greater than about 98.5% (w / w) and about 99.0% (w / w) or greater than about 99.5% (w / w).

[0028] The monoterpene (or sesquiterpene) may be hydroxylated in the presence of a therapeutic agent(s) or The monoterpene (or sesquiterpene) may be formulated into a pharmaceutical composition in the absence of Approximately 0.01% (w / w) to approximately 100% (w / w), approximately 0.1% (w / w) to approximately 80% (w / w), about 1% (w / w) to about 70% (w / w), about 10% (w / w) to about 60% (w / w), about 1% (w / w) to about 10% (w / w), about 1% (w / w) to about 5% (w / w), About 1% (w / w) to about 3% (w / w), about 3% (w / w) to about 10% (w / w), or about It is present in an amount ranging from 0.1% (w / w) to about 20% (w / w).

[0029] Monoterpenes (e.g., perillyl alcohol) range from about 0.050 mg / kg body weight to about 5 Other ranges include about 0.1 mg / kg body weight. g ~ approx. 100mg / kg, approx. 1mg / kg ~ approx. 50mg / kg, approx. 5mg / kg ~ approx. 25 mg / kg and about 10 mg / kg to about 15 mg / kg.

[0030] Monoterpenes or sesquiterpenes may be used in a variety of applications, including, but not limited to, chemotherapeutic agents, immunotherapeutic agents, and the like. therapeutic agents, immunomodulatory agents, antibodies (e.g., monoclonal antibodies), immune cells (e.g., CAR- T cells), vaccines, antibody-drug conjugates, antiviral agents, anti-inflammatory agents, antibacterial agents, antimicrobial agents , in combination with at least one therapeutic agent, including antibiotics and combinations thereof. obtain.

[0031] Anticancer agents that may be used in combination with the purified monoterpenes or sesquiterpenes include: The following effects on cancer cells or subjects: cell death; reduction in cell proliferation; Reduction; inhibition of cell proliferation; apoptosis; necrosis; mitotic catastrophe; cell cycle arrest; reduction in cell size Decreased cell division; Decreased cell viability; Decreased cell metabolism; Cell damage or cytotoxicity an indirect indicator of cell damage or cytotoxicity, e.g., tumor shrinkage; improved survival of a subject or the disappearance of markers associated with unwanted, undesired, or abnormal cell proliferation The present invention may have one or more of the following defects:

[0032] The therapeutic agent may be dissolved in perillyl alcohol. The composition may be used to treat diseases such as cancer. It can be administered alone or in combination with radiation or another agent (e.g., a chemotherapy agent). It can be administered at any time.

[0033] In some embodiments, the agent is an antibody-drug conjugate. Body-drug conjugates combine an antigen-binding fragment with a toxin or drug that induces cytotoxicity in target cells. Suitable toxins or drugs for use in antibody drug conjugates are well known in the art. , will be apparent to those skilled in the art. See, e.g., Peters et al. Biosci. See p. (2015) 35(4):e00225. In some embodiments, Antibody-drug conjugates may contain a linker (e.g., a cleavable linker) that connects the antibody and drug molecule. The amino acid sequence may further comprise a peptide linker such as

[0034] The treatment may be continuous, and the monoterpene (or sesquiterpene) may be administered in a continuous manner (including one or more ) before or after the administration of the therapeutic agent. The pen) and the therapeutic agent(s) may be administered simultaneously.

[0035] The monoterpene (or sesquiterpene) and at least one therapeutic agent are simultaneously administered separately. They may be administered individually or sequentially to provide advantageous combined effects (e.g. , additive or synergistic effects).

[0036] In the case of continuous administration, the monoterpene (or sesquiterpene) is administered first, followed by (1 or or administering the therapeutic agent(s) first and then administering the therapeutic agent(s) first. Administer terpenes (or sesquiterpenes). Monoterpenes (or sesquiterpenes) In embodiments where the therapeutic agent is administered separately, the monoterpene (or sesquiterpene) Administration may occur within seconds, minutes, hours, days, or weeks prior to administration of the therapeutic agent(s). Standing, or alternatively, seconds, minutes, hours, days of administration of the therapeutic agent(s). The time difference between non-simultaneous administrations can be more than one minute, e.g. To be precise, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 3 hours, at least at least 6 hours, at least 9 hours, at least 12 hours, at least 24 hours, at least At least 36 hours or at least 48 hours, max 5 minutes, max 10 minutes, max 15 minutes, max 30 minutes, up to 45 minutes, up to 60 minutes, up to 2 hours, up to 3 hours, up to 6 hours, up to 9 hours, up to 12 hours, up to 24 hours, up to 36 hours or up to 48 hours, or less than 5 minutes, 10 Less than 15 minutes, Less than 30 minutes, Less than 45 minutes, Less than 60 minutes, Less than 2 hours, Less than 3 hours, Less than 6 hours, less than 9 hours, less than 12 hours, less than 24 hours, less than 36 hours, or less than 48 hours The two or more agents may be administered within minutes of each other or within a period of time greater than 48 hours. Approximately 0.5 hours, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 6 hours, approximately 9 hours, approximately 1 hour Within 2 hours, about 15 hours, about 18 hours, about 24 hours, or about 36 hours of each other Approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 8 days, approximately 9 days, approximately 10 days , within about 12 days, about 14 days, or within about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks of each other, It may be administered within about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks. In some cases, even longer intervals are possible.

[0037] The present disclosure also provides a method for producing a compound comprising: (i) at least one monoterpene (or sesquiterpene); and (ii) providing a pharmaceutical composition comprising at least one therapeutic agent;

[0038] The route of administration can be varied and may include intra-arterial delivery, inhalation, intranasal, oral, transdermal, intravenous, subcutaneous or may include intramuscular injection.

[0039] The present invention also provides a method of treating a disease, such as cancer, comprising delivering the composition to a patient. provide.

[0040] The compositions of the present invention contain one or more types of monoterpenes (or sesquiterpenes). Monoterpenes consist of two isoprene units and have the molecular formula C10 H 16 have Monoterpenes include terpenes that are linear (acyclic) but contain a ring. Monoterpenes produced by biochemical modifications such as oxidation or rearrangement of monoterpenes are also suitable. The monoterpenoids and pharmaceutically acceptable salts of the monoterpenes or monoterpenoids are also included in the present invention. Examples of monoterpenes and monoterpenoids include perillyl alcohol (S (-)) and R(+)), geranyl pyrophosphate, ocimene, myrcene, geraniol, Citral, citronellol, citronellal, linalool, pinene, terpineol, Terpinene, Limonene, Terpinene, Phellandrene, Terpinolene, Terpinene-4- ol (or tea tree oil), pinene, terpineol, terpinene; menthol Derived from monocyclic terpenes such as chloral, thymol, and carvocrol Derived terpenoids such as p-cymene; camphor, borneol and eucalyptus Examples include bicyclic monoterpenoids such as benzoyl.

[0041] Monoterpenes can be distinguished by the structure of their carbon skeleton, and include acyclic monoterpenes (e.g., Myrcene, (Z)- and (E)-ocimene, linalool, geraniol, nerol, cinnamal Tolonellol, myrcenol, geranial, citral a, neral, citral b, citronellal), monocyclic monoterpenes (e.g., limonene, terpinene, ferrane) dolen, terpinolene, menthol, carveol, etc.), bicyclic monoterpenes (e.g. , pinene, myrtenol, myrtenal, verbanol, verbanone ), pinocarveol, carne, sabinene, camphene, thujene, etc.) and tricyclic moieties They can be classified as terpenes (e.g., tricyclene). Encyclopedia of Chemical Technology ,Fourth Edition,Volu See me 23, pages 834-835.

[0042] The sesquiterpenes of the present invention consist of three isoprene units and have the molecular formula C 15 H 24 of Sesquiterpenes include terpenes that contain a ring, even if they are linear (acyclic). They may be produced by biochemical modifications such as oxidation or rearrangement of sesquiterpenes. Sesquiterpenoids are also included in the present invention. Examples of sesquiterpenes include farnesol, Farnesal, farnesylic acid and nerolidol.

[0043] Derivatives of monoterpenes (or sesquiterpenes) include, but are not limited to, monoterpenes, Terpene (or sesquiterpene) esters, alcohols, aldehydes, and ketones Monoterpene (or sesquiterpene) alcohols are esters, aldehydes, or may be derivatized to an acid.

[0044] The esters of monoterpene (or sesquiterpene) alcohols of the present invention may be prepared from inorganic acids or can be derived from organic acids. Inorganic acids include, but are not limited to, phosphoric acid, sulfuric acid, Organic acids include, but are not limited to, benzoic acid, fatty acids, acetic acid, and nitric acid. These include carboxylic acids such as propionic acid and monoterpenes (or sesquiterpenes). Examples of esters of carboxylic acid esters (carbonyl alcohols) include, but are not limited to, carboxylic acid esters (carbonyl alcohols). fatty acid esters (e.g., palmitate and linoleate) ter), acetate, propionate (or propanoate) and formate), Phosphates, sulfates and carbamates (e.g., N,N-dimethylaminocarbamate) Examples include esters (bornyl). Wikipedia - Esters. URL: http: / / en. Retrieved from wikipedia.org / wiki / Ester

[0045] Specific examples of monoterpenes that may be used in the present invention include perillyl alcohol (commonly referred to as POH). The perillyl alcohol composition of the present invention is (S)-perillyl alcohol. , (R)-perillyl alcohol, or (S)-perillyl alcohol and (R)-perillyl It may contain mixtures with alcohols.

[0046] The terms "chimeric receptor," "chimeric antigen receptor," or "CAR" are used throughout and functional signaling domains (fu) derived from stimulatory molecules as defined below. at least one extracellular domain containing a functional signaling domain An antigen-binding domain, a transmembrane domain, and a cytoplasmic signaling domain (referred to herein as " The term "intracellular signaling domain" refers to a recombinant polypeptide construct containing an intracellular signaling domain (also referred to as an "intracellular signaling domain"). Lee et al., Clin. Cancer Res. (2012) 18(10): 2780;Jensen et al.,Immunol Rev.(2014)257 (1):127;www.cancer.gov / about-cancer / trea tment / research / car-t-cells. In one embodiment, the stimulatory molecule is , the zeta chain associated with the T cell receptor complex. In one embodiment, the cytoplasmic signaling domain The stimulatory signaling pathway comprises one or more functional signals derived from at least one costimulatory molecule as defined below. Costimulatory molecules also include 4-1BB (i.e., CD137 ), CD27 and / or CD28, or fragments of these molecules. In this context, CARs are extracellular antigen-recognizing molecules that contain functional signaling domains derived from stimulatory molecules. Chimeric fusion proteins containing a recognition domain, a transmembrane domain, and an intracellular signaling domain CARs contain a functional signaling domain derived from a costimulatory molecule and a stimulatory molecule. a functional signal transduction domain derived from the extracellular antigen recognition domain, a transmembrane domain, and and an intracellular signaling domain. R is a signal transduction pathway that binds two functional signaling domains derived from one or more costimulatory molecules. The extracellular antigen recognition domain contains a domain and a functional signal transduction domain derived from a stimulatory molecule. The chimeric fusion protein includes a fusion domain, a transmembrane domain, and an intracellular signaling domain. CARs also include at least two co-stimulatory molecules derived from one or more co-stimulatory molecules. and a functional signaling domain derived from a stimulatory molecule. A protein containing an extracellular antigen-recognition domain, a transmembrane domain, and an intracellular signaling domain. The antigen recognition portion of the CAR can include any antigen-binding antibody fragment. An antibody fragment may comprise one or more CDRs, variable regions (or portions thereof), constant regions, or fragments thereof. It may comprise a region (or portion thereof), or a combination of any of the foregoing.

[0047] As used herein, a chimeric receptor is a receptor that can be expressed on the surface of a host cell and binds an antigen. Chimeric receptors generally refer to non-naturally occurring molecules that contain fragments of the same molecule. The chimeric receptors contain two domains, in addition to the antigen-binding fragments described herein. The antibody comprises a hinge domain, a transmembrane domain, at least one costimulatory domain, and a cytoplasmic synthase. In some embodiments, the chimeric antigen receptor may further comprise one or more of a chimeric antigen receptor signal transduction domain. The La receptor consists of an N-terminal to C-terminal domain, an antigen-binding fragment, a hinge domain, a transmembrane domain, and In some embodiments, the chimeric receptor comprises at least Each further comprises a costimulatory domain.

[0048] In some embodiments, the chimeric receptors described herein comprise an antigen-binding fragment and a transmembrane receptor. The hinge domain may be located between the amino acid sequence and the amino acid sequence. A segment of amino acids commonly found between two domains that contributes to protein flexibility and movement of one or both of the domains relative to one another. Any amino acid that provides such flexibility and movement of the antigen-binding fragment relative to the domain of An acid sequence can be used.

[0049] Any of the chimeric receptors described herein may be prepared by conventional techniques using immunogenic vectors suitable for expression. In some embodiments, the immune cells can be primary T cells or Alternatively, the immune cells may be established NK cell lines (e.g., T cells). In some embodiments, the immune cells may be NK cells, such as NK-92 cells. is CD8(CD8 + ) or CD8 and CD4 (CD8 + / CD4 + ) expressing T In some embodiments, the T cells are T cells of an established T cell line, e.g. , 293T cells or Jurkat cells.

[0050] In some embodiments, an immune cell expressing any of the chimeric receptors described herein is The immune cells reduce the number of target cells (e.g., cancer cells) by at least 20%, e.g., 50%, 80%, %, 100%, 2x, 5x, 10x, 20x, 50x, 100x or more decrease The compound is administered to a subject in an amount effective to

[0051] Cells, e.g., immune cells (e.g., CAR T cells), administered to a mammal (e.g., a human) Typical amounts of ) can range, for example, from 1 million to 100 billion cells. Amounts below or above the exemplary ranges are also within the scope of the present disclosure. The dose ranges from about 1 million to about 50 billion cells (e.g., about 5 million cells, about 25 million cells, about 500 million cells, about 1 billion cells, about 5 billion cells, about 20 billion cells, about 30 billion cells, about 400 billion cells, or a range defined by any two of the foregoing values), preferably about 10 100 million to about 100 billion cells (e.g., about 20 million cells, about 30 million cells, about 40 million million cells, approximately 60 million cells, approximately 70 million cells, approximately 80 million cells, approximately 90 million cells, Approximately 10 billion cells, approximately 25 billion cells, approximately 50 billion cells, approximately 75 billion cells, approximately 90 billion cells, or a range defined by any two of the preceding values), more preferably about 100 million cells ~ about 50 billion cells (e.g., about 120 million cells, about 250 million cells, about 350 million cells) million cells, approximately 450 million cells, approximately 650 million cells, approximately 800 million cells, approximately 900 million cells, Approximately 3 billion cells, approximately 30 billion cells, approximately 45 billion cells, or any two of the preceding values (range defined by the

[0052] In one embodiment, the chimeric receptor (e.g., a nucleic acid encoding the chimeric receptor) is administered to an immune cell. and the subject (e.g., human patient) receives an initial administration of immune cells expressing the chimeric receptor. or receiving an initial dose of an agent (e.g., immune cells expressing a chimeric receptor) one or more times. Subsequent doses of are given 15, 14, 13, 12, 11, and 1 day after the previous dose. At intervals of 0, 9, 8, 7, 6, 5, 4, 3 or 2 days Multiple doses of the drug may be provided to the patient, for example, two, three, or four doses per week of the drug. Four or more doses of the drug may be administered to the subject. Multiple doses (e.g., immune cells expressing chimeric receptors) are administered, followed by a week No drug is administered, and finally one or more booster doses of the drug (e.g., Multiple weekly doses of immune cells may be administered. The cells may be infected for 2, 3, 4, 5, 6, 7, 8 or more weeks. It may be administered every other day for three doses per week.

[0053] In the context of this disclosure, the term "therapeutic" refers to any of the disease states described herein. "Treat," "treatment," etc. are used to describe such conditions. relieve or alleviate at least one symptom associated with or slow the progression of such a condition Within the meaning of this disclosure, the term "treat" also means to arresting the onset, delaying the onset (i.e., the period before clinical manifestations of the disease), and / or This means reducing the risk of developing or worsening a disease or condition, for example, a cancer-related condition. Thus, the term "treat" refers to eliminating or reducing the tumor burden in a patient or preventing metastasis. It can mean to prevent, delay, hinder, etc.

[0054] The methods and compositions described herein are useful in treating, but not limited to, brain tumors, lung cancer, Ear cancer, nose cancer and pharyngeal cancer, hematopoietic cancer, colon cancer, melanoma, pancreatic cancer, breast cancer cancer), prostate cancer, breast cancer cancer), ovarian cancer, basal cell carcinoma cell carcinoma), biliary tract cancer; bladder cancer; bone cancer; breast cancer cervical cancer; choriocarcinoma; colon cancer and rectal cancer rectum cancer; connective tissue cancer; digestive system cancer; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer; intraepithelial neoplasm; kidney cancer ey cancer); laryngeal cancer; liver cancer; fibroma, neuroblastoma; oral cancer (e.g., lip, tongue) , mouth and pharynx; ovarian cancer; pancreatic cancer; prostate cancer state cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer cancer);renal cancer;respiratory system cancer;sarcoma;skin cancer cancer);stomach cancer;testicular cancer;thyroid cancer;uterine cancer may be used to treat urinary system cancers, as well as other carcinomas and sarcomas.

[0055] Carcinomas are cancers of epithelial origin. Carcinomas contemplated for treatment using the methods of the present disclosure include, but are not limited to: Although not exclusively, acinar carcinoma, lobular carcinoma, follicular adenocarcinoma (adenocystic carcinoma, adenomyoepithelioma, cribriform carcinoma and ovarian carcinoma) (also called cystoma), adenomatous carcinoma (carcinoma adenomatous), Adenocarcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, alveolar epithelial carcinoma (including bronchiolar carcinoma, alveolar epithelioma, and pulmonary adenomatosis) Also called basal cell carcinoma, basal cell carcinoma carcinoma basocellulare (basalom cell carcinoma) a) or basiloma (also called pilomatrix carcinoma), basaloid carcinoma , basosquamous cell carcinoma, breast cancer (breast carcinoma), bronchoalveolar epithelial carcinoma, bronchiolar carcinoma, bronchogenic lung Cancer, cerebriform carcinoma, cholangiocarcinoma (bile duct cancer and and cholangiocarcinoma), choriocarcinoma, Mucinous carcinoma (colloid carcinoma), comedonal carcinoma, endometrial cancer, cribriform carcinoma, armor-shaped carcinoma (carcinoma en cuirasse), skin cancer (carcinoma cuirasse), skin cancer (carcinoma en cuirasse) taneum, cylindrical carcinoma, cylindrical cells Carcinoma, ductal carcinoma, dura carcinoma, embryonal carcinoma, medullary carcinoma phaloid carcinoma), epibulbar carcinoma noma), epidermoid carcinoma, epithelial adenoid carcinoma (carcinoma epithelial carcinoma) e adenoides), ulcer cancer, fibrous cancer, gelatiniform cancer (gelatiniform c arcinoma), colloid adenocarcinoma, giant cell carcinoma, giant cell (gigantocellula) re), adenocarcinoma, granulosa cell carcinoma, hematoid carcinoma, hematoid carcinoma a), hepatocellular carcinoma (hepatocellular carcinoma, malignant Hepatocellular carcinoma (also called hepatocellular carcinoma and hepatocarcinoma), Haas hyaline carcinoma, clear cell renal cell carcinoma, infantile fetal carcinoma sexual cancer, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma (int raepithelial carcinoma, Krompecker carcinoma her's carcinoma), Kulchitzky cell carcinoma ll carcinoma, lenticular carcinoma ), carcinoma lenticulare, lipoma mammary carcinoma), lymphoid epithelial carcinoma, breast adenocarcinoma (carcinoma m astitoides), medullary carcinoma (carcinoma medullare), medullary carcinoma (medullary carcinoma), carcinoma mela nodes), melanotic carcinoma, mucinous carcinoma inous carcinoma), mucinous adenocarcinoma (carcinoma muciparu) m), carcinoma mucocellulare, mucoepidermoid carcinoma, Carcinoma mucosum, mucous carcinoma oma), myxomatous carcinoma, nasopharyngeal carcinoma, melanoma (carcinoma nigrum), oat cell carcinoma, carcinoma ossificans, osteoid carcinoma id carcinoma), ovarian carcinoma, papillary carcinoma , periportal carcinoma, pre-invasive cancer, prostate cancer (prostate carcinoma), renal cell carcinoma of the kidney (renal adenocarcinoma, and hyper Also called hypemephoroid carcinoma sarcomatoid carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal cancer , signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma ma), spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, spindle cell carcinoma, spindle cell carcinoma, String carcinoma, angiectatic carcinoma elangiectaticum, telangiectatic carcinoma (carcinoma telan giectodes), transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum) ), tuberous carcinoma, warty carcinoma, choriocarcinoma In a preferred embodiment, the method of the present disclosure includes the step of Subjects with cancer of the cervix, ovary, prostate, lung, colon and rectum, pancreas, stomach, or kidney It is used to treat

[0056] Sarcomas are mesenchymal tumors that arise in bone and soft tissue. Various types of sarcomas are recognized. These include liposarcoma (including myxoid and pleomorphic liposarcoma), smooth Myosinoma, rhabdomyosarcoma, malignant peripheral nerve sheath tumor (malignant schwannoma, neurofibrosarcoma or neurogenic sarcoma), Ewing's tumor (Ewing's tumor of bone), extraosseous (i.e., tumors outside the bone) Ewing's sarcoma, and primitive neuroectodermal tumor [PNET], synovial sarcoma, and angiosarcoma (angiosarcoma), hemangiosarcoma, lymphoma ductosarcoma, Kaposi's sarcoma, hemangioendothelioma, fibrosarcoma, desmoid tumor (also called aggressive fibromatosis), Dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), hemangiopericytoma, malignant interstitial fibroma, alveolar soft part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor (desmoplasia) astic small cell tumor), gastrointestinal stromal tumor (GIST) (GI stromal sarcoma), osteosarcoma (also called osteogenic sarcoma) (skeletal and extraskeletal), and and chondrosarcoma.

[0057] In some embodiments, the cancer being treated may be a refractory cancer. In this context, a "refractory cancer" is a cancer that is resistant to prescribed standard treatments. The cancer may initially appear to respond to treatment (and then recur), or it may not completely respond to treatment. The usual standard of care varies depending on the type of cancer and the stage of progression of the patient. The usual standard of care is chemotherapy, surgery, radiation, or a combination of these. Those skilled in the art are aware of such standard treatments. Subjects being treated according to the present disclosure for cancer may have already been exposed to another treatment for their cancer. Alternatively, if the cancer is likely to be intractable (e.g., analysis of cancer cells, The subject may not have been exposed to another treatment (or given the subject's medical history). Examples of cancers include, but are not limited to, leukemia, melanoma, renal cell carcinoma, colon cancer, liver (liver) cancer, and ovarian cancer. ver) (hepatic) cancer, pancreatic cancer, non-Hodgkin's lymphoma, and lung cancer. do.

[0058] Any of the immune cells expressing the chimeric receptors described herein may be administered as a pharmaceutical composition. The compound may be administered in a pharmaceutically acceptable carrier or excipient.

[0059] The phrase "pharmaceutically acceptable" as used in connection with the compositions and / or cells of the present disclosure is physiologically tolerable and does not cause unexpected side effects when administered to mammals (e.g., humans). It refers to molecular entities and other components of such compositions that do not typically undergo a reaction. As used herein, the term "pharmaceutically acceptable" means any substance or substance that is approved by the federal or state government. approved by a regulatory agency or for use in mammals, and more specifically in humans "Substances" means substances listed in the United States Pharmacopoeia or other generally recognized pharmacopeia. "Acceptable" means that the carrier is compatible with the active ingredients (e.g., nucleic acids, vectors, cells or therapeutic agents) of the composition. and (b) the composition(s) are compatible with the therapeutic antibody and do not adversely affect the subject to which the composition(s) are administered. Any of the pharmaceutical compositions and / or cells used in the method may be frozen. In dry or aqueous solution form, a pharmaceutically acceptable carrier, excipient or stabilizer is added. It can include.

[0060] Pharmaceutically acceptable carriers, including buffers, are well known in the art and include phosphate, citrate, and the like. esters and other organic acids; antioxidants including ascorbic acid and methionine; preservatives; low High molecular weight polypeptides; proteins such as serum albumin, gelatin or immunoglobulins amino acids; hydrophobic polymers; monosaccharides; disaccharides; and other carbohydrates; metal complexes; and and / or non-ionic surfactants. Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins,Ed. See .KEHoover.

[0061] Treatment kit Also within the scope of this disclosure are kits for using the agents / compositions. The kit includes a first pharmaceutical composition comprising at least one monoterpene or sesquiterpene. and a pharmaceutically acceptable carrier, and at least one therapeutic agent and a pharmaceutically acceptable carrier. In another embodiment, the kit may include one or more containers containing a second pharmaceutical composition comprising the compound. The compound contains at least one monoterpene or sesquiterpene and at least one therapeutic agent. and a pharmaceutically acceptable carrier.

[0062] In some embodiments, the kit is for use in any of the methods described herein. The included instructions may include instructions for achieving the intended activity on a subject. The method may include instructions for administering the first and second pharmaceutical compositions to a subject to achieve the desired effect. The kit identifies subjects suitable for treatment based on identifying whether the subject is in need of treatment. In some embodiments, the instructions may further include instructions for selecting. The present invention includes instructions for administering the pharmaceutical composition to a subject.

[0063] Instructions for use of the pharmaceutical compositions described herein generally relate to the intended treatment. The container contains information about the dosage, dosing schedule and route of administration for the unit dose. , may be a bulk package (e.g., a multi-dose package) or a sub-unit dose The instructions provided in the kits of the present disclosure are typically written on a label or package insert. The label or package insert indicates that the pharmaceutical composition is intended to treat a disease or disorder of interest. delaying the onset of the disease or disorder in a subject and / or alleviating the disease or disorder in a subject. Indicates that it is used to mitigate

[0064] The kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to: This includes, but is not limited to, vials, bottles, jars, flexible packaging, etc. Packaging for use in combination with a particular device, such as an administration or infusion device, is also contemplated. The kit may have a sterile access port (e.g., the container may be an intravenous solution bag). or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port.

[0065] The kit may provide additional components such as buffers and interpretive information. The container and any label or insert(s) on or accompanying the container. In some embodiments, the present disclosure provides an article of manufacture comprising the contents of the kit described above. Provide.

[0066] Perillyl alcohol derivatives include perillyl alcohol esters, perillaldehyde, dihydroxybenzoates, and Derivatives of perillyl alcohol include hydroperillic acid and perillic acid. Oxidative and nucleophilic / electrophilic addition derivatives may be included. U.S. Patent Publication No. 200900314 No. 55. U.S. Patent No. 6,133,324 and U.S. Patent No. 3,957,856.

[0067] The present invention also provides a method for producing a compound comprising a monoterpene (or sesquiterpene) and at least one therapeutic agent. The present invention provides a method for treating diseases such as cancer or other nervous system disorders using the monoterpene The moiety (or sesquiterpene) may be administered alone or in combination with a therapeutic agent. Monoterpenes or sesquiterpenes may also be co-administered with a therapeutic agent. or sesquiterpenes) can be administered in combination with a therapeutic agent. The monoterpene (or sesquiterpene) may be administered sequentially or sequentially. It can be administered before, during or after administration.

[0068] Monoterpenes (or sesquiterpenes) are used as solvents or agents to deliver therapeutic agents to the site of the lesion. For example, monoterpenes (or sesquiterpenes) can be used as penetration enhancers. , can be used as a solvent or penetration enhancer for delivering chemotherapeutic agents to tumor cells. The terpene or sesquiterpene may be a component of a vaccine that can be delivered via any suitable route. It can also be used as a solvent.

[0069] The compositions and methods are directed to treating cancers of the nervous system, such as malignant gliomas (e.g., astrocytomas, malignant gliomas, astrocytoma, glioblastoma multiforme), retinoblastoma, pilocytic astrocytoma (grade I) Treatment of cerebrospinal fluid (CSF) in meningiomas, metastatic brain tumors, neuroblastomas, pituitary adenomas, skull base meningiomas, and skull base cancers As used herein, the term "nervous system tumor" refers to a tumor in which a subject has a nervous system tumor. It refers to a condition in which there is malignant growth of cells.

[0070] Cancers that can be treated by the present compositions and methods include, but are not limited to: Lung cancer, ear cancer, nose cancer and pharyngeal cancer, leukemia, colon cancer, melanoma, pancreatic cancer, breast cancer (mamma ry cancer, prostate cancer, breast cancer st cancer), hematopoietic cancer, ovarian cancer, basal cell Cancer (basal cell carcinoma), biliary tract cancer; bladder cancer; bone cancer; breast cancer (br east cancer; cervical cancer; choriocarcinoma; Bowel and rectum cancer; connective tissue cancer; digestive system cancer; endometrium Cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer; intraepithelial neoplasm; Kidney cancer; Laryngeal cancer; Acute myeloid leukemia, acute lymphocytic leukemia leukemia, including chronic myeloid leukemia, chronic lymphocytic leukemia; liver cancer; Hodgkin's lymphoma and Lymphoma, including non-Hodgkin's lymphoma; myeloma; fibroma, neuroblastoma; oral cancer (e.g., Lips, tongue, mouth, and throat; ovarian cancer; pancreatic cancer; prostate cancer prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer cancer);renal cancer;respiratory system cancer;sarcoma;skin cancer(s) stomach cancer; testicular cancer; thyroid cancer; This includes uterine cancer, urinary system cancer, and other carcinomas and sarcomas. No. 355.

[0071] The present invention also relates to the treatment of primary degenerative neurological disorders, including, but not limited to, Alzheimer's disease. To treat CNS disorders, including rheumatoid arthritis, Parkinson's disease, psychological disorders, psychosis, and depression The present invention provides methods and compositions for:

[0072] The composition may be used in combination with radiation therapy.

[0073] The monoterpenes or sesquiterpenes may be used in a variety of applications, including, but not limited to, chemotherapeutic agents, immunosuppressants, and the like. and combination with at least one therapeutic agent, including a therapeutic agent and an antibody (e.g., a monoclonal antibody). It can be used in combination with purified monoterpenes or sesquiterpenes. Anti-cancer drugs that can be used have the following effects on cancer cells or subjects: cell death; Decreased proliferation; decreased cell number; inhibition of cell proliferation; apoptosis; necrosis; mitotic death; cell cycle arrest Decreased cell size; Decreased cell division; Decreased cell viability; Decreased cell metabolism; Cell damage or a marker of cytotoxicity; an indirect indicator of cell damage or cytotoxicity, e.g., tumor shrinkage improving the survival rate of a subject; or preventing undesirable, unwanted, or abnormal cell proliferation The present invention may have one or more of the following associated markers: loss of markers. No. 057.

[0074] Also, monoterpenes (or sesquiterpenes) and, but not limited to, chemotherapy Also included in the present invention are mixtures and / or co-formulations with at least one therapeutic agent comprising the agent.

[0075] Chemotherapeutic agents include, but are not limited to, DNA alkylating agents, topoisomerase inhibitors, Toxicants, endoplasmic reticulum stress inducers, platinum compounds, antimetabolites, vinca alkaloids, taxanes , epothilones, enzyme inhibitors, receptor antagonists, therapeutic antibodies, tyrosine kinase inhibitors, These include radiosensitizers (i.e., Velcade) and chemotherapy combination therapy.

[0076] DNA alkylating agents are well known in the art and are used to treat a variety of tumors. Non-limiting examples of DNA alkylating agents include mechlorethamine, cyclophosphamide (ifo), sufamide, trofosfamide), chlorambucil (melphalan, prednimustine) , nitrogen masterbinds such as bendamustine, uramustine, and estramustine Carmustine (BCNU), lomustine (semustine), fotemustine, nimustine nitrosoureas such as benzoquinone, ranimustine, and streptozocin; busulfan (manno Alkyl sulfonates such as sulfane and treosulfane; Carboquone, ThioTE Aziridines such as PA, triazicon, and triethylenemelamine; hydrazine (procarba triazenes such as dacarbazine and temozolomide; altretamine and mitoxantrone It is bronitr.

[0077] Non-limiting examples of topoisomerase I inhibitors include those described in Pommier Y. (2006) N at.Rev.Cancer 6(10):789-802 and U.S. Patent Publication No. 200 CPT-11 (irinotecan), SN-38, A, described in No. 510250854 PC, NPC, camptothecin, topotecan, mesilate Satecan, 9-nitrocamptothecin, 9-aminocamptothecin, raltotecan, rubican Tecan, siratecan, jamatecan, diflomotecan, Extatecan, BN-80927, DX-8951f and M Camptothecin derivatives including AG-CPT; Li et al. (2000) Bioch emistry 39(24):7107-7116 and Gatto et al.( 1996) Cancer Res.15(12):2795-2800 Protoberberine aldehydes, including berberrubine and coraline. Kaloids and their derivatives; Mahey et al. (2003) Bioorg.M ed.Chem benzo[i]phena, as described in .11(8):1809-1820 Phenanthroline derivatives including thoridine, nitidine and fagaronine; Xu (199 8) Biochemistry 37(10):3558-3566 Benzimidazole and its derivatives; and Foglesong et al. ( 1992) Cancer Chemother.Pharmacol. 30(2):12 3-]25, Crow et al. (1994) J. Med. Chem. 37(19) :31913194 and Crespi et al. (1986) Biochem.B iophys.Res.Commun. 136(2):521-8 Anthracycline derivatives including sorbicin, daunorubicin, and mitoxantrone Topoisomerase II inhibitors include, but are not limited to, etoposide and Dual topoisomerase I and II inhibitors include, but are not limited to, benzodiazepine and teniposide. Although not the case, Denny and Baguley (2003) Curr.Top.M ed.Chem. 3(3):339-353. Naphthecenedione, DACA and other acridines -4-Carboxamides, Intoplicin and Other Benzopyridoindoles, TAS-I 03 and other 7H-indeno[2,1-c]quinolin-7-ones, pyrazoloacridines , XR 11576 and other benzophenazines, XR 5944 and other dimeric compounds 7-oxo-7H-dibenzo[f,ij]isoquinoline and 7-oxo-7H-benz[f,ij]isoquinoline This includes benzo[e]perimidine and anthracenyl amino acid conjugates. However, anthracyclines (aclarubicin, daunorubicin, doxorubicin, Epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin ) and some drugs such as anthracenediones (mitoxantrone and pixantrone) The agent inhibits topoisomerase II and has DNA intercalation activity.

[0078] Examples of endoplasmic reticulum stress inducers include, but are not limited to, dimethylcelecoxib (D MC), nelfinavir, celecoxib, and boron radiosensitizers (i.e., Belkei Examples include bortezomib.

[0079] Platinum-based compounds are a subclass of DNA alkylating agents. Non-limiting examples of such agents include: These include carboplatin, cisplatin, nedaplatin, oxaliplatin, and triprophenone tetranitrate. These include platin, satraplatin, aroplatin, lobaplatin, and JM-216. (McKeage et al. (1997) J. Clin. Oncol. 201:12 32-1237 and generally, CHEMOTHERAPY FOR GYNECOLOGY ICAL NEOPLASM, CURRENT THERAPY AND NOVEL APPROACHES,in the Series Basic and Clini (See Physiological Oncology, Angioli et al. Eds., 2004) .

[0080] Non-limiting examples of antimetabolites include folate-based, i.e., dihydrofolate reductase inhibitors. , e.g., aminopterin, methotrexate, and pemetrexed; thymidylate synthase enzyme inhibitors, e.g., raltitrexed, pemetrexed; purine-based, i.e., adenosine Syndeaminase inhibitors, e.g., pentostatin, thiopurines, e.g., thioguanine and mercaptopurines, halogenated / ribonucleotide reductase inhibitors, e.g. Cladribine, clofarabine, fludarabine, or guanine / guanosine:thiop phosphorus, e.g., thioguanine; or pyrimidine, i.e., cytosine / cytidine: low Methylating agents, such as azacitidine and decitabine, DNA polymerase inhibitors, e.g. cytarabine, a ribonucleotide reductase inhibitor, such as gemcitabine, or thymine / thymidine:thymidylate synthase inhibitors, e.g., fluorouracil (5-F Equivalents of 5-FU include, for example, those described by Papamicheal (1999) ) 5'-deoxy- -5-fluorouridine (doxifluroidine), 1 -Tetrahydrofuranyl-5-fluorouracil (Ftorafur), capecitabine (Zero da), SI (MBMS-247616, tegafur and two modulators, 5-chloro Raltitrexate), consisting of 2,4-dihydroxypyridine and potassium oxonate Sed (Tomudex), Nolatrexed (Thymitaq), AG33 7), LY231514 and its prodrugs, analogs and derivatives such as ZD9331 Body included.

[0081] Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, Examples include vinflunine, vindesine, and vinorelbine.

[0082] Examples of taxanes include, but are not limited to, docetaxel, larotaxel, and orthotaxel. Examples of epothilones include iabenzyl benzoate, benzodiazepine, paclitaxel, and tesetaxel. The drug is iabepilone.

[0083] Examples of enzyme inhibitors include, but are not limited to, farnesyltransferase inhibitors agents (tipifarnib); CDK inhibitors (alvocidib, seliciclib); proteasome inhibitors inhibitors (bortezomib); phosphodiesterase inhibitors (anagrelide; rolipram); IMP dehydrogenase inhibitor (tiazofurin); and lipoxygenase inhibitor (maso Examples of receptor antagonists include, but are not limited to, ERAs ( atrasentan); retinoid X receptor (bexarotene); and sex steroids (test lactones).

[0084] Examples of therapeutic antibodies include, but are not limited to, anti-HER1 / EGFR (cetuximab , panitumumab); anti-HER2 / neu (erbB2) receptor (trastuzumab); anti-E pCAM (catumaxomab, edrecolomab); anti-VEGF-A (bevacizumab); anti-C D20 (rituximab, tositumomab, ibritumomab); anti-CD52 (alemtuzumab and anti-CD33 (gemtuzumab). U.S. Patent No. 5,776,427 and U.S. Patent No. 7,601,355.

[0085] Examples of tyrosine kinase inhibitors include, but are not limited to, ErbB:HER1 / E GFR inhibitors (erlotinib, gefitinib, lapatinib, vandetanib, sulindac) tinib, neratinib); HER2 / neu inhibitors (lapatinib, neratinib); RTK class III: C-kit inhibitors (axitinib, sunitinib, sorafenic acid inhibitors against FLT3 (lestaurtinib), inhibitors against PDGFR (apatitis C virus type 2 inhibitors) xitinib, sunitinib, sorafenib); and inhibitors of VEGFR (Vandetata) nib, semaxanib, cediranib, axitinib, sorafenib); bcr-abl inhibitors against Src (imatinib, nilotinib, dasatinib); inhibitors against Src (bostinib) nib) and an inhibitor of Janus kinase 2 (lestaurtinib).

[0086] Cetuximab is an example of an anti-EGFR antibody. Cetuximab inhibits the epidermal growth factor receptor (EGFR). It is a chimeric human / mouse monoclonal antibody that targets EGFR. Biologically equivalent The term "antibody" as used herein refers to a modified antibody that binds to the same epitope on the EGFR antigen. It inhibits EGFR ligand binding, prevents activation of the EGFR receptor, and inhibits the EGFR pathway. blocking downstream signaling and resulting in substantially equivalent biological responses, such as disrupting cell proliferation. The resulting antibodies are identified.

[0087] Lapatinib (Tykerb®) is a dual EGFR and erbB-2 inhibitor. Lapatinib has been shown to be effective in multiple clinical trials as an anti-cancer monotherapy and in combination with trastuzumab. Ibuprofen, capecitabine, letrozole, paclitaxel, and FOLFIR1 (irinotecan). It is currently being studied in combination with cyclosporine (cyclosporine, 5-fluorouracil, and leucovorin). , metastatic breast cancer, head and neck cancer, lung cancer, gastric cancer Oral treatment for kidney cancer, renal cancer, and bladder cancer It is currently undergoing Phase III trials. The chemical equivalent of lapatinib is a tyrosine kinase inhibitor. (TKI) or a small molecule or compound that is a HER-1 or HER-2 inhibitor Several TKIs have been found to have effective antitumor activity and are approved. Examples of such drugs include, but are not limited to, Xacti (ZD6474), Iressa (gefitinib) and Tarceva (erlotinib), imatinib (STI571; Gleevec), erlotinib (OSI-1774; Ruseva), canertinib (CI1033), semaxinib (SU5416), vatalanib (PTK787 / ZK222584), sorafenib (BAY43-9006), cephalosporin (SUI1248) and lefltmomide (SUI01 Bioequivalents of lapatinib include HER-1 inhibitors and / or HE inhibitors. Examples of such peptides, antibodies, or antibody derivatives thereof that are R-2 inhibitors include: Non-limiting examples include the humanized antibodies trastuzumab and Herceptin.

[0088] PTK / ZKs act on all VEGF receptors (VEGFRs), platelet-derived growth factor (PD) broad specificity "small" antibodies targeting GF receptors, c-KIT and c-Fms. "It is a molecular tyrosine kinase inhibitor. Drevs (2003) Idrugs 6(8) :787-794.PTK / ZK is VEGFR-1(Flt-1), VEGFR-2( Binds to VEGF, including KDR / Flk-1) and VEGFR-3 (Flt-4) Blocks angiogenesis and lymphangiogenesis by inhibiting the activity of all known receptors The chemical name of PTK / ZK is 1-[4-chloroanilino]-4-[ 4-pyridylmethyl]phthalazine succinate or 1-phthalazinamine, N-(4- chlorophenyl)-4-(4-pyridinylmethyl)-butanedioate (1:1) Synonyms and analogs of PTK / TK include vatalanib, CGP79787D, PTK78 7 / ZK 222584, CGP-79787, DE-00268, PTK-787, P TK787A, a VEGFR-TK inhibitor, also known as ZK 222584 and ZK There are.

[0089] Additionally, chemotherapeutic agents that may be used in combination with monoterpenes or sesquiterpenes include , amsacrine, trabectedin, retinoids (alitretinoin, tretinoin), Arsenic oxide, asparagine-depleting substances (asparaginase / pegaspargase), celecoxib Bu, demecolcine, elesclomol, elsamitrucin, etoglucide, lonidamine, Lucanton, Mitoguazone, Mitotane, Oblimersen, Temsirolimus, and Vorinos Tat may be included.

[0090] Other therapeutic agents that can be used with the compositions and methods of the present invention include, for example, CAR-T cells, CAR-macrophages or CAR-NK cells.

[0091] The compositions and methods are directed to improving paracellular permeability, e.g., paracellular permeability of endothelial or epithelial cells. The compositions and methods can be used to increase blood-brain barrier permeability. The effect of administration on the permeability of the blood-brain barrier lasts for 5 minutes to 10 hours. Other ranges include at least about 15 minutes, at least about 30 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 60 minutes, at least about 70 minutes, at least about 80 minutes, at least about 90 minutes, at least about 100 minutes, at least about 120 minutes, at at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 5 hours, at least about 10 hours, at least about 24 hours, at least about 48 hours, or at least about 7 hours 2 hours included.

[0092] The compositions and methods can be used to reduce or inhibit angiogenesis. The products and methods include, but are not limited to, vascular endothelial growth factor (VEGF) and interleukin (IL-1). It can reduce or inhibit the production of pro-angiogenic cytokines, including leukin-8 (IL-8). do.

[0093] The monoterpene or sesquiterpene may be used in combination with an angiogenesis inhibitor. Examples of angiogenesis inhibitors include, but are not limited to, angiostatin, angiozyme , antithrombin III, AG3340, VEGF inhibitors (e.g., anti-VEGF antibodies) , batimastat, bevacizumab (Avastin), BMS-275291, CAI, 2C 3. HuMV833 Canstatin, captopril, carboxyamidotriazole, cartilage Derived inhibitor (CDI), CC-5013, 6-O-(chloroacetylcarbonyl) fumag Roll, COL-3, Combretastatin, Combretastatin A4 Phosphate, Dal Teparin, EMD121974 (Cilengitide), endostatin, erlotinib, Fitinib (Iressa), genistein, halofuginone hydrobromide, Id1, Id3, I M862, imatinib mesylate, IMC-IC11-inducible protein 10, interferon α, interleukin-12, lavendustin A, LY317615 or AE-941 , Marimastat, Maspin, Medroxyprogesterone acetate, Meth -1, Meth-2, 2-methoxyestradiol (2-ME), Neovastat, Theopontin cleavage product, PEX, pigment epithelial growth factor (PEGF) ), platelet factor 4, prolactin fragment, proliferin-related protein (PRP), PT K787 / ZK 222584, ZD6474, recombinant human platelet factor 4 (rPF4); Restin, Squalamine, SU5416, SU6668, SU11248, Suramin, Taki Sole, Tecogalan, Thalidomide, Thrombospondin, TNP-470, Troponin -1, vasostatin, VEG1, VEGF-Trap and ZD6474.

[0094] Non-limiting examples of angiogenesis inhibitors include tyrosine kinase inhibitors, e.g., tyrosine kinase inhibitors, e.g., Inhibition of the enzyme receptors Flt-1 (VEGFR1) and Flk-1 / KDR (VEGFR2) inhibitors of epithelial-derived, fibroblast-derived or platelet-derived growth factors, MMPs (matrix metalloproteinase inhibitors, integrin blockers, pentosan polysulfate, Angiotensin II antagonists, cyclooxygenase inhibitors (aspirin and ibuprofen) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as phenytoin, as well as celecoxib and lorlatinib (including selective cyclooxygenase-2 inhibitors such as ecoxib) and steroids Anti-inflammatory drugs (corticosteroids, mineralocorticoids, dexamethasone, prednisone) Other examples include prednisolone, methylpred, and betamethasone. can be done.

[0095] Modulating or inhibiting angiogenesis, as well as in combination with monoterpenes or sesquiterpenes Other therapeutic agents that may be used include agents that modulate or inhibit the coagulation and fibrinolytic systems. Examples of such agents that modulate or inhibit coagulation and fibrinolysis pathways include, but are not limited to: However, heparin, low molecular weight heparin, and carboxypeptidase U inhibitors (active thrombin) (also known as inhibitors of transactivating fibrinolysis inhibitor [TAFIa]). Publication No. 20090328239. U.S. Patent No. 7,638,549.

[0096] Immunomodulatory agents include, but are not limited to, cytokines, e.g., interleukins , lymphokines, monokines, interferons and chemokines.

[0097] Other penetration enhancers that may be used in conjunction with monoterpenes (or sesquiterpenes) include Fatty acid esters of glycerin, such as, but not limited to, capric acid, caprylic acid , dodecyl oleate; isosorbide, sucrose, polyethylene glycol fat Acid esters; Caproyl lactylate; Laureth-2; Laureth-2 acetate; Laureth -2 benzoate; laureth-3 carboxylic acid; laureth-4; laureth-5 carboxylic acid; Oleus-2; Glyceryl pyroglutamate oleate; Glyceryl oleate; N-laurate N-Myristoylsarcosine;N-Myristoylsarcosine;Noctyl-2-pyrrolidone;Laurua Aminopropionic acid; Polypropylene glycol-4-laureth-2; Polypropylene glycol Chole-4-laureth-5 dimethyl lauramide; Lauramide diethanolamine (D EA), lauryl pyroglutamate (LP), glyceryl monolaurate (GML), Lyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate (G Polyols or ethanol are used for immersion. These may function as penetration enhancers or cosolvents. Additional penetration enhancers are described in U.S. Pat. 785,991, U.S. Patent No. 5,843,468, U.S. Patent No. 5,882,676 and U.S. Patent No. 6,004,578.

[0098] Co-solvents are well known in the art and include, but are not limited to, glycerol. Lu, Polyethylene glycol (PEG), glycol, ethanol, methanol, propane These include alcohol, isopropanol, butanol, etc.

[0099] The compositions may be administered by, but not limited to, intra-arterial, intranasal, oral, ocular, Intraperitoneal administration, inhalation, intravenous administration, intracardiac injection (IC), intracerebroventricular (ICV), intracisternal injection or by injection, subcutaneous administration, implant, vaginal administration, sublingual administration, or urethral administration (e.g., urethral insertion) Subcutaneous administration, intramuscular administration, intravenous administration, transdermal administration, rectal administration, sublingual administration, mucosal administration, Ophthalmic, spinal, intrathecal, intra-articular, intra-arterial, intrathecal, bronchial and Administration may be by any method known in the art, including intravenous and lymphatic drug administration. The formulations may be in the form of gels, ointments, creams, aerosols, etc. Intranasal formulations are administered intranasally. The transdermal formulations can be delivered as a spray or in drops. It can be administered via iontorphoresis. The composition can be delivered using a nebulizer or similar device. tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols It may take the form of a sol or any other suitable composition.

[0100] To prepare such pharmaceutical compositions, monoterpene (or sesquiterpene) capsules are used. One or more of the and / or at least one therapeutic agent may be formulated according to conventional pharmaceutical compounding techniques. The composition may be mixed with a pharmaceutically acceptable carrier, adjuvant and / or excipient. The pharmaceutically acceptable carriers that can be used in the present invention include any of the standard pharmaceutical carriers, e.g. For example, phosphate buffered saline solution, water, and emulsions, e.g., oil / water emulsions or The compositions include water / oil emulsions, as well as various types of wetting agents. excipients, e.g., starch, cellulose, talc, glucose, lactose, sucrose, Gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, Sodium tearate, glycerol monostearate, sodium chloride, skim milk powder, etc. Liquid and semi-solid excipients may further include glycerol, propylene glycol, PEG-40 ... glycol, water, ethanol, and those of petroleum, animal, vegetable or synthetic origin, e.g. A variety of oils may be selected, including peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers for solutions include water, saline, aqueous dextrose, and glycols. For examples of carriers, stabilizers and adjuvants, see Remington's P Harmaceutical Sciences ,edited by EWMar tin(Mack Publishing Company,18th ed.,199 0) The compositions may also include stabilizers and preservatives.

[0101] As used herein, the term "therapeutically effective amount" refers to an amount of a compound that is effective to treat a particular disorder or disease. The amount is sufficient to produce a pharmacological response to treat the disorder or disease. Methods for determining the most effective means and dosage of administration depend on the composition used for treatment, the purpose of treatment, Safety and efficacy may vary depending on the objective, the target cell being treated, and the subject being treated. Treatment doses may generally be titrated to optimize efficacy. The levels and patterns can be used to administer a single dose or multiple doses. Dosage formulations and methods of administering the drugs can be readily determined by one skilled in the art. For example, the composition , about 0.01mg / kg~about 200mg / kg, about 0.1mg / kg~about 100mg / k g or about 0.5 mg / kg to about 50 mg / kg. When the compound is co-administered with another drug or treatment, the effective amount is the same as when the drug is used alone. may be less than the amount required.

[0102] The present disclosure also provides the above composition for intranasal administration. Thus, the composition comprises: It may further comprise a penetration enhancer. ments in Nasal Drug Delivery, 2000. The composition In liquid form such as a solution, emulsion, suspension, or drops, or in powder, gel, or ointment form. Any solid form may be administered intranasally. Devices for delivering intranasal drugs are well known in the art. Nasal drug delivery is well known, including but not limited to, intranasal inhalers, intranasal spray devices, , atomizers, nasal spray bottles, unit dose containers, pumps, droppers, squeeze bottles torrents, nebulizers, metered dose inhalers (MDIs), pressurized dose inhalers, injectors and dual This can be done using a device that includes a nasal delivery device that can accurately deliver the effective dose. The nasal delivery device can be a single unit delivery or a multi-unit delivery. In a specific example, Kurve Technology (Bet ViaNase Electronic Ato (Hell, Washington) The mizer can be used in the present invention (http: / / www.kurvetec The compounds of the present invention can also be used in tubes, catheters, syringes, pack tails, etc. Delivered via packtail, cotton ball, nasal tampon, or by submucosal injection U.S. Patent Publication No. 20090326275 and U.S. Patent Publication No. 200902918 94, U.S. Patent Publication No. 20090281522 and U.S. Patent Publication No. 2009031 No. 7377.

[0103] The composition can be formulated as an aerosol using standard procedures. The terpene (or sesquiterpene) and / or at least one therapeutic agent may be dissolved in a solvent. The formulation may be formulated with or without a carrier. It may be a solution or an aqueous emulsion containing one or more surfactants. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane a suitable propellant such as ethanol, hydrocarbons, compressed air, nitrogen, carbon dioxide or other suitable gas. The aerosol spray can be produced from a pressurized container having a dosage unit containing a metered amount of The pump spray dispenser can be determined by providing a valve for delivering the , a metered dose, or a dose having a specific particle or droplet size. As used herein, the term "aerosol" refers to fine solid particles in a gas or Aerosol refers to a suspension of solution droplets. Specifically, aerosols are used in MDIs, nebulizers, or microdispensers. Monoterpenes (or sesquiterpenes) that can be produced in any suitable device, such as a gas nebulizer. Aerosols also include suspensions of droplets of aerosols (e.g., ethanol) in a gas. Aerosols can also be suspended in air or other carrier gas. Suspended compositions of the present invention include dry powder compositions. Criti cal Reviews in Therapeutic Drug Carrier Systems 6:273-313.Raeburn et al.,(1992) P harmacol.Toxicol.Methods 27:143-159. The composition may be administered nasally as a powder in the form of microspheres or the like delivered by a nasal injector. The composition may be absorbed onto a solid surface, such as a carrier. The powder or microspheres may be administered in a dry, air-dispensable form. The microspheres may be stored in a syringe container. Alternatively, the powder or microspheres may be The drug is delivered in capsules, such as gelatin capsules, or other single-dose units adapted for nasal administration. It may be filled.

[0104] The pharmaceutical compositions can be, for example, gels, ointments, nasal emulsions, lotions, creams, nasal The composition may be placed directly into the nasal cavity in the form of a tampon, dropper, or bioadhesive strip. In certain embodiments, the compound can be delivered to the nasal cavity by, for example, enhancing absorption. To achieve this, it may be desirable to increase the residence time of the pharmaceutical composition in the nasal cavity. Therefore, the pharmaceutical composition may contain bioadhesive polymers, gums (e.g., xanthan gum), chitosan, (e.g., highly purified cationic polysaccharides), pectin (or nasal mucosa) any carbohydrate that thickens like a gel or emulsifies with water), microspheres (e.g., starch, albumin, dextran, cyclodextrin), gelatin, liposomes, Carbamer, polyvinyl alcohol, alginate, acacia, chitosan San and / or cellulose (e.g., methyl or propyl; hydroxyl or carboxyl) may be formulated with .

[0105] The compositions can be administered by oral inhalation into the respiratory tract, ie, the lungs.

[0106] Typical delivery systems for inhalable medications include nebulizer inhalers, dry powder inhalers ( DPIs and metered dose inhalers (MDIs).

[0107] Nebulizer devices produce a stream of high velocity air that causes the liquid form of the therapeutic agent to spray as a mist. The therapeutic agent is formulated in a liquid form, such as a solution or suspension of particles of an appropriate size. In embodiments, the particles are micronized. The term "micronized" refers to particles having a diameter of less than about 10 μm. It is defined as having about 90% or more of the particles. Suitable nebulizer devices include, for example, PAR It is marketed by I GmbH (Starnberg, Germany). The riser equipment includes Respimat (Boehringer Ingelheim), See, for example, U.S. Pat. No. 7,568,480 and U.S. Pat. No. 6,123,068 and WO 97 / 12687. (or sesquiterpenes) are used in nebulizer devices as aqueous solutions or liquid suspensions. It can be formulated to

[0108] DPI devices typically come in the form of a free-flowing powder that can be dispersed into the patient's airstream during inspiration. In the present invention, a DPI device that uses an external energy source is used to administer a therapeutic agent for the treatment of the condition. To obtain a free-flowing powder, a suitable excipient (e.g., lactose) may be used. For example, a dry laminar particle having a particle size of about 1 μm to about 100 μm can be used to formulate a therapeutic agent. The dry process combines lactose with finely divided particles of monoterpene (or sesquiterpene). A dry powder formulation can be made by mixing. The formulation can be formulated without excipients. is packaged into an inhalation cartridge or capsule for use with a dry powder delivery device Examples of commercially available DPI devices include the Diskhaler (GlaxoSmithK line, Research Triangle Park, NC) (e.g., US See Patent No. 5,035,237; Diskus (GlaxoSmithKline ) (see, e.g., U.S. Pat. No. 6,378,519; Turbuhaler (Astr aZeneca, Wilmington, Del.) (e.g., U.S. Pat. No. 4,524, 769); and Rotahaler (GlaxoSmithKline) (e.g. (See, for example, U.S. Patent No. 4,353,365.) Additional Suitable DPI Devices Examples of this are U.S. Pat. No. 5,415,162, U.S. Pat. No. 5,239,993 and U.S. Pat. No. 5,715,810 and references therein.

[0109] MDI devices typically use a compressed propellant gas to deliver a measured amount of therapeutic agent. Formulations for MDI administration include solutions or suspensions of the active ingredient in a liquefied propellant. Examples of propellants include hydrofluoroalklanes. (HFA), e.g., 1,1,1,2-tetrafluoroethane (HFA 134a) and and 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA 227), and chlorofluorocarbons, e.g., CCl3F. Additional components of HFA formulations include cosolvents, e.g., ethanol, pentane, water; and surfactants, such as sorbitan trioleate, oleic acid, lecithin, and glycerin; (See, e.g., U.S. Pat. No. 5,225,183, European Patent No. 0717987, and (See WO 92 / 22286 and WO 92 / 22286). The formulation is delivered to an air inlet that forms part of the MDI device. It is packaged in aerosol canisters. It is specially developed for use with HFA propellants. Examples of MDI devices are U.S. Patent No. 6,006,745 and U.S. Patent No. 6,143,222. 27. A process for preparing suitable formulations and devices suitable for inhalation administration is described. See, for example, U.S. Pat. No. 6,268,533, U.S. Pat. No. 5,983,956, U.S. Pat. US Patent No. 5,874,063 and US Patent No. 6,221,398, and International Publication No. No. 99 / 53901, International Publication No. 00 / 61108, International Publication No. 99 / 55319 and WO 00 / 30614.

[0110] The monoterpene (or sesquiterpene) and / or at least one therapeutic agent is It may also be encapsulated in liposomes or microcapsules for intravenous delivery. A vesicle is a small vesicle composed of a lipid bilayer and an aqueous interior. phospholipids, such as phosphatidylcholines, e.g., lecithin and lysolecithin; acidic phospholipids, e.g., phosphatidylcholines ... Sphatidylserine and phosphatidylglycerol; and sphingophospholipids, Phospholipids, such as phosphatidylethanolamine and sphingomyelin Alternatively, cholesterol may be added. The cells are particles coated with a coating material. The lubricating material may comprise a film-forming polymer, a hydrophobic plasticizer, a surface-active agent or / and a lubricant nitrogen. The polymer may be a mixture of a hydroxyl group-containing polymer and a hydroxyl group-containing polymer. U.S. Patent No. 7,563,768.

[0111] Monoterpenes are also effective via topical administration due to their ability to easily penetrate the dermis. , may be used alone or in combination with at least one therapeutic agent. Also, as a transdermal delivery agent, it can be combined with a narcotic or analgesic agent for transdermal delivery of pain medication. It can be used in combination.

[0112] The present invention also provides the above composition for ocular administration. The compositions described herein may be formulated for ocular administration in a solution containing The compound can be formulated as a solution, emulsion, suspension, etc. A variety of suitable vehicles are known in the art. Specific, non-limiting examples are found in U.S. Pat. No. 6,261,547, U.S. Patent No. 6,197,934, U.S. Patent No. 6,056, 950, U.S. Patent No. 5,800,807, U.S. Patent No. 5,776,445, U.S. Patent No. No. 5,698,219, U.S. Patent No. 5,521,222, U.S. Patent No. 5,403, 841, U.S. Patent No. 5,077,033, U.S. Patent No. 4,882,150 and U.S. Patent No. This is described in US Patent No. 4,738,851.

[0113] The composition can be administered for short or long periods of time. It can be administered to animals, preferably humans. Mammals include, but are not limited to: , mice, rats, rabbits, monkeys, cows, sheep, pigs, dogs, cats, livestock, sports animals This includes animals, pets, horses and primates.

[0114] Devices for intranasal administration include nasal spray devices, atomizers, nebulizers, metered dose devices, MDI (Medium Dispersion Inhaler), Pressurized Dose Inhaler, Injector, Intranasal Inhaler, Nasal Spray Bottle The dispenser may be a syringe, a unit dose container, a pump, a dropper, a squeeze bottle, or a two-way device.

[0115] The agents may be administered simultaneously or sequentially.

[0116] The present invention also provides a method for inhibiting cell proliferation in vitro, ex vivo, or in vivo. wherein cells, such as cancer cells, are immunized with an effective amount of a purified monoclonal antibody described herein. The compositions and methods are effective against chemotherapeutic agents. For example, the compositions and methods can be used to inhibit the growth of cells that are resistant to the can be used to inhibit the growth of temozolomide-resistant cells.

[0117] A pathological cell or tissue, such as a hyperproliferative cell or tissue, is a cell or tissue. can be treated by contacting the tissue with an effective amount of the composition. can be primary cancer cells or American Type Culture Collection (ATC) The pathological cells may be cultured cells available from tissue banks such as CT. , glioma, meningioma, pituitary adenoma cells, or systemic cancer, lung cancer, prostate cancer (prost ate cancer, breast cancer, hematopoietic cancer or ovarian cancer The cells may be cells of CNS metastases from ovarian cancer. It may be derived from an animal, preferably a mammal, and more preferably a human. U.S. Patent Publication No. 200 No. 4 / 0087651. Balassiano et al.(2002) Intern J Mol Med. 10:785-788. Thorne, et al. (2004 ) Neuroscience 127:481-496.Fernandes,et a L. (2005) Oncology Reports 13:943-947.Da F Onseca, et al. (2008) Surgical Neurology 70 :259267.Da Fonseca,et al.(2008) Arch.Immu nol.Ther.Exp. 56:267-276.Hashizume,et al. (2008) Neuroncology 10:112-120. Cancer stem cells (CSCs) or tumor-initiating cells are undifferentiated cells that possess stem cell characteristics, such as the ability to self-renew. However, CSCs exhibit poor self-renewal. tem cells, cancer, and cancer stem cells. N ature 2001,414(6859):105-11. Furthermore, glioma CSCs It is resistant to chemotherapy and radiotherapy. Bao et al., Glioma st em cells promote radioresistance by pref erential activation of the DNA damage re sponse. Nature .2006,444(7120):756-60.Rich et al.,Chemotherapy and cancer stem cell ls. Cell Stem Cell. 2007;1(4):353-5. The method includes inhibiting the proliferation of cancer stem cells, including, but not limited to, glioblastoma cancer stem cells. It can be used to

[0118] The following examples are offered for illustrative purposes only and are not intended to limit the invention. stomach.

[0119] Example 1 NEO100-mediated human CAR T cell delivery to the brain and tumor Preparation of human CAR T cells Human CAR T cells (CD19 and Lym-1) were obtained from Dr. Epstein (USC) ) provided by the National Institute of Infectious Diseases. Chimeric antigen receptors (CARs) consist of three distinct modules: These include an extracellular antibody-based recognition site, a transmembrane module that anchors the molecule in the cell membrane, and an active site. It is a synthetic molecule containing a chimeric intracellular signaling domain that transmits an activation signal. nsen et al.,Designing chimeric antigen r eceptors to effectively and safely target t tumors.Curr.Opin.Immunol.2015,33,9-15. CD19-targeted CAR T cells are a promising treatment for relapsed or refractory (R / R) acute lymphoblastic leukemia (ALL) Remarkable results have been achieved in the treatment of patients with leukemia (ALL). Ruella et al.,Dual CD19 and CD123 targeting preven ts antigen-loss relapses after CD19-dire cted immunotherapies.J.Clin.Invest.2016, 126,(10),3814-3826.Maude et al.,CD19-tar got chimeric antigen receptor T-cell t therapy for acute lymphoblastic leukemia. Blood 2015,125,(26),4017-23.Grupp et al. ,Durable Remissions in Children with Rel apsed / Refractory ALL Treated with T Cell s Engineered with a CD19-Targeted Chimer ic Antigen Receptor(CTL019).Blood 2015,1 26,(23),681-681. Mouse nuclei were isolated from Raji lymphoma cells. Immunization of the mouse strain produced the mouse IgG2a monoclonal antibody Lym-1. accomplished. Epstein et al.,Two new monoclonal an tibodies,Lym-1 and Lym-2,reactive with h uman B-lymphocytes and derived tumors,wi th immunodiagnostic and immunotherapeuti c potential.Cancer Res.1987,47,(3),830-4 Lym-1 is a discontinuous conformational epitope on several HLA-DR subtypes. and exhibits higher binding affinity for malignant B cells than for normal B cells. al.,Critical Lym-1 binding residues on polymorphic HLA-DR molecules.Mol Immunol 1999,36,(11-12),789-97. As shown in Figure 1, Lym-1 C Schematic diagram of the AR construct and the CD19(FMC 63)CAR construct.

[0120] 0.9% saline for use in IV injection with and without intracardiac NEO100 Two million CD19 human CAR T cells and Lym-1 human CAR T cells suspended in saline working solution CAR T cells.

[0121] NEO100 cardiac puncture NEO100 suspended in 0.9% saline: Working solution for intracardiac injection of 3% NEO100 Preparation of the solution.

[0122] Standard Operating Procedure for Ultrasound-Guided Cardiac Puncture Briefly, animals were anesthetized using 2% isoflurane gas and placed on a platform for cardiac puncture. The left ventricle was then inserted through the skin and muscle layers under ultrasound imaging guidance. Then, quickly penetrate the needle into the intercostal space.

[0123] A sign of successful needle insertion into the left ventricle is the presence of fresh arterial blood (as opposed to dark red venous blood) in the syringe. The contrasting pink color is the reflux. 40 μl of 3% NEO100 saline solution is slowly added. Direct cell injection into the heart was performed to complete the intracardiac administration. If this occurs, localized microinfarction may occur, leading to hemopericardium and eventual death. Therefore, to minimize these potential adverse effects, (1) visualization of the course; (2) to ensure that the needle enters only the left ventricle, and (3) to subsequently measure only the post-injection ECG. Ultrasound using a small 30G needle monitors the heart through visualization of cardiac wall function rather than through the use of ultrasound. Wave-guided injection is important. The fine gauge of the needle allows the cells to be injected through a cardiac puncture. When doing so, make sure the cells do not clump together.

[0124] Confirmation of intracardiac injection A sign of successful needle insertion into the left ventricle is the presence of fresh arterial blood (as opposed to dark red venous blood) in the syringe. It is a backflow of blood (contrasting pink color).

[0125] Immediately after completion of the NEO100 injection, a tail vein catheter pre-primed with saline solution was inserted. Two million human CAR T cells in 40 μl of PBS were injected through the catheter.

[0126] To avoid the above potential adverse effects of direct cell injection via intracardiac administration, this study A two-step procedure was established for the experiment.

[0127] Step 1: Intracardiac administration by slow injection of 40 μl of 3% NEO100 in saline This procedure allowed NEO100 to exert its BBB-disrupting function. do.

[0128] Step 2: Two million CAR T cells were injected IV through a tail vein catheter.

[0129] Assessment of CAR T-cell spreading by IHC and confocal imaging Cerebral perfusion - 10 ml through the left ventricle to eliminate any residual fluid remaining in the blood vessels after euthanasia The test animals were perfused with 0.9% normal saline solution to flush out the blood. Then, the brains were removed. The tissue was then extracted, embedded in OCT, and stored at −80°C for subsequent analysis.

[0130] Confocal imaging - 8 μM fresh frozen sectioned tissue using a cryostasis machine Sections were prepared and mounted on microslides. Before confocal examination, DAPI mounting was performed. Brain sections were cover-slip mounted using a budding solution.

[0131] IHC staining - A standardized IHC staining procedure was employed to identify the brain and formed tumors (GL The penetration of human CAR T cells into the 261 mouse glioma was detected. Rabbit CD3 antibody (CD3ε (D7A6E™) XP® Rabbit mAb) (#85061) (Cell Signaling, Boston, MA) Human-derived CD3-positive cells were identified (as shown in Figure 2).

[0132] Testing a syngeneic mouse glioma animal model in C57 BL / 6 mice Immunocompetent C57 BL / 6 mice were inoculated with 100,000 GL261 mouse glioma cells. Three weeks after tumor cell injection, brain tumor-bearing mice were given intravenous (IV) injection of 1000 mg / kg ... IV) and a combination of IV and intracardiac (IC) delivery of 2 million human CAR T cells (anti-C The treated mice were euthanized 6 hours after the intervention. Intracardiac administration: After intracardiac injection of 3% NEO100 in PBS, 2 million anti-CD19 CAR T cells or Lym-1 CAR T cells administered For intravenous administration: 2 million anti-C in 40 ul of PBS injected via the tail vein. D19 CAR T cells or Lym-1 CAR T cells were suspended.

[0133] The brains were perfused with 0.9% saline solution, extracted, and stored at -80°C for subsequent analysis. o C It remained.

[0134] The antibodies administered in the test include a control antibody for negative staining: Rabbit (DA1E)m Ab IgG isotype and detect CD3-positive cells in vitro and in vivo Antibody used to detect: CD3ε (D7A6E™) XP® Rabb It mAb (#85061) is included.

[0135] conclusion No detectable CD3-positive cells were found in the normal C57 BL / 6 mouse brain. .

[0136] Human CAR mediated by NEO100 compared to conventional intravenous (IV) injection Intracardiac injection of T cells (anti-CD19 and Lym-1) led to their penetration into tumors formed in the brain. can be significantly increased.

[0137] The 3% NEO100-mediated intracardiac injection did not cause any serious adverse effects or animal death. stomach.

[0138] In normal areas of the brain treated with intracardiac injection of NEO100, the serotonin levels were significantly higher than in samples treated with IV injection alone. Many CD3-positive cells were observed.

[0139] Example 2: C57 BL / 6 mice bearing intracranial syngeneic mouse glioma (GL261) Anti-mouse PD-1 antibody-mediated therapeutic effects in mice Immunocompetent C57 BL / 6 mice were inoculated with 100,000 GL261 mouse glioma cells. Seven days after injection, the mice were randomly divided into four experimental groups and treated on the same day. has started.

[0140] Group 1, control: IV and intracardiac injection of 40 μl of saline solution (5).

[0141] Group 2, antibody-treated mice: 40 μl of anti-mouse PD1 antibody at a dose of 2.5 mg / kg IV(5).

[0142] Group 3, NEO100-treated mice: intracardiac injection of 40 μl of 5% NEO100 (5).

[0143] Group 4, NEO100 and antibody-treated mice: 40 μl of 5% NEO100 was injected intracardially. intravenously, followed by 40 μl of anti-PD1 antibody at a dose of 2.5 mg / kg IV (6).

[0144] The results are shown in Figure 3. Intracardiac injection of NEO100 (equivalent to intra-arterial injection in mice) significantly reduced the antibody They then demonstrated that the BBB can be opened by intracranially implanting mouse G cells. A syngeneic model was performed using L26 glioma cells. Saline, NEO100 alone , intravenous anti-PD1 administration alone, or intracardiac NEO100 administration followed by intravenous anti-PD1 administration Mice were treated with intravenous administration of anti-PD1 in combination with NEO100. All mice survived, except for one mouse that received intravenous anti-PD1 therapy. Both died.

[0145] Perillyl alcohol is used in interventional neuroradiology to It can be administered via a vascular angiogram, etc.

[0146] statistical analysis The Kaplan-Meier method was used to plot the animal survival data. One-way analysis of variance was used for the test. Groups were analyzed using Tukey's method to adjust for multiple comparisons. Grouped comparisons were performed. The log-rank (Mantel-Cox) test was used to compare survival curves. A statistical evaluation result of p<0.05 was considered significant.

[0147] Control vs. IC NEO100 + IV anti-mouse PD-1: ***P<0.0003 Control vs. IV anti-mouse PD-1: ns, p=0.31 IV anti-mouse PD-1 vs. IC NEO100 + IV anti-mouse: **P<0.005 Control vs. IC NEO100: ns, p=0.397 [Example 3] NEO100 was administered across an in vitro BBB model, and NEO100 inhibited the target This may allow the recognized antibodies to temporarily cross the in vitro BBB model. It was demonstrated that this was the case (Fig. 4A to Fig. 4D).

[0148] Transiently close the BBB using perillyl alcohol (e.g., NEO100) for intra-arterial delivery disrupts the brain's natural barrier, allowing previously impermeable small or large molecules to penetrate the brain An experiment was conducted to see if this was possible.

[0149] Perillyl alcohol (e.g., NEO100) is administered by intracardiac injection (in mice). Intra-arterial injection) and intravenous infusion may be included.

[0150] The formulation was 10% NEO100 (glycerol 27.5 ml + ethanol 27.5 ml + NEO100 3.0ml).

[0151] Cerebral perfusion - Before euthanasia, test animals were perfused with 0.9% normal saline solution through the left ventricle. Brains were removed, embedded in OCT, and stored at -80°C for subsequent analysis.

[0152] Ultrasound-guided cardiac puncture - Briefly, anesthetize the animal using 2% isoflurane gas. The animal was fixed on a platform for cardiac puncture. Under ultrasound imaging guidance, the skin was Rapidly penetrate the needle through the ventricle and muscle layer into the intercostal space. A sign of successful insertion is the presence of fresh arterial blood (pink in color as opposed to dark red venous blood) in the syringe. ) is a countercurrent.

[0153] Evans blue is an azo dye that has a very high affinity for serum albumin Extravasation of stained albumin from the circulation could be visualized.

[0154] Deliver NEO100 via intracardiac injection (left ventricle) to inhibit Evans Blue, a BBB-impermeant We determined whether there was increased brain uptake of a soluble small molecule (dopamine) or antibody. Figure 5A shows the intracardiac injection (IC) of a mixture of NEO100 and 2% Evans Blue (EB). Cardiac puncture was followed by immediate intravenous administration of 2% Evans blue (volume 40 μl). Different concentrations of NE0100 (40 μl in 0.9% saline) were tested by administering After perfusion, the brain was removed. The results were obtained by perfusing 1:1000 diluted (6.5 mM 40 μl) N This indicates that EO100 remains effective in disrupting the BBB.

[0155] Figure 5B shows the brain response after administration of NEO100 by IC (intracardiac injection) or IV injection. EB transmission of

[0156] The experimental groups included: IC 2%EB alone IC 20% ethanol + 2% EB IC 20% ethanol + 2% EB + 5% NEO100 IC 20% ethanol + 5% NEO100 followed by 2% EB tail vein injection IV 20% ethanol + 2% EB + 5% NEO100 IV 20% ethanol + 2% EB

[0157] FIG. 6 shows that brains treated with intracardiac injection of 5% NEO100 showed significantly higher leukemia rates compared to normal brains. This showed dramatic disruption of tight junctions.

[0158] Pharmacological treatment of Parkinson's disease (PD) is primarily based on dopamine (DA) replacement therapy. It is a symptomatic treatment, which is based on the fact that exogenous DA and other catecholamines have their BBB penetration Dopamine is a water-soluble, hydrophilic drug. Therefore, it does not meet the properties of a substance that can enter the brain by penetrating the BBB.

[0159] Figure 7 shows that NEO100 mediated dopamine delivery across the disrupted blood-brain barrier. This shows that:

[0160] Figure 8 shows the measurement of BBB opening and closing time. Inject 5% NEO100 (v / v) via intracardiac puncture (IC), followed by 0.5 min after IC injection. 2% Evans at different time points such as 15 min, 30 min, 1 h, 2 h, 3 h and 4 h Sublure was injected intravenously.

[0161] The experimental procedures included: 1. Intracardial injection (IC): 5%NEO100.

[0162] 2. Followed by intravenous (IV) injection of 2% EB at different times.

[0163] 3. Test animals were euthanized 1 hour after IV injection.

[0164] Figure 9 shows the activity of anti-mouse IgG antibody (rabbit) in the absence or presence of perillyl alcohol. Anti-mouse IgG H&L (Texas Red)-Ab6726) delivery is shown.

[0165] Figure 10 shows the effect of anti-PD-1 antibody (Armenian) in the absence or presence of perillyl alcohol. Delivery of hamster anti-mouse CD279 (PD-1) monoclonal antibody (J43) PD-L1 binds to PD-1 and inhibits T cells from killing tumor cells. Blocking PD-L1 or PD-1 allows T cells to kill tumor cells.

[0166] NEO100 is safe when administered intra-arterially.

[0167] Example 4: Treatment of intracranial Raji lymphoma xenografts in NSG mice NEO100-mediated human CAR T cell (Lym-1 CAR) delivery in mice (a) Intracranial lymphoma xenograft: 50,000 (5x10 4 ) human B-cell lymphoma cells, Raji's-Luc / G FP was injected intracranially into NSG mice.

[0168] (b) Confirmation of tumor uptake: Five days after tumor cell injection, optical imaging was performed to confirm tumor uptake. (100% tumor uptake).

[0169] (c) Initiation of CAR T infusion via tail vein catheter and intracardiac (IC) NEO100 : Three experimental groups were established: (1) control, (2) IV CAR T (5x10e6), ( 3)IV CAR T(5x10e6)+IC NEO100(0.3%v / v=492 μM) (d) Monitoring of NSG mice bearing IC lymphoma: The health status of the mice was monitored by weight during treatment. Tumor growth was monitored by RT.

[0170] (e) Animal survival rate (Kaplan-Meier curve) As can be seen from the survival curves (Fig. 11), control mice, i.e., those with human B-cell lymphoma, Mice injected with the cells died within 15 to 20 days after injection, whereas Lym-1 CAR T Mice injected with cells plus NEO100 survived (P=0.0029).

[0171] [Example 5] Intranasal inhalers (e.g., Kurve Technology (Bethell, Was ViaNase Electronic Atomizer manufactured by P OH. The intranasal delivery system manufactured by Kurve Technology The device can accurately deliver a prescribed amount of drug (e.g., 0.2 to 6 mL). The device is filled and cleaned in the same manner as the blister. In a chinch test, drugs can be delivered to the olfactory region.

[0172] Male athymic nu / nu mice (6-8 weeks old) are used in this study. The glioma model can be established as follows: ketamine (80 mg / kg) and Intraperitoneal injection of xylazine (10 mg / kg) was administered to 6-8 week-old athymic nu / nu mice. Mice were anesthetized. For the intracranial glioma model, a stereotactic head frame (Harvard A Place the mouse in the apparatus and administer local anesthetic (0.25% xylocaine 0.2 cc) ) is injected into the right frontal scalp. A small incision is made using a knife blade and a drill bit is used to A small opening is made in the right frontal skull at the level of the coronal suture. In the syringe, glioma cells (1 × 10 5 cells / 10 μl), for example, U-87 human glioma cells The tip of the needle was precisely placed in the right frontal lobe of the rat, and the Hamilton syringe was filled with Use the control push to slowly inject the cells. Once the injection is complete, remove the syringe and Remove the needle and close the wound.

[0173] Two weeks after surgical implantation, the mice were divided into four groups (6 mice / group) and administered saline drops. only (control), crude POH (0.03%, 50 μl / drop, 1 per nostril) from Sigma drops), POH (purified to >98.5% purity; 0.03%, 50 μl / drop, 1 per nostril The rats were treated with TMZ (5 mg / kg, oral gavage) and TMZ (5 mg / kg, oral gavage). It functions as:

[0174] Brains are harvested and tumor size is determined. Mice are followed until neurological deficits occur. In our experience, the survival time was 100% in untreated mice after transplantation. approximately 4 weeks in TMZ-treated mice and up to 8 weeks in TMZ-treated mice.

[0175] RG2 rat glioma cells (1 × 10 5 An immunocompetent syngeneic rat model will also be used, in which rats are transplanted with 1000 cells / 10 ul of IgG. Furthermore, RG2 cells are free to migrate and thus infiltrate the parenchymal tissue of rats. Therefore, we investigated the anti-invasive properties of POH using the rat RG2 model.

[0176] [Example 6] A recent clinical study in Brazil showed that perillyl alcohol was effective in patients with recurrent malignant glioma. Intranasal delivery of the drug resulted in regression or stabilization of the disease, with 140 treated patients Fifty percent of cases achieved a progression-free interval of 6 months, and some patients enjoyed disease remission for as long as 3 years. Furthermore, the treatment had few side effects. Da Fonseca et al. orrelation of tumor topography and perit umoral edema of recurrent malignant glio mas with therapeutic response to intrana sal administration of perylyl alcohol. I nvest New Drugs 2009, Jan 13. Patients suffering from malignant glioma were administered purified POH (with a purity of over 98.5%). To investigate whether POH can be delivered directly to brain tumor cells, In order to 11 C-labeled POH is delivered to the patient, followed by positron emission tomography (PET) imaging. The distribution of purified POH will be investigated by performing gauging. A limited treatment trial will be conducted using escalating doses of inhaled POH. Three groups will be used to evaluate patients. The dose was gradually increased, and each group received 0.05% (w / v), 1% (w / v), 1.5% (w / v) ), 2% (w / v), and 2.5% (w / v) purified POH (purity >98.5%) were added to the nasal The 2% (w / v) is the one currently used in Brazil. Delivery is via It is administered via the aNase nasal inhaler three times daily. PET imaging study. Siemen s Using the Biograph TruePoint HD PET / CT Scanner , 11 After intranasal inhalation of 5-10 mCi of C-POH formulation, pathologically confirmed malignant glioma was observed. Static imaging was performed in a single bed position over the skull. A 10-minute acquisition is used, starting at 30 minutes after inhalation. The study was performed at 3-minute intervals for 2 hours to assess the progressive accumulation of brain and tumor tissue. Depending on the situation and the level of residual and accumulated activity, imaging beyond 2 hours may be attempted. For all patients, coregistrated PET / CT images were compared with contrast-enhanced MRI studies to assess activity accumulation and Correlation with contrast enhancement patterns is evaluated.

[0177] The scope of the present invention is not limited by what has been particularly shown and described above. If so, there are suitable alternatives to the illustrated examples of materials, configurations, constructions and dimensions. In describing this invention, numerous references are made to the subject matter, including patents and various publications. Citation and discussion of such references is not intended to be limiting unless expressly stated otherwise. Any references are provided for clarity of disclosure and are not intended to be limiting of the scope of the invention described herein. No admission is made that the invention is prior art. All references are incorporated herein by reference in their entirety. Variations, modifications, and other implementations of what is disclosed may depart from the spirit and scope of the present invention. While particular embodiments of the present invention have been shown and described, It is understood that changes and modifications can be made without departing from the spirit and scope of the invention. It will be apparent to those skilled in the art that the matter set forth in the foregoing description and accompanying drawings is offered by way of example only. are provided as a guide only and not as a limitation.

Claims

1. 1. A pharmaceutical composition for treating cancer of the central nervous system in a mammal, comprising: comprising a therapeutic agent and a monoterpene, the monoterpene is perillyl alcohol; the therapeutic agent is an antibody or antibody fragment; the monoterpene is administered by intracardiac injection and the therapeutic agent is administered intravenously; Pharmaceutical compositions.

2. 10. The pharmaceutical composition of claim 1, wherein the monoterpene and the therapeutic agent penetrate the blood-brain barrier of the mammal.

3. The pharmaceutical composition of claim 1 , wherein the central nervous system is the brain.

4. 10. The pharmaceutical composition of claim 1, wherein the perillyl alcohol is administered at a dose ranging from 0.050 mg / kg body weight to 500 mg / kg body weight.

5. The pharmaceutical composition of claim 1 , wherein the mammal is a human.

6. The pharmaceutical composition of claim 1 , wherein the mammal has cancer.

7. The pharmaceutical composition of claim 1 , wherein the cancer of the central nervous system is glioblastoma.

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