Therapeutic nanoparticles for treatment of neuroblastoma and other cancers

Abstract

To provide a therapeutic nanoparticle comprising an oncologic drug and taurolidine, which harness the synergistic effect of taurolidine on these oncologic drugs so as to allow for greater efficiency and reduced toxicity associated with the oncologic drugs.SOLUTION: Provided is a therapeutic nanoparticle, comprising at least one oncologic drug and taurolidine, whereby to provide the simultaneous delivery of the at least one oncologic drug and taurolidine, thereby harnessing the synergistic effect of taurolidine on the at least one oncologic drug. Preferably, the at least one oncologic drug comprises TNF-related apoptosis-inducing ligand (TRAIL).SELECTED DRAWING: None

Description

[Technical field]

[0001] References to prior pending patent applications This patent application claims the benefit of pending U.S. Provisional Patent Application No. 62 / 277,243, entitled "NANOPARTICLE SYSTEM FOR THE TREATMENT OF NEUROBLASTOMA," filed on January 11, 2016 by CorMedix Inc. and Robert DiLuccio (Attorney Docket No. CORMEDIX-14 PROV), which is incorporated herein by reference.

[0002] Technical Field The present invention relates generally to therapeutic compositions, and more particularly to therapeutic compositions for the treatment of neuroblastoma and other cancers. [Background technology]

[0003] Neuroblastoma (NB) is the most common extracranial solid cancer of childhood and the most common cancer of infancy. Incidence is approximately 650 cases per year in the United States and 100 cases per year in the United Kingdom. Nearly half of all neuroblastoma cases occur in children under the age of 2. Neuroblastoma causes neuroendocrine tumors that arise from any neural crest element of the sympathetic nervous system (SNS). Neuroendocrine tumors most frequently arise in one of the adrenal glands, but can also arise in neural tissue in the neck, chest, abdomen, or pelvis.

[0004] Neuroblastoma is one of the few human malignancies known to show spontaneous regression from an anaplastic state to a completely benign cellular appearance. Neuroblastoma is an extremely heterogeneous disease that is stratified into three risk categories: low, intermediate, and high risk. Low-risk neuroblastoma disease is most common in infancy and childhood, and good outcomes with observation alone or surgery are common, whereas high-risk neuroblastoma disease is difficult to treat successfully even with the most intensive and multi-modal oncological therapy available.

[0005] Nasal neuroblastoma, also known as olfactory neuroblastoma, is thought to arise from the olfactory epithelium and its classification remains controversial. However, as it is not a malignant tumor of the sympathetic nervous system, nasal neuroblastoma is a distinct clinical entity and is classified differently from neuroblastoma. Not to be confused.

[0006] Signs and Symptoms Early symptoms of neuroblastoma are often vague, making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on the site of the primary tumor and any metastases.

[0007] In the abdomen, the tumors may cause abdominal swelling and constipation. · Tumors in the chest can cause breathing problems. A tumor compressing the spinal cord can cause weakness and the inability to stand, crawl, or walk.

[0008] Bone lesions in the legs and hips can cause pain and lameness. Tumors of the eye or bones around the orbit can cause obvious bruising and swelling. · Bone marrow infiltration can cause pallor due to anemia.

[0009] Neuroblastoma often spreads to other parts of the body before any symptoms become evident, and metastasis occurs in 50-60% of all neuroblastoma cases. The most common site (i.e., primary tumor site) for neuroblastoma to arise is the adrenal gland. This is seen in 40% of localized tumors and 60% of cases of widespread neuroblastoma disease. Neuroblastoma can arise anywhere along the sympathetic nervous chain from the neck to the pelvis. Different locations include the neck (1%), chest (19%), abdomen (30%, non-adrenal), or pelvis (1%). In rare cases, no primary tumor may be found.

[0010] Rare but characteristic features include transverse myelopathy (spinal cord compression due to tumor, 5% of cases), refractory diarrhea (vasoactive intestinal peptide secretion due to tumor, 4% of cases), Homer's syndrome (cervical tumor, 2.4% of cases), opsocinus myoclonus syndrome and ataxia (suspected paraneoplastic causes, 1.3% of cases), and hypertension ( These include catecholamine secretion or renal artery compression (1.3%).

[0011] cause The etiology of neuroblastoma is poorly understood. The majority of cases are sporadic and non-familial. Approximately 1-2% of cases are inherited in families and are associated with specific genetic mutations. Familial neuroblastoma in some cases is caused by rare germline mutations in the anaplastic lymphoma kinase (ALK) gene. Germline mutations in the PHOX2A or KIF1B genes have also been implicated in familial neuroblastoma. Neuroblastoma is also a feature of neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, and Beckwith-Wiedemann syndrome.

[0012] Intratumoral MYCN oncogene amplification is a common finding in neuroblastoma. The degree of amplification shows a bimodal distribution, either 3-10 fold or 100-300 fold. The presence of this mutation is highly correlated with the advanced stage of the disease (Reference 1).

[0013] Duplicated segments of the LMO1 gene in neuroblastoma tumor cells have been shown to increase the risk of developing an aggressive form of cancer (Reference 2). Neuroblastoma is associated with copy number variations within the NBPF10 gene, resulting in 1q21.1 depletion syndrome or 1q21.1 duplication syndrome (Reference 3).

[0014] Several risk factors for neuroblastoma have been proposed and are the subject of ongoing research. Because neuroblastoma is characterized by its early onset, most studies have focused on parental factors related to conception and pregnancy. Factors that have been investigated include occupation (i.e., exposure to chemicals in certain industries), smoking, alcohol use, use of medications during pregnancy, and birth factors, but the results are inconclusive (Ref. 4).

[0015] Other studies have investigated possible associations between atopy and exposure to infections during infancy (5), the use of hormones and fertility drugs (6), and maternal use of hair dyes (7).

[0016] biochemistry Approximately 90% of neuroblastoma cases have elevated levels of catecholamines or their metabolites in the urine or blood, such as dopamine, homovanillic acid (HVA), and / or vanillylmandelic acid (VMA) (8).

[0017] treatment When neuroblastoma lesions are localized, they are generally curable. However, long-term survival in children aged 18 months or older with advanced disease is limited by aggressive multimodal oncology therapy, including intensive chemotherapy, surgery, radiation therapy, stem cell transplantation, and the differentiation agent isotretinoin (13-cis- Despite the use of anti-GD2 (also known as retinoic acid), immunotherapy with anti-GD2, and immunotherapy with anti-GD2 monoclonal antibodies, the results have been unsuccessful.

[0018] Biological and genetic features have been identified that, when added to classical clinical staging, allow for the allocation of patients into risk groups for planning treatment intensity. These criteria, such as the patient's age, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc oncogene amplification (N-myc regulates microRNAs), have been used to classify patients into low, intermediate, and high-risk disease states. A recent biological study (COG ANBL00B1) analyzed 2687 neuroblastoma patients to determine the distribution (spectrum) of risk assignments: 37% of neuroblastoma cases were low risk, 18% were intermediate risk, and 45% were high risk. There is some evidence that high-risk and low-risk types are caused by different mechanisms and are not simply two different manifestations of the same mechanism (Reference 9).

[0019] The treatments for these different risk categories are very different. Low-risk disease can often be cured without any treatment at all, or with just surgery. · Medium-risk disease is treated with surgery and chemotherapy.

[0020] High-risk neuroblastoma is treated with intensive chemotherapy, surgery, radiation therapy, bone marrow / hematopoietic stem cell transplantation, biologic therapy with 13-cis-retinoic acid (isotretinoin or Accutane), and antibody therapy, usually with the administration of the cytokines GM-CSF and IL-2.

[0021] With current treatments, patients with low- and intermediate-risk neuroblastoma disease have an excellent prognosis. Cure rates are greater than 90% for low-risk and 70-90% for intermediate-risk. In contrast, over the past 20 years, treatment of high-risk neuroblastoma has resulted in cure rates of only about 30%. With the addition of antibody therapy, survival rates for high-risk neuroblastoma disease have increased significantly. In March 2009, a Children's Oncology Group study of 226 high-risk patients showed that Early analysis of the COG study showed that 2 years after stem cell transplantation, It was shown that 66% of patients who received the h14.18 antibody (along with GM-CSF and IL-2) were alive and disease-free, compared with only 46% of patients who did not receive the antibody. Randomization was halted to allow all patients in the trial to receive antibody therapy (Reference 10).

[0022] Combinations of chemotherapy drugs have been found to be effective against neuroblastoma. Commonly used agents for induction and stem cell transplant conditioning are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan, topoisomerase II inhibitors), and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in the induction and have been found to be effective against recurrent disease.

[0023] The recent focus has been on de-escalating treatment for low- and intermediate-risk neuroblastoma patients while maintaining survival rates at 90%. A study of 467 intermediate-risk patients enrolled in clinical trial A3961 by the Children's Oncology Group Division of the NIH study NCT00499616 from 1997 to 2005 confirmed the assumption that treatment could be successfully de-escalated for this risk group. Those with favorable characteristics (tumor grade and response) received four cycles of chemotherapy, those with unfavorable characteristics received eight cycles, and 3-year event-free (symptom-free) survival and overall survival rates remained stable at 90% for the entire group. Future plans include intensifying treatment for patients with 1p36 or 11q23 chromosomal abnormalities and those lacking early response to treatment (refs. 11, 12).

[0024] Meanwhile, the focus over the past 20 years has been on enhancing treatment for patients with high-risk neuroblastoma. Research continues into variations in chemotherapy induction, timing of surgery, stem cell transplantation regimens, various radiation delivery schemes, and the use of monoclonal antibodies and retinoids to treat minimal residual disease. Recently, randomized phase III clinical trials have been conducted to improve survival in high-risk disease. 1982-1985: The European Neuroblastoma Study Group (ENSG1) enrolled 167 children and randomized them to melphalan autologous bone marrow transplantation or no further treatment (no radiation therapy in any child). There were 65 patients in each of the transplant and non-transplant groups. A recent long-term follow-up report revealed a significantly better 5-year event-free survival rate for stage 4 neuroblastoma in children over 1 year of age in the melphalan transplant group versus no further treatment, i.e., 33% vs. 17%, respectively (Ref. 13).

[0025] 1990-1999: A European study (EU-20592 or CCLGNB-1990-11) randomized 262 high-risk children over the age of 1 year and found that rapid induction (10-day cycles) was associated with higher survival rates than standard induction (21-day cycles) at the same total dose. The 10-year event-free survival rates were 27% and 18%, respectively. Both groups received a mild surgical procedure, no radiation therapy, and autologous bone marrow or stem cell transplant with melphalan only (Reference 14).

[0026] 1991-1996: Two consecutive randomized phase III trials of 379 patients with high-risk neuroblastoma were conducted by the Children's Cancer Group (CCG-389). 1) and showed improved survival with myeloablative therapy (total body irradiation) and 13-cis-retinoic acid (Accutane) in 50 patients in each of four study arms (Reference 15).

[0027] 1996-2003: The German (GPOH) trial NB97 evaluated the outcomes of 295 patients with high-risk neuroblastoma randomized to stem cell transplantation or consolidation chemotherapy. The results showed increased survival rates with stem cell transplantation (Reference 16).

[0028] 2000-2006: A recent study (COG-A3937) questioned the need for stem cell purging for CEM-LI (carboplatin, etoposide, melphalan, localized radiation) transplants. The study enrolled 486 patients. Stem cell purging was not found to improve survival (Ref. 17).

[0029] 2000-2012: Early investigations in a concurrent study (COG-ANBL0032) determined that the use of antibody ch14.18 in conjunction with interleukin-2 and GMCSF (retrospectively studied in German GPOH NB90 and NB97 at low doses and without cytokines) improved survival. A total of 423 patients were included. A follow-up Phase 3 study, COG-ANBL0931, began in January 2010 with 105 patients to gather further safety and efficacy data for FDA approval (Ref. 18).

[0030] 2002-2008: SIOP (International Society of Paediatric Oncology) formed the European SIOP Neuroblastoma Group (SIOPEN) in 1994 and activated the 2002 Phase III High-Risk Neuroblastoma Protocol (SIOP-EUROPE-HR-NBL-1) with “accelerated” COJEC (8 cycles of chemotherapy given at 10-day intervals) followed by transplant randomization to CEM (carboplatin, etoposide, melphalan) or BuMel (busulfan, melphalan), and ch14.18 antibody treatment (as in COG) with or without subcutaneous IL2. The study was adjusted to randomly assign children to receive either GCSF or M-CSF. The benefit of growth factors (GCSF) was reported in this study, and all patients received retinoic acid. The trial enrolled 1,000 patients (175 per year) (Ref. 18).

[0031] 2005–2010: The German randomization of NB2004 included MIBG and topotecan in up-front therapy, with a total of 642 patients from all risk groups (almost half were high risk). After transplant, the high-risk protocol included 6 months of cis-retinoic acid, 3 months off, and another 3 months of retinoic acid (Ref. 19).

[0032] 2007: The COG Phase III ANBL0532 trial began in December 2007 with 495 patients comparing single versus multiple (tandem) transplants. Induction began with two cycles of topotecan (Ref. 20).

[0033] In addition to these phase III trials, several research institutions are offering pilot treatment protocols. For example, St. Jude (Children's Research Hospital) completed a trial of a new frontline chemotherapy regimen in 23 children (2007). This included irinotecan and gefitinib, followed by 16 months of maintenance chemotherapy with alternating oral 13-cis-retinoic acid and topotecan after stem cell transplant. Memorial Sloan Kettering Cancer Center in New York offers a treatment that includes the mouse-derived monoclonal antibody 3F8, which has been used in protocols since the mid-1980s. This antibody is used for treatment of minimal residual disease or consolidation instead of stem cell transplant. A new pilot protocol, COG-ANBL09P1, available to newly diagnosed (high-risk) children at several Children's Oncology Group (COG) centers, offers MIBG radiation therapy and chemotherapy as a transplant regimen (Ref. 21).

[0034] Some children (especially those with high-risk cases) do not fully respond to frontline treatments (have a complete response or a very good partial response) and are considered refractory. These "refractory" children are excluded from frontline therapy (clinical trials) and are therefore eligible for clinical trials with novel therapies. Many high-risk children have a good response to frontline therapy and achieve remission, but the disease later returns (recurs). These children are also eligible for novel therapies being tested in clinical trials.

[0035] Chemotherapy with topotecan and cyclophosphamide is often used in the refractory setting and after relapse. A randomized trial of 119 patients comparing topotecan alone with topotecan and cyclophosphamide (2004) found a complete or partial response rate of 31% and a 2-year progression-free survival rate of 36% in the topotecan and cyclophosphamide group. Irinotecan (intravenous or oral) and oral temozolomide are also used in refractory and recurrent neuroblastoma (Ref. 22).

[0036] Many phase I and II trials are currently testing new agents for children with neuroblastoma that has relapsed or is resistant to initial therapy. Researchers are currently investigating new agents, alone or in new combinations, using small molecule targeted therapies, 131-I MIBG radiation therapy, angiogenic agents, novel monoclonal antibodies, vaccines, oncolytic viruses, and new myeloablative regimens.

[0037] A group of 16 U.S. children's hospitals known as the New Advances in Neuroblastoma Therapy (NANT) consortium has The NANT consortium coordinates the MIBG radiotherapy trials. The consortium includes trials using an oral powder formulation of fenretinide, intravenous fenretinide, a bisphosphonate (Zometa) with other agents, and a combination of I-131 MIBG and the inhibitor vorinostat. The authors also provide a study on this topic (Ref. 23).

[0038] Other research groups, such as the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC), are also conducting clinical trials to treat recurrent neuroblastoma. European institutions are investigating novel therapies, including haploidentical stem cell transplants, to treat recurrences. Many hospitals are also conducting their own institutional studies.

[0039] The protein p53 is thought to play a role in the development of resistance to chemotherapy. A November 2009 study in mice showed that activating the tumor suppressor p53 with the new drug nutlin-3 can slow tumor growth. In this study, Tom Van Maerken, M.D., of Ghent University Hospital in Belgium, and his colleagues used nutlin-3 to neutralize MDM2, a protein that binds to p53 and blocks its ability to induce programmed cell death. Previous studies have shown that nutlin-3 can specifically prevent MDM2 from disabling p53. Summary of the Invention [Problem to be solved by the invention]

[0040] Object of the invention The drug taurolidine has been observed to have the ability to enhance the activity of several oncological drugs.

[0041] As a result, one object of the present invention is to take advantage of the synergistic effects of Taurolidine with these oncological drugs, allowing for greater efficacy and reduced toxicity associated with the oncological drugs.

[0042] Another object of the present invention is to provide for the simultaneous delivery of one or more oncological drugs and taurolidine by creating nanoparticles that contain one or more oncological drugs and taurolidine with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncological drugs and taurolidine), thereby taking advantage of the synergistic effects of taurolidine with these oncological drugs.

[0043] Yet another object of the present invention is to create nanoparticles comprising one or more oncological drugs and taurolidine, with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncological drugs and taurolidine), and further comprising a coating configured to locally release the one or more oncological drugs and taurolidine to the site of the cancer, e.g., the tumor. In one preferred form of the invention, the coating is configured to prevent premature exposure of the one or more oncological drugs and taurolidine to the body before they are delivered to the site of the cancer, e.g., the tumor. This can be important to prevent undesirable side effects from the one or more oncological drugs, premature hydrolysis of taurolidine, etc. In one preferred form of the invention, the coating comprises an absorbent polymer or lipid.

[0044] Yet another object of the present invention is to provide nanoparticles comprising one or more oncological drugs and taurolidine, with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncological drugs and taurolidine), and further comprising a coating, said coating configured to target the nanoparticles to the site of cancer (e.g., tumor) to improve the efficacy of the oncological drug and taurolidine for the treatment of cancer. In one preferred form of the invention, In the present invention, the coating comprises binding molecules configured for targeted delivery of the nanoparticles to specific tissues.

[0045] Another object of the present invention is to provide nanoparticles specifically configured for the treatment of neuroblastoma and / or other specific cancers.

[0046] Taurolidine Overview Taurolidine (bis(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)-methane) has antibacterial and antilipopolysaccharide properties. It is derived from the amino acid taurine. Its immunomodulatory effects are reported to be mediated by the priming and activation of macrophages and polymorphonuclear leukocytes.

[0047] Taurolidine is used to treat patients with peritonitis and as an antiendoxic agent in patients with systemic inflammatory response syndrome. Taurolidine is used to treat severe abdominal sepsis and peritonitis. Taurolidine is a life-saving antibacterial agent for the treatment of gastrointestinal and inflammatory diseases. Taurolidine is active against a broad range of microorganisms, including gram-positive and gram-negative bacteria, fungi, mycobacteria, and bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate-resistant Staphylococcus aureus (VISA), vancomycin-resistant Staphylococcus aureus (VRSA), oxacillin-resistant Staphylococcus aureus (ORSA), and vancomycin-resistant enterococci (VRE), which are resistant to a variety of antibiotics. In addition, Taurolidine also exhibits some antitumor properties, and early clinical trials with the drug to treat gastrointestinal malignancies and tumors of the central nervous system have shown positive results.

[0048] Taurolidine is the active ingredient in antimicrobial catheter lock solutions for the prevention and treatment of catheter-related bloodstream infections (CRBSIs) and is suitable for use in all catheter-based vascular access devices. Bacterial resistance to Taurolidine has not been observed in various studies.

[0049] Taurolidine acts by a non-selective chemical reaction. In aqueous solution, the parent molecule taurolidine forms an equilibrium with taurultam and N-hydroxymethyltaurultam, with taurinamide being the downstream derivative. The active group of taurolidine is the N-methylol derivative of taurultam and taurinamide, which reacts with bacterial cell walls, cell membranes, and proteins, as well as with primary amino groups of endotoxins and exotoxins. Microorganisms are killed and the resulting toxins are inactivated. In vitro destruction time is 30 minutes. Proinflammatory cytokines and enhanced tumor necrosis factor (TNF) levels are reduced when taurolidine is used as a catheter lock solution. Taurolidine reduces bacterial and fungal adhesion to host cells by disrupting pili and flagella, thus preventing biofilm formation.

[0050] Taurolidine has been administered intravenously in doses of 5 g over 2 hours, every 4 hours for at least 48 hours, for the treatment of a variety of septic conditions.

[0051] Synergistic activity of Taurolidine has been observed in the following applications involving the use of oncological drugs: Karlisch et al. (Reference 24) observed the effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine on apoptosis and proliferation in human rhabdomyosarcomas, leiomyosarcoma, and epithelioid cell sarcomas. Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumors, accounting for 1% of all adult malignancies. Although the treatment of STS should be individualized and multimodal, complete surgical resection with clear margins remains the mainstay of treatment. Disseminated soft tissue sarcomas remain a therapeutic dilemma. Commonly used chemotherapy drugs such as doxorubicin and ifosfamide have been found to be effective in less than 30% of these cases. Karlisch et al. therefore investigated the effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine on apoptosis and proliferation in human rhabdomyosarcomas, leiomyosarcoma, and epithelioid cell sarcomas. The in vitro apoptotic and antiproliferative effects of related apoptosis-inducing ligand (TRAIL) and taurolidine were tested on rhabdomyosarcoma (A-204), leiomyosarcoma (SK-LMS-1) and epithelioid cell sarcoma (VA-ES-BJ) cell lines. Viability, apoptosis and necrosis were quantified by FACS analysis (propidium iodide / annexin V staining). Gene expression was analyzed by DNA microarray and results were verified by rtPCR for selected genes. Changes in protein levels were recorded by Western blot analysis. Cell proliferation was analyzed by bromodeoxyuridine (BrdU) ELISA assay. Single substances TRAIL and taurolidine significantly induced apoptotic cell death and reduced proliferation in rhabdomyosarcoma and epithelioid cell sarcoma cells. The combination of TRAIL and taurolidine produced a synergistic apoptotic effect in all three cell lines. In particular, rhabdomyosarcoma cells only 18% of viable cells remained after 48 hours of incubation (p<0.05). Analysis of differentially regulated genes revealed that taurolidine and TRAIL affected apoptotic pathways, including the TNF receptor-associated mitochondrial pathway. Microarray analysis revealed significant expression changes of various genes involved in different apoptotic pathways and crosstalk with other pathways at multiple levels. This in vitro study shows that TRAIL and taurolidine synergize to induce apoptosis and inhibit proliferation in different human STS cell lines. The effects on gene expression differed relevantly between sarcoma entities. These results provide experimental support for in vivo studies evaluating the effects of TRAIL and taurolidine in STS and support an individualized therapy approach.

[0052] Harati et al. (Reference 25) observed that TRAIL and taurolidine enhanced the anticancer activity of doxorubicin, trabectedin, and mafosfamide in HT1080 human fibrosarcoma cells. Disseminated fibrosarcoma remains a therapeutic dilemma due to the lack of effective cytostatic drugs. Thus, it was observed that the combination of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and taurolidine with established and novel chemotherapeutic drugs in human fibrosarcoma (HT1080) improved apoptosis. Materials and Methods: Human fibrosarcoma cells (HT1080) were incubated with doxorubicin, mafosfamide and trabectedin, alone and in combination with taurolidine and TRAIL. Viable, apoptotic and necrotic cells were quantified using flow cytometry analysis. Cell proliferation was analyzed using a bromodeoxyuridine (BrdU) ELISA assay. Results: Doxorubicin and trabectedin administered alone induced apoptotic cell death and significantly reduced proliferation in HT1080 cells. In combination therapy, the addition of taurolidine and TRAIL led to a stronger decrease in the degree of cell viability compared to monotherapy. Trabectedin and taurolidine showed a greater potential for inhibiting proliferation than doxorubicin alone. Conclusion: When combined with TRAIL and taurolidine, treatment with doxorubicin and trabectedin exhibited stronger apoptosis-inducing and antiproliferative effects.

[0053] Martinotti et al. (Reference 26) studied in vitro screening of ascorbic acid-drug synergistic combinations for the treatment of malignant mesothelioma. Malignant mesothelioma (MMe) is a lethal tumor arising from the mesothelium of the serous cavity as a result of exposure to asbestos. Current clinical studies consist of combination therapies, but effective therapies have not yet been established, and there is an urgent need for new curative therapies. Ascorbic acid is a nutrient that is also known as a therapeutic drug in cancer treatment. In this study, Martinotti et al. investigated the efficacy of ascorbic acid in combination with drugs used in MMe therapy, such as cisplatin, etoposide, gemcitabine, imatinib, paclitaxel, and raltitrexed, as well as promising antitumor compounds, such as taurolidine, a-tocopherol succinate, and epigallocatechin-3-gallate (EGCG). The cytotoxicity of ascorbic acid on MMe cells was tested. From the dose-response curves obtained for each compound by applying the neutral red uptake (NRU) assay to MMe cells growing in vitro, it was possible to determine IC50 values ​​for each compound used alone. The NRU data obtained from each ascorbic acid / drug combination was then analyzed through Tallarida isobolograms at IC50 concentrations. Around the same time (Tallarida, 2000), synergistic interactions of ascorbic acid / gemcitabine and ascorbic acid / EGCG were revealed. These results were further confirmed by comparison between theoretical additive IC50 and IC50 observed from fixed ratio dose-response curves using the Chou and Talalay combination coefficient (Chou and Talalay, 1984) over a wide range of IC levels. Synergistic interactions were also demonstrated by examining the rates of apoptosis and necrosis using caspase 3 and lactate dehydrogenase assays, respectively. Thus, the data showed that ascorbic acid / gemcitabine and ascorbic acid / EGCG exhibited synergistic effects on MMe cell viability, suggesting their potential use in the clinical treatment of this problematic cancer.

[0054] Daigeler et al. (Reference 27) observed a synergistic apoptotic effect of taurolidine and TRAIL on esophageal squamous cell carcinoma cells. Surgical resection is considered the treatment of choice for esophageal cancer, but the median survival rate at 20 months after treatment is disappointing. Adjuvant or neoadjuvant radiotherapy or chemotherapy has limited benefit and, to date, benefits have only been observed in certain tumor stages. New therapeutic options are therefore needed. As an alternative chemotherapy, Daigeler et al. tested the antibiotic taurolidine, alone and in combination with rhTRAIL (recombinant human TNF-related apoptosis-inducing ligand), on KYSE270 human esophageal cancer cells. Viability, apoptosis, and necrosis were visualized by TUNEL assay and quantified by FACS analysis. Gene expression was analyzed by RNA microarray. The most effective concentration of taurolidine as a single substance (250 mmol / l) induced up to 40% apoptosis 12 hours after administration, leaving only 4% viable cells after 48 hours. In comparison, rhTRAIL had no significant effect. The combination of both substances doubled the effect of taurolidine alone. Gene expression profiling revealed that taurolidine downregulated endogenous TRAIL, TNFRSF1A, TRADD, TNFRSF1B, TNFRSF21 and FADD, as well as MAP2K4, JAK2 and Bcl2, Bcl211, APAFl and caspase-3. TNFRSF25, cytochrome-c, caspase-1, -8, -9, JUN, GADD45A and NFKBIA were upregulated. TRAIL reduced the expression of endogenous TRAIL, Bcl211 and caspase-1. BIRC2, BIRC3, TNFAIP3, and NFKBIA were upregulated. The combination agents upregulated endogenous TRAIL, NFKBIA, and JUN, whereas DFFA and TRAF3 were downregulated when compared to taurolidine as a single agent. Daigeler et al. concluded that taurolidine overcomes TRAIL resistance in KYSE270 cells. The synergistic effect relies on the same and distinct apoptotic pathways, which, when jointly triggered, result in an amplified response.Several apoptotic pathways, including TNF receptor-related and mitochondrial pathways, were differentially regulated by the agents at the gene expression level. Furthermore, transcription factors, especially NFKB, also seemed to be affected. Endogenous TRAIL expression was increased by the combination of agents but decreased by each agent alone. Given that non-toxic taurolidine could reduce the toxicity and dose of rhTRAIL, combination therapy of taurolidine and rhTRAIL may provide a new option for the treatment of esophageal cancer.

[0055] Chromik et al. (Reference 28) observed a synergistic effect of taurolidine and rhTRAIL on apoptosis induction in HCT15 colon cancer cells. Induction of apoptosis in tumor cells by TRAIL (TNF-related apoptosis-inducing ligand) is a useful therapeutic approach in oncology. Taurolidine is a promising treatment option, but toxicity and resistance to TRAIL are limiting factors. Taurolidine is a low-toxicity antineoplastic drug and therefore a potential candidate for combination therapy with TRAIL. The aim of Chromik et al.'s study was to evaluate the combination therapy of TRAIL and taurolidine in the HCT15 human colon cancer cell line. HCT15 cells were cultured and incubated with increasing concentrations of recombinant human TRAIL (50-500 ng / mL) or taurolidine (50-1000 mmol / L) to evaluate the dose-dependent effects of both substances on apoptosis and necrosis. Then, in a second experiment, cells were incubated with TRAIL alone (50 and 250 ng / mL) or taurolidine (100 and 1000 mmol / L) as well as with a combination of both drugs at different concentrations. At various time points (3-36 h), cell viability, apoptosis, and necrosis were quantified by FACS analysis using propidium iodide and Annexin V staining. Results are expressed as means and statistical analysis was performed by ANOVA, pairwise comparison with Tukey's test. P values ​​<0.05 were considered statistically significant. Incubation with taurolidine induced dose-dependent cell death with maximal effects at 100mmol / l and 1000mmol / l after 24 and 36 h, resulting in a decrease in viable cells from 60% to 17-33%. TRAIL at 250ng / mL and 500ng / mL reduced viable cells from 70% to 6-7% as early as 6 h, but viable cells were partially restored to 13% after 36 h. Combined treatment with taurolidine (100mmol / l) and TRAIL (50ng / mL) resulted in sustained induction of apoptosis after 24 and 36 h, indicating a significant synergistic effect of both substances that clearly exceeded the merely additive effect. After 24 h of incubation with taurolidine (100 mmol / l) and TRAIL (50 ng / mL), only 2.1% of the cells were viable, compared with 43.9% with taurolidine 100 mmol / l alone and 17.7% with TRAIL 50 ng / mL. Similar results were observed after 36 h. Chromik et al. were the first to demonstrate a synergistic effect of recombinant human TRAIL and taurolidine on the induction of apoptosis in human colon cancer cells in vitro.Combination therapy of TRAIL and taurolidine resulted in sustained cell death superior to single agent application. The combination of TRAIL with non-toxic taurolidine provides a new therapeutic rationale for oncology therapy.

[0056] Braumann et al. (reference 29) observed local and systemic chemotherapy with taurolidine and taurolidine / heparin in rats with colon cancer undergoing laparotomy. Experimental studies of the therapy of abdominal malignancies have shown that various cytotoxic drugs inhibit intraperitoneal (ip) tumor growth. Nevertheless, there is no generally accepted method to prevent tumor recurrence. The effects of both taurolidine or taurolidine / heparin on ip and sc tumor growth after subcutaneous (sc) and ip injection of 104 colon adenocarcinoma cells (DHD / K12 / TRb) were studied in 105 rats undergoing midline laparotomy. Animals were randomized into 7 groups and operated on during a 30-minute period. To investigate the ip (local) effect of either taurolidine or heparin on tumor growth, the substances were applied. The ip systemic and ip effects were evaluated after iv injection of the substances. Both application forms were also combined to analyze synergistic effects. Tumor weights as well as abdominal wound metastasis incidence were examined 4 weeks after the intervention. To evaluate the efficacy of the drugs, blood was collected and peripheral white blood cell counts were measured. IP tumor growth in rats receiving IP application of taurolidine (median 7.0 mg, P = 0.05) and taurolidine / heparin (median 0 mg, P = 0.02) was significantly reduced compared to the control group (median 185 mg). Simultaneous infusion of both drugs also reduced IP tumor growth (median 4 mg, P = 0.04), whereas IV injection of the substances did not produce a local effect. In contrast, SC tumor growth was not different in all groups. Abdominal wound recurrences were rare and did not differ in all groups. Independent of the drug and the mode of application, the surgery itself caused a slight leukopenia immediately after surgery and a leukopenia in the subsequent course. IP therapy, either with taurolidine or in combination with heparin, inhibited local tumor growth and abdominal wound recurrence in rats undergoing midline laparotomy. Neither the ip nor iv application, nor the combination of the two drugs, had any effect on sc tumor growth. The substances did not alter the changes in peripheral leukocytes.

[0057] Stendel et al. (Reference 30) observed the enhancement of Fas ligand-mediated programmed cell death by taurolidine. Taurolidine was found to have a direct and selective antineoplastic effect on brain tumor cells. The ability of taurolidine to exert antineoplastic effects by enhancing Fas-mediated apoptosis in various malignant glioma cell lines was investigated. Materials and Methods: Human-derived U373 cells were cultured and incubated with taurolidine to calculate the median inhibitory concentration (IC50). Flow cytometric analysis was performed to evaluate changes in DNA content. Cells were qualitatively and quantitatively examined using light and electron microscopy. LN-18 and LN-229 cells were incubated in the absence or presence of either Fas ligand, taurolidine or their respective combinations. Cell viability was determined by the addition of 2-fold concentrated WST-1 reagent. Mitochondrial succinate reductase activity was measured with an ELISA reader. Results: Exposure of 0373 cells to taurolidine resulted in a concentration-dependent (IC50 35.8±2.2mg / mL) loss of cell viability. Flow cytometric analysis showed a concentration-dependent appearance of DNA debris in the sub-G0 / G1 region. In the presence of 6.25vol.% Fas ligand, LN-18 cells showed a loss of cell viability of over 90%, whereas LN-299 cells only decreased at higher concentrations of Fas ligand. Taurolidine alone had no appreciable effect on LN-18 cell viability over the range of concentrations tested, but was able to potentiate the effect of Fas ligand on LN-18 cells. Exposure of LN-229 cells to taurolidine alone caused a substantial loss of cell viability of approximately 70% at the highest concentration tested. Cell destruction by Fas ligand (10vol.%) was potentiated in the presence of taurolidine. Conclusion: The antineoplastic activity of taurolidine appears to be based in part on the enhancement of Fas ligand-induced apoptosis. Furthermore, taurolidine has been shown to have antineoplastic effects independent of Fas ligand. It is likely that taurolidine exerts its antineoplastic activity through multiple mechanisms.

[0058] In another study, Braumann et al. (reference 31) evaluated the effect of intraperitoneal and systemic application of taurolidine and taurolidine / heparin during laparoscopy on intraperitoneal (ip) and subcutaneous (sc) tumor growth in rats. The researchers investigated the problem of port site metastasis and possible pathomechanisms after laparoscopic resection of malignant tumors. There is no generally accepted method to prevent the engraftment of these tumors so far. The effect of either taurolidine or taurolidine / heparin on ip and sc tumor growth after sc and ip injection of 104 colon adenocarcinoma cells (DHD / K12 / TRb) was studied in 105 rats undergoing laparoscopy with carbon dioxide. The animals were then randomly assigned to seven groups. Pneumoperitoneum was established for 30 min with carbon dioxide (8 mmHg). Three incisions were used: one in the center for the pneumoperitoneum needle and one each in the left and right lower quadrants for trocars. To study the IP (local) effect of Taurolidine and Heparin on tumor growth, the substances were instilled IP. A systemic effect was expected when the substances were applied IV. The synergistic effect of combining both modes of application was analyzed. The number and weight of tumors, as well as the incidence of abdominal wall and port site metastases, were examined 4 weeks after the intervention. Blood was collected to evaluate the effect of Taurolidine and Heparin on the systemic immune response 7 days before laparoscopy, 2 hours, 2 days, 7 days, and 4 weeks after surgery, and peripheral lymphocytes were measured. IP tumor weights were significantly reduced in rats receiving Taurolidine (median 7 mg) and Taurolidine / Heparin (0 mg) IP compared to the control group (52 mg) (P=0.001). There was no difference in sc tumor growth between the groups (P=0.4). Trocar recurrence was reduced when Taurolidine was applied IP (3 / 15), IPIV (4 / 15), and in combination with heparin IP (4 / 15) compared to the control group (10 / 15). Immediately after the intervention, both treated and untreated groups showed peripheral lymphopenia. IP therapy in combination with Taurolidine and heparin inhibited IP tumor growth and trocar recurrence. Neither IP nor systemic application, nor the combination of Taurolidine and heparin, reduced SC tumor growth. The interventions were associated with increased lymphocyte counts. This induced lymphopenia, which was compensated for by the second day.

[0059] Monson et al. (ref. 32) observed that taurolidine inhibited tumor necrosis factor (TNF) toxicity, with evidence of synergy between TNF and endotoxin. The use of recombinant tumor necrosis factor (TNF) in the treatment of solid tumors has been limited due to its life-threatening toxicity. Furthermore, TNF may be a major mediator of endotoxin action. Recent evidence suggests that synergy between endotoxin (picogram levels) and TNF may contribute to this toxicity. The use of the antiendotoxin taurolidine can reduce TNF toxicity by interfering with this synergy. C57 / BL6 mice (n=140) were administered a toxic dose (12 micrograms / mouse IV) of TNF. Four groups were studied. Group A received taurolidine (200 mg / kg IV) 30 min before TNF, group B received taurolidine (200 mg / kg IV) 30 min after TNF, group C received the same volume (0.5 ml) of saline 30 min before TNF, and group D received taurolidine (200 mg / kg IP) 45 min before TNF. The mortality rate of mice receiving intravenous taurolidine 30 min before TNF was 8.8%, which was significantly lower than the mortality rate achieved in groups B, C, and D (33% vs. 39.4% vs. 50%) (P<0.005). MTT (3-(4,5-dimethylthinzol-2-yl)-2,5-diphenyl tetrazolium bromide)) assay Further experiments with taurolidine indicated that this was not due to a direct interaction between taurolidine and TNF, but was probably due to interfering with the synergistic action of endotoxin and TNF. Combination therapy studies in mouse models also showed that taurolidine did not reduce the antitumor effect of TNF against the TNF-sensitive murine fibrosarcoma cell line Meth-A sarcoma.

[0060] Synergistic activity of taurolidine with drugs for the treatment of neuroblastoma. Eschenburg et al. (Reference 33) observed that taurolidine cooperates with antineoplastic drugs in neuroblastoma cells. In neuroblastoma, the outcome of stage 4 disease remains poor, so the development of new therapeutic approaches is urgently needed. Taurolidine, known to inhibit catheter infection, has shown antineoplastic activity in various cancers. The proliferation of neuroblastoma cell lines was recently shown to be inhibited by taurolidine. Further analysis disclosed a significant negative proliferation effect of taurolidine on four neuroblastoma cell lines, SH-EP TET21N, SK-N-AS, SK-N-BE(2)-M17 and SK-N-SH. The detected IC50 (51-274 mM; 48 h) was promising and corresponds to clinically achievable plasma concentrations. Apoptosis was induced in a time-dependent manner (76-86%; 48 h) mediated by the simultaneous activation of intrinsic and extrinsic pathways. This was confirmed by cleavage of caspases-3, -8 and -9 and by blocking apoptosis by pan-caspase inhibition. Application of Taurolidine resulted in a marked potentiation of the cytotoxic drugs vincristine / doxorubicin (2 / 3 in 4 cell lines), making Taurolidine a promising candidate for inclusion in future neuroblastoma treatment regimens.

[0061] Eschenburg et al. (Reference 33) also observed that taurolidine specifically inhibited the proliferation of neuroblastoma cell lines in vitro. The antineoplastic properties of taurolidine have been demonstrated in a variety of human cancer cells. However, data on neuroblastoma are scarce. Therefore, Eschenburg et al. sought to evaluate the effect of taurolidine on the proliferation of neuroblastoma cell lines. Materials and Methods: Neuroblastoma SK-N-BE(2)-M17 and SK-NSH cells and non-malignant human umbilical vein endothelial cells (as control) were incubated with increasing concentrations of Taurolidine (100, 250, 500 mM). Cell proliferation was examined after 12, 24, and 48 hours of exposure. Results: Inhibition of cell proliferation by taurolidine was observed in both malignant cell lines. When compared with human umbilical vein endothelial cells, the neuroblastoma cell line responded significantly better to taurolidine. did. Conclusion: The observed negative effects on cell proliferation, which were highly pronounced in SK-N-BE(2)-M17 and SK-N-SH, imply a specific mode of action of Taurolidine, which seems to depend on differences at the cellular and molecular levels. Further studies are required to evaluate its mechanism and possible clinical use. [Means for solving the problem]

[0062] The present invention takes advantage of the synergistic properties of taurolidine with various oncological drugs. More specifically, the present invention includes providing and using nanoparticles that contain one or more oncological drugs and taurolidine with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncological drugs and taurolidine), thereby providing for the simultaneous delivery of one or more oncological drugs and taurolidine, thereby taking advantage of the synergistic effect of taurolidine with these oncological drugs.

[0063] In one preferred form of the invention, the nanoparticles comprise one or more oncological drugs and taurolidine, with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or one or more oncological drugs and taurolidine), and further comprise a coating configured to locally release the one or more oncological drugs and taurolidine at the site of the cancer, e.g., the tumor. In one preferred form of the invention, the coating is configured to prevent premature exposure of the one or more oncological drugs and taurolidine to the body before they are delivered to the site of the cancer, e.g., the tumor. This can be important to prevent undesirable side effects from the one or more oncological drugs, premature hydrolysis of taurolidine, etc. In one preferred form of the invention, the coating comprises an absorbent polymer or lipid.

[0064] Also, in one preferred form of the invention, the nanoparticles comprise one or more oncological drugs and taurolidine, with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncological drugs and taurolidine), and further comprise a coating configured to target the nanoparticles to the site of cancer (e.g., tumor) to improve the efficacy of the one or more oncological drugs and taurolidine for the treatment of cancer. In one preferred form of the invention, the coating comprises a binding molecule configured for targeted delivery of the nanoparticles to a specific tissue.

[0065] Also, in one preferred form of the invention, the nanoparticles are specifically adapted for the treatment of neuroblastoma and / or other specific cancers. In one preferred embodiment of the invention, with at least one oncology drug; and Taurolidine and The present invention provides for simultaneous delivery of at least one oncological drug and taurolidine, thereby taking advantage of the synergistic effect of taurolidine with the at least one oncological drug.

[0066] In another preferred embodiment of the present invention, there is provided a method of treating cancer, the method comprising the steps of: with at least one oncology drug; and Taurolidine and providing a therapeutic nanoparticle comprising: The therapeutic nanoparticles are delivered to the body to provide simultaneous delivery of the at least one oncological drug and Taurolidine, thereby providing a therapeutic effect of Taurolidine on the at least one oncological drug. Use synergies This includes: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] The present invention takes advantage of the synergistic properties of taurolidine with various oncological drugs. More specifically, the present invention includes providing and using nanoparticles that contain one or more oncological drugs and taurolidine with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncological drugs and taurolidine), thereby providing for the simultaneous delivery of one or more oncological drugs and taurolidine, thereby taking advantage of the synergistic effect of taurolidine with these oncological drugs.

[0068] In one preferred form of the invention, the nanoparticles comprise one or more oncological drugs and taurolidine, with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or one or more oncological drugs and taurolidine), and further comprise a coating configured to locally release the one or more oncological drugs and taurolidine at the site of the cancer, e.g., the tumor. In one preferred form of the invention, the coating is configured to prevent premature exposure of the one or more oncological drugs and taurolidine to the body before they are delivered to the site of the cancer, e.g., the tumor. This can be important to prevent undesirable side effects from the one or more oncological drugs, premature hydrolysis of taurolidine, etc. In one preferred form of the invention, the coating comprises an absorbent polymer or lipid.

[0069] Also, in one preferred form of the invention, the nanoparticles comprise one or more oncological drugs and taurolidine, with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncological drugs and taurolidine), and further comprise a coating configured to target the nanoparticles to the site of cancer (e.g., tumor) to improve the efficacy of the one or more oncological drugs and taurolidine for the treatment of cancer. In one preferred form of the invention, the coating comprises a binding molecule configured for targeted delivery of the nanoparticles to a specific tissue.

[0070] Also, in one preferred form of the invention, the nanoparticles are specifically adapted for the treatment of neuroblastoma and / or other specific cancers. More specifically, the present invention takes advantage of the synergistic properties of Taurolidine and various oncological drugs by encapsulating them in specific nanoparticle systems designed to locally release the oncological drug and Taurolidine at the site of cancer, e.g., the tumor.

[0071] Several absorbable polymer systems can be used to optimize the release profile of the oncological drug(s) and taurolidine. In particular, those created from combinations of copolymers and multimers derived from polymers constructed from l-lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate. These include polyethylene glycols (PEGs) that can be either linear or multi-arm in structure. ) may be bonded to a glycol.

[0072] Optimization of the system containing Taurolidine, oncological drug(s) and polymer in nanoparticles will lead to improved treatment of cancer in general and neuroblastoma in particular. Additionally, studies have demonstrated cannabinoid activity against N-type calcium channels, glycine receptor channels, and voltage-gated potassium channels in neuroblastoma. Each of these is believed to be specific for neural tissue and absent from reticuloendothelial system (RES) cells. Thus, providing nanoparticles with binding molecules that target neural tissue (e.g., N-type calcium channels, glycine receptor channels, and voltage-gated potassium channels in neuroblastoma) enhances targeted delivery of the nanoparticles to neural tissue, and therefore the efficacy of the oncological drug(s) (which is further enhanced by the presence of synergistic taurolidine).

[0073] It is generally important that the binding molecules of the nanoparticles have no other significant biological activity. To achieve specific binding without other significant biological activity, fragment antigen-binding (Fab) fragments of monoclonal antibodies (regions on the antibody that bind to the antigen) are utilized. However, it is preferable not to use anti-voltage-gated potassium channel antibodies (e.g., KvR) as targets, since severe autoimmune encephalitis syndromes derived from anti-voltage-gated potassium channel antibodies have been recently reported. Other targets have also reported cases of autoimmune encephalitis as the etiology of paraneoplastic syndromes. So far, none of these targets are as severe as KvR disease, but this may be by chance. Therefore, care must be taken in the selection of binding molecules used to target nervous tissue.

[0074] In one preferred form of the invention, the coating of the nanoparticles includes a monoclonal antibody against N-type calcium channels (e.g., an anti-N-type calcium channel outer surface Fab fragment) to bind the nanoparticles to neural tissue (e.g., neuroblastoma tumors).By doing so, the oncological drug(s) and taurolidine are delivered simultaneously to the neural tissue (via the targeted nanoparticles), with taurolidine providing a synergistic effect on the oncological drug(s), thereby providing an enhanced effect of the oncological drug(s) on the targeted neural tissue.

[0075] In one particularly preferred form of the invention, the anti-N-type calcium channel outer surface Fab fragment incorporated into the coating of the nanoparticle is Ca v 2.2, or any combination thereof.

[0076] Thus, in one aspect of the invention, nanoparticles are provided that contain a cytotoxic chemotherapeutic drug(s) and a synergistic taurolidine in a suitable buffer to provide enhanced hydrolytic stability of the taurolidine and / or one or more oncological drugs and the taurolidine. The surface of the nanoparticles is a lipid envelope or polymer that modulates the release profile of the chemotherapeutic drug(s) and the synergistic taurolidine. The surface of the nanoparticles preferably includes binding molecules that target neural tissue.

[0077] It will be appreciated that the present invention provides nanoparticles that can be used to treat neuroblastoma in a patient, said nanoparticles comprising a chemotherapeutic agent(s) and a synergistic amount of taurolidine, said chemotherapeutic agent(s) and taurolidine being encapsulated in a polymer that modulates the release characteristics of the chemotherapeutic agent and taurolidine.

[0078] Modifications of the Preferred Embodiments It should be understood that numerous additional changes may be made by those skilled in the art to the details, materials, steps, and arrangements of parts described and illustrated herein to explain the nature of the invention, yet still fall within the principles and scope of the invention.

[0079] References

[0080] [Table 1]

[0081] [Table 2]

[0082] [Table 3]

[0083] [Table 4]

[0084]

Table 5

[0085]

Table 6

Claims

1. 1. A therapeutic nanoparticle comprising: at least one oncology drug; Taurolidine and thereby providing simultaneous delivery of at least one oncological drug and taurolidine, thereby taking advantage of the synergistic effect of taurolidine on the at least one oncological drug.

2. The therapeutic nanoparticle of claim 1, wherein at least one oncological drug comprises TNF-related apoptosis-inducing ligand (TRAIL).

3. The therapeutic nanoparticle of claim 2, configured to target at least one from the group consisting of soft tissue sarcoma, esophageal cancer and colon cancer cells.

4. The therapeutic nanoparticle of claim 1, wherein at least one oncological drug comprises recombinant human TNF-related apoptosis-inducing ligand (rhTRAIL).

5. The therapeutic nanoparticle of claim 4, configured to target at least one from the group consisting of esophageal cancer and colon cancer cells.

6. The therapeutic nanoparticle of claim 1, wherein at least one oncological drug comprises a Fas ligand.

7. The therapeutic nanoparticle of claim 6, configured to target brain tumor cells.

8. The therapeutic nanoparticle of claim 1, wherein at least one oncological drug comprises tumor necrosis factor (TNF).

9. The therapeutic nanoparticle of claim 8, configured to target solid tumor cancer.

10. The therapeutic nanoparticle of claim 1, wherein at least one oncological drug comprises an anti-neoplastic agent.

11. The therapeutic nanoparticle of claim 10, configured to target neuroblastoma.

12. The therapeutic nanoparticle of claim 1, wherein at least one oncological drug comprises a cytotoxic drug.

13. The therapeutic nanoparticle of claim 12, wherein the cytotoxic drug comprises at least one from the group consisting of vincristine and doxorubicin.

14. The therapeutic nanoparticle of claim 12, configured to target neuroblastoma.

15. The therapeutic nanoparticle of claim 1, further comprising at least one excipient.

16. The therapeutic nanoparticle of claim 15, wherein at least one excipient comprises taurolidine and / or at least one oncological drug and a buffer to provide enhanced hydrolytic stability of taurolidine.

17. The therapeutic nanoparticle of claim 1, further comprising a coating configured to locally release at least one oncological drug and taurolidine at the site of the cancer.

18. The therapeutic nanoparticle described in claim 17, wherein the cancer site is a tumor.

19. The therapeutic nanoparticle of claim 17, wherein the coating is configured to prevent premature exposure of the at least one oncological drug and taurolidine to the body prior to delivery to the cancer site.

20. The therapeutic nanoparticle of claim 17, wherein the coating is configured to prevent at least one from the group consisting of undesirable side effects from at least one oncological drug, and premature hydrolysis of taurolidine and / or at least one oncological drug and taurolidine.

21. The therapeutic nanoparticle of claim 17, wherein the coating comprises at least one from the group consisting of absorbable polymers and absorbable lipids.

22. The therapeutic nanoparticle of claim 21, wherein the coating is created from a combination of copolymers and multimers derived from polymers constructed from at least one from the group consisting of l-lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate.

23. The therapeutic nanoparticle of claim 22, wherein the coating further comprises a glycol.

24. The therapeutic nanoparticle of claim 23, wherein the glycol comprises polyethylene glycol (PEG).

25. The therapeutic nanoparticle of claim 24, wherein the glycol comprises a linear or multi-branched structure.

26. The method of claim 25, wherein the coating is configured to target the nanoparticles to the site of cancer to improve the effectiveness of at least one oncological drug and taurolidine for the treatment of cancer. Item 18. The therapeutic nanoparticles described in item 17.

27. The therapeutic nanoparticle of claim 26, wherein the coating comprises a binding molecule configured to target delivery of the nanoparticle to a specific tissue.

28. The therapeutic nanoparticle of claim 27, wherein the binding molecule comprises a fragment antigen-binding (Fab) fragment of a monoclonal antibody.

29. The therapeutic nanoparticle of claim 27, wherein the binding molecule is configured to target neural tissue.

30. The therapeutic nanoparticle of claim 29, wherein the binding molecule is configured to target at least one from the group consisting of N-type calcium channels, glycine receptor channels, and voltage-gated potassium channels of neuroblastoma.

31. The therapeutic nanoparticle of claim 29, wherein the target neural tissue comprises a neuroectodermal tumor.

32. The therapeutic nanoparticle of claim 31, wherein the binding molecule binds to a neuroectodermal tumor expressing an N-type calcium channel.

33. The therapeutic nanoparticle of claim 32, wherein the binding molecule comprises an anti-N-type calcium channel outer surface Fab fragment.

34. The therapeutic nanoparticle of claim 33, wherein the anti-N-type calcium channel outer surface Fab fragment comprises Ca v 2.2, or a binding equivalent thereof.

35. The therapeutic nanoparticle of claim 27, wherein the binding molecule is embedded or covalently attached to the surface of the nanoparticle.

36. The therapeutic nanoparticle of claim 1, further comprising a coating configured to locally release at least one oncological drug and taurolidine to a cancer site, said coating comprising an absorbent polymer, and said coating being created from a combination of copolymers and multimers derived from polymers constructed from at least one from the group consisting of l-lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate.

37. The therapeutic nanoparticle of any one of claims 1 to 36, wherein the nanoparticle is for use in a method of treating cancer, the method comprising: providing said therapeutic nanoparticles; and Delivering said therapeutic nanoparticles to the body to provide simultaneous delivery of said at least one oncology drug and Taurolidine. The nanoparticles comprising: