Therapeutic nanoparticles for treatment of neuroblastoma and other cancers

Abstract

Therapeutic nanoparticles for use in the treatment of neuroblastoma and other cancers. Therapeutic nanoparticles comprising: at least one tumor drug; and taurolidine, thereby providing simultaneous delivery of the at least one tumor drug and taurolidine, thereby utilizing the synergistic effect of taurolidine on the at least one tumor drug.

Description

[0001] This application is a divisional application of an invention patent application, the parent case of which is a Chinese patent application with an application date of January 11, 2017, application number 201780016573.5, and invention name "Therapeutic Nanoparticles for Treating Neuroblastoma and Other Cancers". This patent application claims the benefit of the pending prior U.S. provisional patent application serial number 62 / 277,243 (attorney file number CORMEDIX-14PROV) filed by CorMedix Inc. and Robert DiLuccio on 01 / 11 / 2016 regarding NANOPARTICLE SYSTEM FOR THE TREATMENT OF NEUROBLASTOMA, which is hereby incorporated by reference. Technical Field

[0002] The present invention relates generally to therapeutic compositions and more particularly to therapeutic compositions for treating neuroblastoma and other cancers. Background Art

[0003] Neuroblastoma (NB) is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an incidence of 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, arising from any neural crest unit of the sympathetic nervous system (SNS). Neuroendocrine tumors most often originate in one of the adrenal glands, but it can also develop in the nerve tissue of the neck, chest, abdomen, or pelvis.

[0004] Neuroblastoma is one of the few human malignancies known to exhibit spontaneous regression from an undifferentiated state to a completely benign cellular appearance. Neuroblastoma is a disease that exhibits extreme heterogeneity and is stratified into three risk categories: low, intermediate, and high risk. Low-risk neuroblastoma disease is most common in infants, and "good outcomes" are common with observation or surgery alone, while high-risk neuroblastoma disease is difficult to successfully treat even with the most intensive multimodal oncology therapies available.

[0005] Estheroblastoma, also known as olfactory neuroblastoma, is thought to arise from the olfactory epithelium, and its classification remains controversial. However, because it is not a sympathetic nervous system malignancy, estheroblastoma is a distinct clinical entity and should not be confused with neuroblastoma.

[0006] Signs and symptoms

[0007] The first symptoms of neuroblastoma are often vague, making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on the primary tumor location and metastases, if present.

[0008] In the abdomen, a tumor may cause a bloated abdomen and constipation.

[0009] A tumor in the chest may cause breathing problems.

[0010] A tumor that compresses the spinal cord may cause weakness and an inability to stand, crawl, or walk.

[0011] Damage to the bones in the legs and hips may cause pain and lameness.

[0012] Tumors in the bones around the eye or orbit may cause significant bruising and swelling.

[0013] Bone marrow infiltration may cause pallor from anemia.

[0014] Neuroblastoma often spreads to other parts of the body before any symptoms are apparent, and 50-60% of all neuroblastoma cases present with metastases.

[0015] The most common location of neuroblastoma origin (i.e., the location of the primary tumor) is in the adrenal glands. This occurs in 40% of cases of localized tumors and 60% of cases of widespread neuroblastoma disease. Neuroblastoma can also develop anywhere along the sympathetic nervous system chain from the neck to the pelvis. The frequencies in different locations include: neck (1%), chest (19%), abdomen (30% non-adrenal), or pelvis (1%). In rare cases, the primary tumor cannot be distinguished.

[0016] Rare but characteristic presentations include transverse myelopathy (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal polypeptide secretion, 4% of cases), Homer syndrome (cervical tumor, 2.4% of cases), opsocinus myoclonus syndrome and ataxia (suspected paraneoplastic causes, 1.3% of cases), and hypertension (catecholamine secretion or renal artery compression, 1.3% of cases).

[0017] reason

[0018] The cause of neuroblastoma is not fully understood. The vast majority of cases are sporadic and non-familial. About 1-2% of cases occur in families and have been associated with specific gene mutations. In some cases, familial neuroblastoma 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 disease and Berkeley-Wiedemann syndrome.

[0019] Amplification of the MYCN oncogene within tumors is a common finding in neuroblastoma. The degree of amplification shows a bimodal distribution: 3- to 10-fold or 100- to 300-fold. The presence of this mutation is highly correlated with advanced disease (Ref. 1).

[0020] Repeated segments of the LMO1 gene within neuroblastoma tumor cells have been shown to increase the risk of developing an aggressive form of the cancer (Ref. 2).

[0021] Neuroblastoma has been associated with copy number variations within the NBPF10 gene, resulting in either lq21.1 deletion syndrome or lq21.1 duplication syndrome (Ref. 3).

[0022] Several risk factors for neuroblastoma have been proposed and are the subject of ongoing research. Due to the characteristic early onset of neuroblastoma, many studies have focused on parental factors related to conception and pregnancy. Factors investigated have included occupation (i.e., exposure to chemicals in specific industries), smoking, alcohol consumption, use of medical drugs during pregnancy, and reproductive factors, but the results have been inconclusive (Reference 4).

[0023] Other studies have examined possible links with atopy and early-life exposure to infections (Ref. 5), use of hormones and fertility drugs (Ref. 6), and maternal use of hair dyes (Ref. 7).

[0024] Biochemistry

[0025] In approximately 90% of neuroblastoma cases, elevated levels of catecholamines or their metabolites are found in the urine or blood. Catecholamines and their metabolites include dopamine, homovanillic acid (HVA) and / or vanillylmandelic acid (VMA) (Ref. 8).

[0026] treat

[0027] Neuroblastoma is generally curable when lesions are localized. However, long-term survival of children older than 18 months with advanced disease is poor, even with aggressive multimodal oncologic therapy, such as intensive chemotherapy, surgery, radiation therapy, stem cell transplantation, use of the differentiation agent isotretinoin (also known as 13-cis retinoic acid), immunotherapy with anti-GD2, immunotherapy with anti-GD2 monoclonal antibody therapy, etc.

[0028] Biological and genetic features have been identified, which, when added to classical clinical staging, have allowed patients to be assigned to risk groups for planning treatment intensity. These criteria include the patient's age, the extent of disease spread, microscopic appearance and genetic features, including DNA ploidy and N-myc oncogene amplification (N-myc regulatory microRNA), and are used to classify patients into low-risk, medium-risk and high-risk disease states. Recent biological studies (COG ANBL00B1) analyzed 2687 neuroblastoma patients and determined a risk distribution spectrum: 37% of neuroblastoma case risk is low risk, 18% is medium risk, and 45% is high risk. There is some evidence that high-risk and low-risk types are caused by different mechanisms, and are not just two different expression levels of the same mechanism (reference 9).

[0029] The treatments for these different risk categories are very different.

[0030] Low-risk disease can often be observed without any treatment at all, or cured with surgery alone.

[0031] Intermediate-risk disease is treated with surgery and chemotherapy.

[0032] High-risk neuroblastoma is treated with intensive chemotherapy, surgery, radiation therapy, bone marrow / hematopoietic stem cell transplantation, biologic-based therapy with 13-cis retinoic acid (isotretinoin or isotretinoin), and antibody therapy usually administered with the cytokines GM-CSF and IL-2.

[0033] For current treatment, patients with low-risk and medium-risk neuroblastoma disease have excellent prognosis, wherein the cure rate is higher than 90% for low risk, and 70-90% for medium risk. In contrast, over the past two decades, the therapy for high-risk neuroblastoma has obtained only about 30% cure rate. The addition of antibody therapy has significantly improved the survival rate of high-risk neuroblastoma disease. In March 2009, an early analysis of the Children's Oncology Group (COG) study with 226 high-risk patients showed that two years after stem cell transplantation, 66% of the group randomly receiving chl4.18 antibody (with GM-CSF and IL-2) survived and were disease-free, compared to only 46% in the group not receiving the antibody. Randomization stopped, so all patients selected for the trial received antibody therapy (reference 10).

[0034] Chemotherapeutic agents used in combination have been found to be effective against neuroblastoma. Agents commonly used for induction and stem cell transplantation 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 induction, which have been found to be effective against relapsed disease.

[0035] The recent emphasis is to reduce the treatment for low-risk and medium-risk neuroblastoma patients while maintaining the survival rate at 90%. The study of 467 medium-risk patients selected in the clinical trial A3961 with the Children's Oncology Group part of the NIH study NCT00499616 from 1997 to 2005 confirmed the hypothesis that the treatment can be successfully reduced for this risk group. Those patients with favorable characteristics (tumor grade and response) receive four cycles of chemotherapy, and those patients with unfavorable characteristics receive eight cycles, wherein three years of event-free survival and overall survival are stable at 90% for the entire group. Future plans are to strengthen the treatment of those patients with 1p36 or 11q23 chromosome aberrations and those patients who lack early treatment responses to treatment (references 11, 12).

[0036] In contrast, the past 20 years or more have focused on intensifying the treatment for patients with high-risk neuroblastoma. Chemotherapy-induced mutations, timing of surgery, stem cell transplantation regimens, various radiation delivery regimens, and the use of monoclonal antibodies and retinoids to treat minimal residual disease continue to be examined. Recent phase III clinical trials with randomization have been conducted to improve survival in high-risk disease:

[0037] 1982-1985: The European Neuroblastoma Study Group (ENSG1) enrolled 167 children and randomized to melphalan autologous bone marrow transplantation or no further therapy (no radiation therapy was given to any of the children). The transplant and non-transplant groups each had 65 patients, and a recent long-term follow-up report revealed significantly better 5-year event-free survival for stage 4 neuroblastoma in the melphalan transplant group versus no further treatment at an age of more than 1 year: 33% versus 17%, respectively (Ref. 13).

[0038] 1990-1999: A European study (EU-20592 or CCLGNB-1990-11) randomized 262 high-risk children over 1 year old and revealed higher survival with rapid sequence induction (10-day cycles) versus standard induction (21-day cycles) with the same total dose. The 10-year event-free survival was 27% and 18%, respectively, using a non-aggressive surgical approach, no radiation therapy, and autologous bone marrow or stem cell transplantation with melphalan alone for both groups (Ref. 14).

[0039] 1991-1996: Two sequential randomized Phase III trials of 379 high-risk neuroblastoma patients were conducted by the Children's Cancer Group (CCG-3891), which demonstrated improved survival with myeloablative therapy (using total body irradiation) and 13-cis retinoic acid (isotretinoin), with 50 patients in each of the four arms of the study (Ref. 15).

[0040] · 1996-2003: German (GPOH) study NB97 compared the outcome of 295 high-risk neuroblastoma patients randomized for stem cell transplantation or consolidation chemotherapy. Results showed increased survival with stem cell transplantation (Ref. 16).

[0041] 2000-2006: A recent study (COG-A3973) questioned the need for stem cell ablation for CEM-LI (carboplatin, etoposide, melphalan, with local irradiation) transplantation and 486 patients were enrolled in the study. Stem cell ablation was not found to improve survival (Ref. 17).

[0042] 2000-2012: A concurrent study (COG-ANBL0032) determined in early review that antibody chl4.18 with interleukin 2 and GMCSF (retrospective study at lower doses and without cytokines in German GPOH NB90 and NB 97) improved survival, with a total of 423 patients. A subsequent Phase III study, COG-ANBL0931, opened in January 2010 to accrue 105 patients to collect further safety and efficacy data for FDA approval (reference 18).

[0043] 2002-2008: SIOP (International Society of Paediatric Oncology) established the European SIOP Neuroblastoma Group (SIOPEN) in 1994, and activated the Phase III high-risk neuroblastoma protocol (SIOP-EUROPE-HR-NBL-1) in 2002, which used "fast" COJEC (8 cycles of chemotherapy given at 10-day intervals), followed by transplantation randomized to CEM (carboplatin, etoposide, melphalan) or BuMel (busulfan, melphalan), and amended the study to randomize children to chl4.18 antibody treatment with or without subcutaneous IL2 (without GM-CSF as given in COG). The study reported the benefits of growth factors (GCSF), and all patients received retinoic acid. The trial involved 1000 patients (175 per year) (Reference 18).

[0044] 2005-2010: The German NB2004 randomization included MIBG therapy and topotecan use in upfront treatment and involved a total of 642 patients for all risk groups (roughly half were high risk). After transplantation, the high-risk regimen involved 6 months of cis-retinoic acid, 3 months of rest in between, and another 3 months of retinoic acid (Ref. 19).

[0045] • 2007: The COG phase III ANBL0532 trial opened in December 2007 to accrue 495 patients and compared single versus tandem transplantation and started with two cycles of induction with topotecan (Ref. 20).

[0046] In addition to these phase III studies, some research institutions also provide experimental treatment programs. For example, St.Jude completed (2007) testing a new upfront chemotherapy program in 23 children, which included irinotecan and gefitinib, with 16 months of maintenance chemotherapy after stem cell transplantation, using alternating oral 13-cis retinoic acid and topotecan. Memorial Sloan-Kettering Cancer Center in New York provides treatment including the mouse-derived monoclonal antibody 3F8 used in the program since the mid-1980s. The antibody is used to treat minimal residual disease or consolidation instead of stem cell transplantation. The new experimental program COG-ANBL09P1 available for newly diagnosed (high-risk) children in several Children's Oncology Group (COG) centers provides MIBG radiotherapy and chemotherapy for transplantation programs (reference 21).

[0047] Some children (especially in high-risk cases) do not respond to first-line treatment at all (with a complete response or a very good partial response) and are labeled refractory. These "refractory" children are removed from first-line therapy (clinical trials) and are eligible for clinical trials using new therapies. Many high-risk children have a good response to first-line therapy and achieve remission, but later the disease recurs (relapses). These children are also eligible for new therapies tested in clinical trials.

[0048] Chemotherapy with topotecan and cyclophosphamide is often used in the refractory setting and after relapse. A randomized study (2004) with 119 patients comparing topotecan alone with topotecan and cyclophosphamide revealed a complete or partial response rate of 31% in the topotecan and cyclophosphamide group, with a two-year progression-free survival of 36%. Irinotecan (intravenous or oral) and oral temozolomide are also used for refractory and recurrent neuroblastoma (Ref. 22).

[0049] Many Phase I and Phase II trials are currently testing new agents for neuroblastoma in children who have relapsed or are resistant to initial therapy. Investigators are currently studying new agents alone and in new combinations, using small molecule targeted therapies, 131-I MIBG radiation therapy, angiogenic agents, new monoclonal antibodies, vaccines, oncolytic viruses, and new myeloablative regimens.

[0050] A group of 16 children's hospitals in the United States, called the New Advances in Neuroblastoma Therapy (NANT) consortium, coordinates trials of I-131MIBG radiation therapy. The NANT consortium also provides trials using oral powder formulations of fenretinide, intravenous fenretinide, bisphosphonates (Zometa) and other agents, and combining I-131MIBG with the inhibitor vorinostat (reference 23).

[0051] Other research groups, such as the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC), are also conducting clinical trials to treat relapsed neuroblastoma. European institutions are studying new treatments for relapse, including haploidentical stem cell transplantation. Many hospitals are also conducting their own institutional studies.

[0052] 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 could slow tumor growth. In the study, Tom Van Maerken, a doctor at Ghent University Hospital in Belgium, and colleagues used nutlin-3 to neutralize MDM2, a protein that binds to the p53 protein and hinders p53's ability to trigger programmed cell death. Earlier studies had shown that nutlin-3 could specifically prevent MDM2 from disabling p53. Summary of the invention

[0053] Purpose of the Invention

[0054] The drug taurolidine has been observed to have the ability to enhance the activity of many oncology drugs.

[0055] Therefore, one object of the present invention is to exploit the synergistic effects of taurolidine on these oncology drugs in order to allow for greater efficacy and reduced toxicity associated with oncology drugs.

[0056] Another object of the present invention is to produce nanoparticles comprising one or more oncology drugs and taurolidine, with or without additional excipients (e.g., a buffer to provide enhanced hydrolytic stability of taurolidine and / or one or more oncology drugs and taurolidine), thereby providing simultaneous delivery of one or more oncology drugs and taurolidine, thereby utilizing the synergistic effects of taurolidine on these oncology drugs.

[0057] Another object of the present invention is to produce nanoparticles comprising one or more oncology drugs and taurolidine, with or without additional excipients (e.g., buffers, to provide enhanced hydrolytic stability of taurolidine and / or one or more oncology drugs and taurolidine), and further comprising a coating, the coating being configured to locally release the one or more oncology drugs and taurolidine to a cancer site, such as a tumor. In a preferred form of the present invention, the coating is configured to prevent the one or more oncology drugs and taurolidine from being prematurely exposed to the body prior to delivery to a cancer site, such as a tumor. This is important for preventing undesirable side effects from one or more oncology drugs, premature hydrolysis of taurolidine, and the like. In a preferred form of the present invention, the coating comprises an absorbable polymer or lipid.

[0058] Yet another object of the present invention is to provide nanoparticles comprising one or more oncology drugs and taurolidine, with or without additional excipients (e.g., buffers, to provide enhanced hydrolytic stability of taurolidine and / or one or more oncology drugs and taurolidine), and further comprising a coating, wherein the coating is configured to target the nanoparticles to the site of cancer (e.g., a tumor) to improve the efficacy of the oncology drug and taurolidine for treating cancer. In a preferred form of the present invention, the coating comprises a binding molecule configured to target the nanoparticles to a specific tissue.

[0059] Additionally, another object of the present invention is to provide nanoparticles specifically configured for the treatment of neuroblastoma and / or other specific cancers. Specific implementation plan

[0060] Taurolidine in general

[0061] Taurolidine (bis(1,1-dioxoperhydro-1,2,4-thiadiazin-4)-methane) has antimicrobial and anti-lipopolysaccharide properties. It is derived from the amino acid taurine. Its immunomodulatory effects are reported to be mediated through the priming and activation of macrophages and polymorphonuclear leukocytes.

[0062] Taurolidine has been used to treat patients with peritonitis, and as an anti-endotoxin agent in patients with systemic inflammatory response syndrome. It is a life-saving antimicrobial for severe abdominal sepsis and peritonitis. Taurolidine is active against a wide range of microorganisms, including gram-positive bacteria, gram-negative bacteria, fungi, mycobacteria, and bacteria resistant to various antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-sensitive Staphylococcus aureus (VISA), vancomycin-resistant Staphylococcus aureus (VRSA), oxacillin-resistant Staphylococcus aureus (ORSA), and vancomycin-resistant Enterococcus (VRE). In addition, taurolidine exhibits some antitumor properties, wherein positive results are seen in early clinical studies using the drug to treat gastrointestinal malignancies and central nervous system tumors.

[0063] Taurolidine is the active ingredient in antimicrobial lock solutions used to prevent and treat catheter-related bloodstream infections (CRBSIs) and is indicated for all catheter-based vascular access devices. Bacterial resistance to taurolidine has never been observed in various studies.

[0064] Taurolidine works by non-selective chemical reactions. In aqueous solution, the parent molecule taurolidine forms an equilibrium with taurultam and N-hydroxymethyl taurultam, and taurinamide is a downstream derivative. The active group of taurolidine is an N-hydroxymethyl derivative of taurultam and taurinamide, which reacts with primary amino groups of bacterial cell walls, cell membranes and proteins, as well as endotoxins and exotoxins. Microorganisms are killed and the toxins produced are inactivated; the destruction time is 30 minutes in vitro. When taurolidine is used as a catheter sealing fluid, proinflammatory cytokines and enhanced tumor necrosis factor (TNF) levels are reduced.

[0065] Taurolidine reduces the adhesion of bacteria and fungi to host cells by disrupting pili and flagella and thus preventing biofilm formation.

[0066] Doses of 5 g of taurolidine were given intravenously over 2 hours every 4 hours for at least 48 hours for the treatment of various septic conditions.

[0067] Synergistic activity of taurolidine has been observed in the following applications involving the use of oncology drugs:

[0068] Karlisch et al. (reference 24) observed the effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine on apoptosis and proliferation in human rhabdomyosarcoma, leiomyosarcoma and epithelioid cell sarcoma. Soft tissue sarcoma (STS) is a heterogeneous group of malignant tumors, representing 1% of all malignant tumors in adults. Therapy for STS should be individualized and multimodal, but complete surgical resection with clear margins remains the mainstay of treatment. Disseminated soft tissue sarcoma still represents a treatment dilemma. Commonly used chemotherapeutic agents such as doxorubicin and ifosfamide have been shown to be effective in less than 30% of these cases. Therefore, Karlisch et al. tested the apoptosis and antiproliferative effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine on rhabdomyosarcoma (A-204), leiomyosarcoma (SK-LMS-1) and epithelioid cell sarcoma (VA-ES-BJ) cell lines in vitro. Viability, apoptosis and necrosis were quantified by FACS analysis (propidium iodide / annexin V staining). Gene expression was analyzed by DNA microarray, and the results were verified by rtPCR for selected genes. Protein level changes 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 proliferation reduction in rhabdomyosarcoma and epithelioid cell sarcoma cells. The combined use of TRAIL and taurolidine resulted in a synergistic apoptotic effect in all three cell lines, especially in rhabdomyosarcoma cells, leaving 18% of viable cells after incubation for 48 hours (p<0.05). Analysis of differentially regulated genes revealed that taurolidine and TRAIL affect apoptotic pathways, including mitochondrial pathways associated with TNF-receptors. Microarray analysis revealed significant expression changes in various genes, which are involved in different apoptotic pathways and crosstalk with other pathways at multiple levels. This in vitro study confirmed that TRAIL and taurolidine synergistically induce apoptosis and inhibit proliferation in different human STS cell lines. The effect on gene expression is correspondingly different in sarcoma entities. These results provide experimental support for in vivo trials to evaluate the effects of TRAIL and taurolidine in STS and sustain an approach to individualized treatment.

[0069] 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 still represents a therapeutic dilemma due to the lack of effective cytostatic agents. Therefore, it was observed that tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and taurolidine, in combination with confirmed and new chemotherapeutic agents for human fibrosarcoma (HT1080), improved apoptosis.

[0070] Materials and Methods: Human fibrosarcoma cells (HT1080) were incubated with doxorubicin, mafosfamide and trabectedin alone and in combination with taurolidine and TRAIL. Live cells, apoptotic cells and necrotic cells were quantified using flow cytometry analysis. Cell proliferation was analyzed using bromodeoxyuridine (BrdU) ELISA assay.

[0071] Results: Single application of doxorubicin and trabectedin induced apoptotic cell death and significantly reduced proliferation of HT1080 cells. In combination therapy, the addition of taurolidine and TRAIL resulted in a stronger reduction in the extent of cell viability when compared to single therapy. Trabectedin and taurolidine showed greater potential for inhibiting proliferation than doxorubicin alone.

[0072] Conclusions: Treatment with doxorubicin and taurolidine exhibited stronger apoptosis-inducing and anti-proliferative effects when used in combination with TRAIL and taurolidine.

[0073] Martinotti et al. (reference 26) studied the in vitro screening of synergistic ascorbate-drug combinations for the treatment of malignant mesothelioma. Malignant mesothelioma (MMe) is a lethal tumor of the mesothelium of the serous cavity due to exposure to asbestos. Current clinical studies consist of combined treatments, but effective therapies have not yet been established, and there is an urgent need for new treatment methods. Ascorbic acid is a nutrient that is also known as a drug in cancer treatment. In this study, Martinotti et al. tested the cytotoxicity of ascorbate combined with drugs used in MMe therapy (e.g., cisplatin, etoposide, gemcitabine, imatinib, paclitaxel, and raltitrexed), as well as promising antitumor compounds (such as taurolidine, a-tocopherol succinate, and epigallocatechin-3-gallate (EGCG)) to MMe cells. The dose-response curve obtained for each compound was determined by applying neutral red uptake (NRU) to MMe cells grown in vitro, allowing IC50 values ​​to be measured for each compound used alone. Thereafter, by analyzing the NRU data obtained from each ascorbic acid / drug combination in the isobologram (Tallarida, 2000) of Tallarida under IC50 level, the synergistic interaction about ascorbic acid / gemcitabine and ascorbic acid / EGCG was revealed.By using the combination index of Chou and Talalay (Chou and Talalay, 1984), by theoretical additivity IC50 and the IC50 observed from the fixed ratio dose-response curve, and the comparison of the IC level across a wide range, these results were further confirmed.By using caspase 3 and lactate dehydrogenase assays to check apoptosis and necrosis rate, synergistic interaction was also shown.Therefore, data indicate that ascorbic acid / gemcitabine and ascorbic acid / EGCG show the synergistic influence on MMe cell viability, and prompt their possible use in the clinical treatment of this problematic cancer.

[0074] Daigeler et al. (reference 27) observed the synergistic apoptotic effect of taurolidine and TRAIL on esophageal squamous cell carcinoma cells. The treatment option for esophageal cancer is to consider surgical resection, but the median survival rate at 20 months after treatment is discouraging. The benefits of adjuvant or neoadjuvant radiotherapy or chemotherapy are limited, and so far, only the benefits for certain tumor stages have been determined. Therefore, new treatment options are needed. As an alternative chemotherapeutic drug, 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 shown by TUNEL determination and quantified by FACS analysis. Gene expression was analyzed by RNA microarray. The most effective concentration of taurolidine as a single substance (250mmol / l) induced apoptosis to a maximum of 40% after a 12-hour dose, leaving 4% of viable cells after 48 hours; in contrast, rhTRAIL had no significant effect. The combination of two substances doubled the effect of taurolidine alone. Gene expression profile analysis revealed that taurolidine down-regulated endogenous TRAIL, TNFRSF1A, TRADD, TNFRSF1B, TNFRSF21 and FADD, as well as MAP2K4, JAK2 and Bcl2, Bcl211, APAF1 and caspase-3. TNFRSF25, cytochrome-c, caspase-1, -8, -9, JUN, GADD45A and NFKBIA were up-regulated. TRAIL reduced endogenous TRAIL, Bcl211 and caspase-1 expression. BIRC2, BIRC3, TNFAIP3 and NFKBIA were up-regulated. The combined substances up-regulated endogenous TRAIL, NFKBIA and JUN, while DFFA and TRAF3 were down-regulated compared to taurolidine as a single substance. Daigeler et al. concluded that taurolidine overcame TRAIL resistance in KYSE270 cells. Synergy depends on the same and different apoptotic pathways, which trigger together, resulting in amplified responses. Several apoptotic pathways, including TNF-receptor related and mitochondrial pathways, are differentially regulated at the gene expression level by the substance. Other transcription factors appear to be affected, particularly NFKB. The combination of the substances increases endogenous TRAIL expression, while each single substance reduces it. Considering that nontoxic taurolidine can reduce the toxicity and dosage of rhTRAIL, a combination therapy with taurolidine and rhTRAIL can provide a new option for the treatment of esophageal cancer.

[0075] Chromik et al. (reference 28) observed the synergistic effect of taurolidine and rhTRAIL for apoptosis induction in HCT15 colon cancer cells. Inducing apoptosis by TRAIL (TNF-related apoptosis-inducing ligand) in tumor cells is a promising treatment option in oncology, although toxicity and resistance to TRAIL are limiting factors. Taurolidine is an antitumor agent with low toxicity, and is therefore a potential candidate for combined therapy with TRAIL. The target of Chromik et al.'s research is to evaluate the combined treatment of TRAIL and taurolidine in HCT15 human colon cancer cell lines. HCT15 cells are cultured and incubated with increasing concentrations of recombinant human TRAIL (50 to 500ng / mL) or taurolidine (50 to 1000mmol / l) to evaluate the dose-dependent effects of two substances on apoptosis and necrosis. Thereafter, in a second experiment, cells are incubated with single TRAIL (50 and 250ng / mL) or taurolidine (100 and 1000mmol / l) and with a combination of two agents at different concentrations. At different time points (3 to 36 hours), quantitative cell viability, apoptosis and necrosis were analyzed by FACS analysis with propidium iodide and annexin V staining. The results are expressed as mean values, statistically analyzed by ANOVA, and paired comparisons were performed by Tukey's test. P value < 0.05 is considered statistically significant. Incubation with taurolidine causes dose-dependent cell death induction, wherein 100mmol / l and 1000mmol / l have maximum effects after 24 hours and 36 hours, causing viable cells to be reduced to 17-33% from 60%. 250Ng / mL and 500ng / mL TRAIL cause viable cells to be reduced to 6-7% from 70% as early as 6 hours, and viable cells partially recover to 13% after 36 hours. The combined treatment of taurolidine (100mmol / l) and TRAIL (50ng / mL) causes the continuous induction of apoptosis after 24 hours and 36 hours, showing the significant synergistic effect of the two substances, which obviously exceeds the simple additive effect. After 24 hours of incubation with taurolidine (100mmol / l) and TRAIL (50ng / mL), only 2.1% of the cells were alive, compared to 43.9% for taurolidine 100mmol / l alone and 17.7% for TRAIL 50ng / mL. Similar results were obtained after 36 hours. Chromik et al. first showed a synergistic effect of recombinant human TRAIL and taurolidine on apoptosis induction of human colon cancer cells in vitro. Combination treatment with TRAIL and taurolidine resulted in sustained cell death, which was superior to single agent application. The combination of TRAIL and non-toxic taurolidine provides a new therapeutic principle in tumor therapy.

[0076] Braumann et al. (reference 29) observed local and systemic chemotherapy using taurolidine and taurolidine / heparin in rats with colon cancer undergoing laparotomy. Experimental studies in the treatment of malignant abdominal tumors have shown that different cytotoxic agents suppress intraperitoneal (ip) tumor growth. However, there is no generally accepted method for preventing tumor recurrence. After subcutaneous (sc) and ip injection of 104 colon adenocarcinoma cells (DHD / K12 / TRb), the effects of taurolidine or taurolidine / heparin on ip and sc tumor growth were investigated in 105 rats undergoing midline laparotomy. Animals were randomly divided into 7 groups and operated within 30 minutes. In order to investigate the ip (local) effects of taurolidine or heparin on tumor growth, the substances were applied. Ip systemic and ip effects were evaluated after iv injection of the substances. Two application forms were also combined to analyze synergistic effects. Tumor weight and the incidence of abdominal wound metastasis were measured 4 weeks after intervention. In order to evaluate the effect of the reagent, blood was collected to determine the peripheral leukocyte count. IP tumor growth was significantly reduced in rats receiving ip application of taurolidine (median 7.0 mg, P=0.05) and taurolidine / heparin (median 0 mg, P=0.02) when compared to the control group (median 185 mg). Simultaneous instillation of both agents also reduced ip tumor growth (median 4 mg, P=0.04), while iv injection of the substances did not cause local effects. In contrast, sc tumor growth was not different in all groups. Abdominal wound recurrence was rare and not different in all groups. Independent of the agent and form of application, the surgery itself caused a mild leukopenia shortly after surgery, as well as leukocytosis during the subsequent process. Taurolidine or ip therapy in combination with heparin inhibited local tumor growth and abdominal wound recurrence in rats undergoing midline laparotomy. Neither ip or iv application nor the combination of both agents affected sc tumor growth. These substances did not alter the changes in peripheral blood leukocytes.

[0077] Stendel et al. (reference 30) observed that taurolidine enhanced Fas ligand-mediated programmed cell death. Taurolidine was found to have direct and selective antitumor effects on brain tumor cells. The ability of taurolidine to exert antitumor effects by enhancing Fas-mediated apoptosis in different malignant glioma cell lines was investigated.

[0078] Materials and methods: U373 cells of human origin were cultured and incubated with taurolidine, and the median inhibitory concentration (IC50) was calculated. Flow cytometry analysis was performed to evaluate the changes in DNA content. Optical microscopy and electron microscopy were used to examine cells qualitatively and quantitatively. In the absence or presence of Fas ligand, taurolidine or their respective combinations, LN-18 and LN-229 cells were incubated. Cell viability was determined by adding double concentrated WST-1 reagent. The activity of mitochondrial succinate reductase was measured in an ELISA reader.

[0079] Results: 0373 cells were exposed to taurolidine resulting in a concentration-dependent (IC50 35.8+2.2mg / mL) loss of cell viability. Flow cytometry analysis confirmed the concentration-dependent appearance of DNA fragmentation in the sub-G0 / G1 region. In the presence of 6.25% by volume of Fas ligand, LN-18 cells showed more than 90% loss of cell viability, while the viability of LN-229 cells was reduced only at higher concentrations of Fas ligand. Within the concentration range investigated, taurolidine alone did not significantly affect the viability of LN-18 cells, but was able to enhance the effect of Fas ligand on LN-18 cells. At the highest concentration tested, LN-229 cells were exposed to taurolidine alone resulting in a considerable loss of approximately 70% cell viability. In the presence of taurolidine, cell destruction by Fas ligand (10% by volume) was enhanced.

[0080] Conclusion: The antitumor activity of taurolidine appears to be based in part on the enhancement of Fas ligand-induced apoptosis. In addition, taurolidine was shown to have antitumor effects that are independent of Fas ligand. It is possible that taurolidine exerts its antitumor activity based on different mechanisms.

[0081] In another study, Braumann et al. (reference 31) evaluated the effects of intraperitoneal and systemic application of taurolidine and taurolidine / heparin on intraperitoneal (ip) and subcutaneous (sc) tumor growth in rats during laparoscopy. The researchers investigated the problem and possible pathological mechanisms of portal metastasis after laparoscopic resection of malignant tumors. There is no generally accepted method to prevent the implantation of these tumors so far. After sc and ip injection of 104 colon adenocarcinoma cells (DHD / K12 / TRb), the effects of taurolidine or taurolidine / heparin on ip and sc tumor growth were investigated in 105 rats undergoing laparoscopy with carbon dioxide. The animals were then randomly divided into seven groups. Carbon dioxide was used to establish pneumoperitoneum for 30 minutes (8 mmHg). Three incisions were used: the midline for the insufflation needle, and the right and left entrances of the lower abdomen for the trocar. In order to investigate the ip (local) effects of taurolidine and heparin on tumor growth, these substances were instilled ip. When the substance is applied iv, systemic effects are expected. When the two forms of application are combined, the synergistic effect is tested. The number and weight of tumors, as well as the incidence of metastases in the abdominal wall and hilar sites, were determined 4 weeks after intervention. Blood was collected to evaluate the effects of taurolidine and heparin on systemic immune responses: 7 days before laparoscopy, 2 hours, 2 days, 7 days and 4 weeks after surgery, and peripheral lymphocytes were determined. When compared with the control group (52 mg), the ip tumor weight in rats that received taurolidine (median 7 mg) and taurolidine / heparin (0 mg) ip was significantly reduced (P=0.001). There was no difference in sc tumor growth between the groups (P=0.4). Compared with the control group (10 / 15), when taurolidine ip (3 / 15), ipiv (4 / 15) and combined with heparin ip (4 / 15) were applied, the trocar recurrence rate was reduced. Shortly after the intervention, the treated and untreated groups showed a decrease in peripheral lymphocytes. IP treatment with taurolidine and a combination of 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 intervention induced lymphopenia, which was compensated the next day.

[0082] Monson et al. (reference 32) observed that taurolidine inhibited tumor necrosis factor (TNF) toxicity, as well as evidence of synergistic effects of TNF and endotoxin. The use of recombinant tumor necrosis factor (TNF) in the treatment of solid tumors has been limited by life-threatening toxicity. In addition, TNF may be the primary mediator of endotoxin effects. Recent evidence suggests that synergy between endotoxin (at picogram levels) and TNF may contribute to this toxicity. The use of the anti-endotoxin taurolidine may reduce TNF toxicity by interfering with this synergy. C57 / BL6 mice (n=140) received a toxic dose (12 micrograms / mouse IV) of TNF. Four groups were studied. Group A received taurolidine (200 mg / kg IV) 30 minutes before TNF, Group B received TNF followed by taurolidine (200 mg / kg IV) 30 minutes later, Group C received the same volume (0.5 ml) of saline 30 minutes before TNF, and Group D received taurolidine (200 mg / kg IP) 45 minutes before TNF. The mortality rate of those mice that received intravenous taurolidine 30 minutes before TNF was 8.8%. This was significantly lower (P<0.005) than the mortality rate achieved in Groups B, C, and D (33% vs. 39.4% vs. 50%). Further experiments using MTT (3-(4,5-dimethylthiazolyl-2-microliter)-2,5-diphenyltetrazolium bromide) assays showed that this was not due to a direct interaction of taurolidine with TNF, but was likely due to a synergistic effect of interfering endotoxin and TNF.

[0083] Combination therapy studies in a mouse model also demonstrated that taurolidine did not reduce the antitumor efficacy of TNF against the TNF-sensitive mouse fibrosarcoma cell line Meth-A sarcoma.

[0084] Synergistic activity of taurolidine with drugs used to treat neuroblastoma

[0085] Eschenburg et al. (reference 33) observed that taurolidine cooperates with antitumor drugs in neuroblastoma cells. In neuroblastoma, the outcome of stage 4 disease remains poor, and there is therefore an urgent need to develop new treatments. Taurolidine, which is known to inhibit catheter infection, has shown antitumor activity in various cancers. As recently demonstrated, the growth of neuroblastoma cell lines is inhibited by taurolidine. Further analysis revealed a significant negative growth 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 hours) is valuable and corresponds to clinically achievable plasma levels. Apoptosis is induced in a time-dependent manner mediated by simultaneous activation of intrinsic and extrinsic pathways (76-86%; 48 hours). This is confirmed by cleavage of caspase-3, -8, and -9 and abolition of apoptosis by pan-caspase inhibition. The use of taurolidine resulted in a significant potentiation of the cytotoxic drugs vincristine / doxorubicin (2 / 3 of 4 cell lines), making taurolidine a promising candidate to be included in future neuroblastoma treatment regimens.

[0086] Eschenburg et al. (reference 33) also observed that taurolidine specifically inhibited the growth of neuroblastoma cell lines in vitro. The anti-tumor properties of taurolidine have been demonstrated on various human cancer cells. However, data on neuroblastoma are lacking. Therefore, Eschenburg et al. attempted to evaluate the effect of taurolidine on the growth of neuroblastoma cell lines.

[0087] Materials and Methods: Neuroblastoma SK-N-BE(2)-M17 and SK-NSH cells and non-malignant human umbilical vein endothelial cells (as a control) were incubated with increasing concentrations of taurolidine (100, 250, 500 mM). Cell growth was examined after 12, 24 and 48 hours of exposure.

[0088] Results: Cell growth inhibition by taurolidine was observed in both malignant cell lines. Neuroblastoma cell lines were significantly more sensitive to taurolidine when compared to human umbilical vein endothelial cells.

[0089] Conclusions: The highly unique negative effects on cell growth observed in SK-N-BE(2)-M17 and SK-N-SH illustrate a specific mode of action of taurolidine that appears to depend on differences at the cellular and molecular levels. Further investigation is warranted to evaluate its mechanism and possible clinical use. SUMMARY OF THE INVENTION

[0091] The present invention utilizes the synergistic properties of taurolidine with various tumor drugs. More specifically, the present invention includes the provision and use of nanoparticles, which contain one or more tumor drugs and taurolidine, with or without additional excipients (e.g., buffers, to provide enhanced hydrolytic stability of taurolidine and / or the one or more tumor drugs and taurolidine), thereby providing simultaneous delivery of the one or more tumor drugs and taurolidine, thereby utilizing the synergistic effect of taurolidine on these tumor drugs.

[0092] In a preferred form of the invention, the nanoparticles comprise one or more oncology drugs and taurolidine, with or without additional excipients (e.g., buffers, to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncology drugs and taurolidine), and further comprise a coating configured to locally release the one or more oncology drugs and taurolidine to a cancer site, such as a tumor. In a preferred form of the invention, the coating is configured to prevent the one or more oncology drugs and taurolidine from being prematurely exposed to the body before being delivered to a cancer site (e.g., a tumor). This is important for preventing undesirable side effects from the one or more oncology drugs, premature hydrolysis of taurolidine, and the like. In a preferred form of the invention, the coating comprises an absorbable polymer or lipid.

[0093] In addition, in a preferred form of the invention, the nanoparticles comprise one or more oncology drugs and taurolidine, with or without additional excipients (e.g., buffers, to provide enhanced hydrolytic stability of taurolidine and / or one or more oncology drugs and taurolidine), and further comprise a coating, wherein the coating is configured to target the nanoparticles to the site of cancer (e.g., tumor) to improve the efficacy of the one or more oncology drugs and taurolidine for treating cancer. In a preferred form of the invention, the coating comprises a binding molecule configured to target the nanoparticles to specific tissues.

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

[0095] In one preferred form of the invention, there is provided a therapeutic nanoparticle comprising:

[0096] at least one oncology drug; and taurolidine,

[0097] Thereby, simultaneous delivery of the at least one oncology drug and taurolidine is provided, thereby taking advantage of the synergistic effect of taurolidine on the at least one oncology drug.

[0098] In another preferred form of the present invention, there is provided a method for treating cancer, the method comprising:

[0099] Provided are therapeutic nanoparticles comprising:

[0100] at least one oncology drug; and taurolidine; and

[0101] The therapeutic nanoparticles are delivered to the body so as to provide simultaneous delivery of the at least one oncology drug and taurolidine, thereby taking advantage of the synergistic effect of taurolidine on the at least one oncology drug.

[0102] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0103] The present invention utilizes the synergistic properties of taurolidine with various tumor drugs. More specifically, the present invention includes the provision and use of nanoparticles, which contain one or more tumor drugs and taurolidine, with or without additional excipients (e.g., buffers, to provide enhanced hydrolytic stability of taurolidine and / or the one or more tumor drugs and taurolidine), thereby providing simultaneous delivery of the one or more tumor drugs and taurolidine, thereby utilizing the synergistic effect of taurolidine on these tumor drugs.

[0104] In a preferred form of the invention, the nanoparticles comprise one or more oncology drugs and taurolidine, with or without additional excipients (e.g., buffers, to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncology drugs and taurolidine), and further comprise a coating configured to locally release the one or more oncology drugs and taurolidine to a cancer site, such as a tumor. In a preferred form of the invention, the coating is configured to prevent the one or more oncology drugs and taurolidine from being prematurely exposed to the body before being delivered to a cancer site (e.g., a tumor). This is important for preventing undesirable side effects from the one or more oncology drugs, premature hydrolysis of taurolidine, and the like. In a preferred form of the invention, the coating comprises an absorbable polymer or lipid.

[0105] In addition, in a preferred form of the invention, the nanoparticles comprise one or more oncology drugs and taurolidine, with or without additional excipients (e.g., buffers, to provide enhanced hydrolytic stability of taurolidine and / or the one or more oncology drugs and taurolidine), and further comprise a coating, wherein the coating is configured to target the nanoparticles to the site of cancer (e.g., tumor) to improve the efficacy of the one or more oncology drugs and taurolidine for treating cancer. In a preferred form of the invention, the coating comprises a binding molecule configured to target the nanoparticles to specific tissues.

[0106] Additionally, in a preferred form of the invention, the nanoparticles are specifically configured for the treatment of neuroblastoma and / or other specific cancers.

[0107] More specifically, the present invention utilizes the synergistic properties of taurolidine and various tumor drugs by encapsulating taurolidine and various tumor drugs in a specific nanoparticle system, and the nanoparticle system is designed to locally release the tumor drugs and taurolidine to the cancer site, such as a tumor.

[0108] Many absorbable polymer systems can be used to optimize the release properties of tumor drugs and taurolidine, especially those produced by the combination of copolymers and multimers derived from polymers, which are constructed from l-lactide, glycolide, e-caprolactone, p-dioxanone and trimethylene carbonate. These can also be combined with glycols such as polyethylene glycol (PEG), which can be linear or multi-arm structures.

[0109] Optimization of systems containing taurolidine, tumor drugs, and polymers in nanoparticles resulted in improved treatments for cancer in general and neuroblastoma in particular.

[0110] In addition, studies have shown the activity of cannabinoids to neuroblastoma N-type calcium channels, glycine receptor channels and voltage-gated potassium channels. It is believed that each of these is specific for neural tissue, and it is not believed that it is present in reticuloendothelial system (RES) cells. Therefore, providing nanoparticles with binding molecules to target neural tissue (e.g., neuroblastoma N-type calcium channels, glycine receptor channels and voltage-gated potassium channels) enhances the targeted delivery of nanoparticles to neural tissue, and therefore enhances the effectiveness of tumor drugs (which is further enhanced by the presence of synergistic taurolidine).

[0111] Generally, it is important that the binding molecule of nanoparticle does not have other significant biological activities. In order to achieve specific binding without other significant biological activities, the fragment antigen binding (Fab) fragment of monoclonal antibody (it is the region bound to the antigen on the antibody) is utilized. However, because the syndrome of severe autoimmune encephalitis caused by anti-voltage-gated potassium channel antibodies has been described recently, it is preferred not to use anti-voltage-gated potassium channel antibodies (e.g., KvR) as targets. Other targets have also reported cases of autoimmune encephalitis as the cause of disease of paraneoplastic syndrome. So far, none of these targets is as serious as KvR disease, but this may be due to random chance. Therefore, the binding molecule for targeting neural tissue must be carefully selected.

[0112] In a preferred form of the invention, the coating for the nanoparticles comprises a monoclonal antibody against an N-type calcium channel (e.g., an anti-N-type calcium channel outer Fab fragment) for binding the nanoparticles to neural tissue (e.g., a neuroblastoma tumor) such that one or more tumor drugs and taurolidine (via targeted nanoparticles) are simultaneously delivered to the neural tissue, wherein taurolidine provides a synergistic effect for the one or more tumor drugs, thereby providing enhanced efficacy of the one or more tumor drugs against targeted neural tissue.

[0113] In a particularly preferred form of the invention, the anti-N-type calcium channel outer Fab fragment incorporated into the coating for the nanoparticles comprises Ca v 2.2 or its combined equivalent.

[0114] Therefore, in one form of the invention, nanoparticles containing cytotoxic chemotherapeutic drugs and synergistic taurolidine in an appropriate buffer are provided to provide enhanced hydrolytic stability of taurolidine and / or one or more tumor drugs and taurolidine. The surface of the nanoparticles is a lipid envelope or polymer that regulates the release properties of the chemotherapeutic drugs and synergistic taurolidine. The surface of the nanoparticles preferably includes binding molecules to target neural tissue.

[0115] It will be appreciated that the present invention provides nanoparticles that can be used to treat neuroblastoma in a patient, wherein the nanoparticles comprise a chemotherapeutic drug and a synergistic amount of taurolidine, wherein the chemotherapeutic drug and taurolidine are encapsulated in a polymer that modulates the release properties of the chemotherapeutic drug and taurolidine.

[0116] Modifications of the Preferred Embodiments

[0117] It should be understood that those skilled in the art may make numerous additional changes to the details, materials, steps, and arrangements of components described and illustrated herein to explain the essence of the present invention while remaining within the principles and scope of the present invention.

[0118] References

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Claims

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

2. The therapeutic nanoparticle according to claim 1, wherein the at least one tumor drug comprises TNF-related apoptosis-inducing ligand (TRAIL), Preferably, the therapeutic nanoparticles are configured to target at least one of soft tissue sarcoma, esophageal cancer, and colon cancer cells; and / or wherein the at least one tumor drug comprises recombinant human TNF-related apoptosis-inducing ligand (rhTRAIL), Preferably, wherein the therapeutic nanoparticles are configured to target at least one of esophageal cancer and colon cancer cells; and / or wherein the at least one tumor drug comprises Fas ligand, preferably, wherein the therapeutic nanoparticle is configured to target brain tumor cells; and / or wherein the at least one tumor drug comprises tumor necrosis factor (TNF), Preferably, wherein the therapeutic nanoparticle is configured to target solid tumor cancer; and / or wherein the at least one tumor drug comprises an anti-tumor drug, Preferably, wherein the therapeutic nanoparticles are configured to target neuroblastoma; and / or wherein the at least one tumor drug comprises a cytotoxic drug, Preferably, the cytotoxic drug comprises at least one of vincristine and doxorubicin, and / or Preferably, wherein the therapeutic nanoparticles are configured to target neuroblastoma; and / or wherein the therapeutic nanoparticle further comprises at least one excipient, Preferably, wherein said at least one excipient comprises a buffer so as to provide enhanced hydrolytic stability of said taurolidine and / or said at least one oncology drug and said taurolidine; and / or wherein the therapeutic nanoparticle further comprises a coating configured to locally release the at least one oncology drug and taurolidine to the cancer site, Preferably, the cancer site is a tumor, and / or Preferably, wherein the coating is configured to prevent premature exposure of the at least one oncology drug and taurolidine to the body prior to delivery to the cancer site, and / or Preferably, wherein the coating is configured to prevent at least one of undesirable side effects from the at least one oncology drug, and premature hydrolysis of the taurolidine and / or the at least one oncology drug and the taurolidine, and / or preferably, wherein the coating comprises at least one of an absorbable polymer and an absorbable lipid, More preferably, wherein the coating is produced from a combination of copolymers and multimers derived from a polymer constructed from at least one of l-lactide, glycolide, e-caprolactone, p-dioxanone and trimethylene carbonate, further preferably, wherein the coating further comprises a glycol, Still further preferably, wherein the diol comprises polyethylene glycol (PEG), Still further preferably, the diol comprises a linear or multi-arm structure, and / or Preferably, wherein the coating is configured to target the nanoparticles to a cancer site so as to improve the efficacy of the at least one oncology drug and taurolidine for treating the cancer, More preferably, wherein the coating comprises a binding molecule configured to target the delivery of the nanoparticle to a specific tissue, Further preferably, wherein the binding molecule comprises a fragment antigen binding (Fab) fragment of a monoclonal antibody, and / or further preferably, wherein the binding molecule is configured to target neural tissue, Still further preferably, the binding molecule is configured to target at least one of a neuroblastoma N-type calcium channel, a glycine receptor channel and a voltage-gated potassium channel, and / or Still further preferably, the targeted neural tissue comprises a neuroectodermal tumor, More preferably, the binding molecule binds to a neuroectodermal tumor expressing an N-type calcium channel, Still further preferably, wherein the binding molecule comprises an anti-N-type calcium channel Fab fragment, Still further preferably, the anti-N-type calcium channel outer Fab fragment comprises Ca v 2.2 or its equivalent in combination, and / or Further preferably, the binding molecule is embedded in or covalently bound to the surface of the nanoparticle.

3. A method for treating cancer, comprising: Provided is a therapeutic nanoparticle comprising; at least one oncology drug; and taurolidine; and The therapeutic nanoparticles are delivered to the body so as to provide simultaneous delivery of the at least one oncology drug and taurolidine, thereby taking advantage of the synergistic effect of taurolidine on the at least one oncology drug.

4. The method according to claim 3, wherein The at least one tumor drug comprises TNF-related apoptosis-inducing ligand (TRAIL), Preferably, the therapeutic nanoparticles are configured to target at least one of soft tissue sarcoma, esophageal cancer, and colon cancer cells; and / or wherein the at least one tumor drug comprises recombinant human TNF-related apoptosis-inducing ligand (rhTRAIL), Preferably, wherein the therapeutic nanoparticles are configured to target at least one of esophageal cancer and colon cancer cells; and / or wherein the at least one tumor drug comprises Fas ligand, Preferably, wherein the therapeutic nanoparticles are configured to target brain tumor cells; and / or wherein the at least one tumor drug comprises tumor necrosis factor (TNF), Preferably, wherein the therapeutic nanoparticle is configured to target solid tumor cancer; and / or wherein the at least one tumor drug comprises an anti-tumor drug, Preferably, wherein the therapeutic nanoparticles are configured to target neuroblastoma; and / or wherein the at least one tumor drug comprises a cytotoxic drug, Preferably, the cytotoxic drug comprises at least one of vincristine and doxorubicin, and / or Preferably, wherein the therapeutic nanoparticles are configured to target neuroblastoma; and / or wherein the therapeutic nanoparticle further comprises at least one excipient, Preferably, wherein said at least one excipient comprises a buffer so as to provide enhanced hydrolytic stability of said taurolidine and / or said at least one oncology drug and said taurolidine; and / or wherein the therapeutic nanoparticle further comprises a coating configured to locally release the at least one oncology drug and taurolidine to the cancer site, Preferably, the cancer site is a tumor, and / or Preferably, wherein the coating is configured to prevent premature exposure of the at least one oncology drug and taurolidine to the body prior to delivery to the cancer site, and / or Preferably, wherein the coating is configured to prevent at least one of undesirable side effects from the at least one oncology drug, and premature hydrolysis of the taurolidine and / or the at least one oncology drug and the taurolidine, and / or preferably, wherein the coating comprises at least one of an absorbable polymer and an absorbable lipid, More preferably, wherein the coating is produced from a combination of copolymers and multimers derived from a polymer constructed from at least one of l-lactide, glycolide, e-caprolactone, p-dioxanone and trimethylene carbonate, further preferably, wherein the coating further comprises a glycol, Still further preferably, wherein the diol comprises polyethylene glycol (PEG), Still further preferably, the diol comprises a linear or multi-arm structure, and / or Preferably, wherein the coating is configured to target the nanoparticles to a cancer site so as to improve the efficacy of the at least one oncology drug and taurolidine for treating the cancer, More preferably, wherein the coating comprises a binding molecule configured to target the delivery of the nanoparticle to a specific tissue, Further preferably, wherein the binding molecule comprises a fragment antigen binding (Fab) fragment of a monoclonal antibody, and / or further preferably, wherein the binding molecule is configured to target neural tissue, Still further preferably, the binding molecule is configured to target at least one of a neuroblastoma N-type calcium channel, a glycine receptor channel and a voltage-gated potassium channel, and / or Still further preferably, the targeted neural tissue comprises a neuroectodermal tumor, More preferably, the binding molecule binds to a neuroectodermal tumor expressing an N-type calcium channel, Still further preferably, wherein the binding molecule comprises an anti-N-type calcium channel Fab fragment, Still further preferably, the anti-N-type calcium channel outer Fab fragment comprises Ca v 2.2 or its equivalent in combination, and / or Further preferably, the binding molecule is embedded in or covalently bound to the surface of the nanoparticle.