WO2022108559A1 - A new drug carrier system for treatment of ovarian cancer which is resistant to platinum - Google Patents
A new drug carrier system for treatment of ovarian cancer which is resistant to platinum Download PDFInfo
- Publication number
- WO2022108559A1 WO2022108559A1 PCT/TR2021/051191 TR2021051191W WO2022108559A1 WO 2022108559 A1 WO2022108559 A1 WO 2022108559A1 TR 2021051191 W TR2021051191 W TR 2021051191W WO 2022108559 A1 WO2022108559 A1 WO 2022108559A1
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- WO
- WIPO (PCT)
- Prior art keywords
- carboplatin
- lipid
- drug carrier
- ovarian cancer
- treatment
- Prior art date
Links
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- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to nanotechnology-based alternative drug carrier systems in the treatment of cancer.
- Ovarian cancer is the 7th most common and the 8th most fatal type of cancer among women. All over the world, 240000 women are diagnosed with ovarian cancer every year, causing the death of 150000 women annually with a 5-year survival period of less than 45%. With ovarian cancer being less common in women under the age of 40, more than 90% of ovarian cancers seen over the age of 40 are epithelial tumors. The risk of disease increases with age. Even though ovarian cancer is one of the most susceptible tumors with a treatment respond rate of approximately 60-80%, even in advanced stages, it is still the most fatal gynecological cancer.
- cancer occurs in 3 types of tissues: epithelial tissue surrounding the egg, stromal cells responsible for hormone production, and germ cells. 90% of ovarian cancers are of epithelial origin whereas 10% are of germ and stromal cell origin.
- Epithelial ovarian cancer is classified in different ways such as high- and low-grade serous, mucinous, clear cell and endometrioid ovarian cancers localized in the intraperitoneal cavity with different morphologies and clinical appearances. Low-grade serous tumors develop slowly and are resistant to chemotherapy whereas high-grade serous ovarian cancers are cancers that spread rapidly to the peritoneal cavity but are sensitive to chemotherapy. Endometrioid and mucinous cancers are generally low-grade tumors and are limited in the ovaries.
- Treatment of ovarian cancer mainly consists of surgery, radiotherapy, chemotherapy, immunotherapy, and combinations thereof. All or some of the tumor is removed by surgery. Radiotherapy is performed by placing the source of radiation in or near the tumor or by intravenous delivery of the liquid radiation source to the patient through a device that targets certain parts of the body, from outside the body. The most commonly known cancer treatment is chemotherapy. Chemotherapy is used to kill cancer cells or to shrink the tumor, to prevent its growth or spread.
- Ovarian cancer and fallopian tube cancers are generally divided into 4 different stages (FIGO system). Staging in ovarian cancer is important in terms of determining how common cancer is; that is because cancer shows different prognosis at different stages and requires a different treatment method.
- First stage ovarian cancer includes cases in which the tumor is located in one or both ovaries and has not spread to the organs, lymph nodes or outside of the abdomen in the pelvic or lower abdominal region.
- Surgical intervention in early-stage ovarian cancer is defined as “staging surgery” since the tumor is removed and all areas having the possibility of spreading are sampled. Survival is between 80-95% when staging surgery is performed according to the procedure.
- Chemotherapy given to prevent possible recurrences as a result of staging surgery is called “Adjuvant Chemotherapy”.
- the combination of paclitaxel and carboplatin is used in patients with high risk, with carboplatin being recommended as the standard treatment in adjuvant chemotherapy in stage I ovarian cancer.
- the prolonged use of this treatment causes a serious increase in toxicity.
- Second stage ovarian cancer is limited to the ovaries and other lower abdominal organs.
- the cancer has not yet spread to the upper abdomen, lymph nodes, or out of the abdomen.
- the tumor spreads to the uterus and/or fallopian tubes in stage IIA cancers.
- the tumor spreads to other intra-pelvic organs and is limited to the pelvis in stage IIB.
- the standard treatment of second stage ovarian cancer consists of chemotherapy following surgical intervention.
- the likelihood of recurrence of cancer in patients with stage IIA is 30-40%. However, this rate increases even more in patients with later stage IIB.
- a combination of six cycles of intravenous taxane and carboplatin is recommended as standard treatment for this stage according to the National Comprehensive Cancer Network (NCCN) guidelines.
- NCCN National Comprehensive Cancer Network
- Ovarian cancer spreads to the abdominal membrane or lymph nodes in the upper abdominal region other than the ovary in the third stage; however, it has not yet shown spreading to outside of the abdominal region or to the liver.
- the standard of care for stage three ovarian cancer is chemotherapy consisting of a combination of platinum and taxane administered following surgical intervention.
- chemotherapy consisting of a combination of platinum and taxane administered following surgical intervention.
- less than 40% of the patients receiving standard treatment can have a life span of more than 10 years. This is because the entire cancer tissue cannot be removed with surgical intervention and the chemotherapy applied afterwards is not sufficient in killing the remaining cancer cells alone.
- Surgical treatment in Stage III requires advanced surgical procedures in the form of clearing all tumor foci beyond staging surgery.
- One of the combinations of cisplatin/docataxel, docataxel/carboplatin, paclitaxel/carboplatin, pegylated liposomal doxorubicin/carboplatin can be used in the cases where tumor is removed suboptimally.
- Intraperitoneal treatments can be added to intravenous treatments in patients whose tumors have been removed optimally and more successful results are obtained.
- Intravenous paclitaxel is administered on the first day, intraperitoneal cisplatin on the second day, and intraperitoneal paclitaxel on the eighth day in this standard treatment.
- the long duration of this treatment causes a very serious increase in toxicity, affecting the success of the treatment.
- the disease is called “platinum-resistant disease” and “unresponsive ovarian cancer” if the patient does not respond to chemotherapy clinically after the completion of chemotherapy cures.
- targeted treatment and immunotherapy are applied to patients with recurrent ovarian cancer, such as angiogenesis inhibitors, angiopoietin inhibitors, PARP inhibitors, EGFR tyrosine kinase inhibitors, folate receptor alpha inhibitors, in order to reinforce treatment, rather than the first-line treatment.
- Stage IV ovarian cancer is a systemic involvement condition in which cancer extends out of the intraabdominal cavity or organ metastases occur.
- the fourth stage consists of surgery and subsequent chemotherapy if the standard treatment of ovarian cancer is appropriate. It has been observed that the use of paclitaxel in combination with platinum in the chemotherapy of advanced stage ovarian cancer prolongs the life span. Response rates have increased in recent years, with the addition of Bevacizumab (Avastin®), a monoclonal antibody that acts by binding to the human vascular endothelial growth factor (VEGF) on the surface of blood and lymph vessels, to this dual chemotherapy. Sustained treatment is recommended as the possibility of recurrence of the disease is inevitable in stage IV. However, the overall survival advantage with topotecan, anthracycline or platinum did not provide very high results for this purpose.
- Bevacizumab Avastin®
- VEGF vascular endothelial growth factor
- chemotherapeutic drugs used in the treatment of standard ovarian cancer prevent the growth and proliferation of malignant cells and lead to their death with their cytotoxic effects.
- a radical treatment is possible with the destruction of all cells without a single malignant cell remaining in the body.
- An important factor limiting the therapeutic efficacy of anticancer drugs is the reduced sensitivity of tumor cells to the drug, in other words, the development of resistance to the drug.
- Platinum-based drugs such as cisplatin and carboplatin are one of the most important chemotherapeutics in the treatment of ovarian cancer.
- the anticancer activity of these alkylating agents is based on their interaction with DNA and the formation of intra-chain and inter-chain cross-links.
- the side effects and pharmacokinetic profile of the second-generation platinum compound carboplatin are different from cisplatin, even though cisplatin and carboplatin have similar mechanisms of action.
- the nephrotoxic effect, gastrointestinal side effects, and neurotoxicity of carboplatin are less than those of cisplatin; therefore, carboplatin is the most commonly used platinum agent in ovarian cancer chemotherapy.
- Carboplatin is used in first-line treatment; however, it has some important hematological side effects and leads to limited high dose requirement therapeutic activity due to low cellular intake of carboplatin.
- Carboplatin which is frequently used in the stages of ovarian cancer, initially responds to chemotherapy, but drug resistance develops in the treatment procedure in the long run.
- Drug resistance to chemotherapeutics is the cause of cancer treatment failure, and death, due to metastatic disease in 90% of patients.
- One of the most important causes of drug resistance development in ovarian cancer is the change in the DNA repair mechanisms due to silencing tumor suppressor genes through epigenetic changes, and the increase in the tolerance of cancer cells to chemotherapeutics and changes in the uptake of chemotherapeutics into cancer cells.
- DNA methylation is one of the basic epigenetic mechanisms that enables gene silencing.
- Methylation-dependent silencing in the hMLH1 tumor suppressor gene in ovarian cancer cells is a process that develops during treatment and is determining in the sensitivity to platinum compounds. Therefore, it is thought that ensuring the re-expression of tumor suppressing genes with DNA methyl transferase inhibitors can make ovarian cancer cells sensitive to chemotherapeutics, and the combined application of these inhibitors with carboplatin will be a new method for overcoming drug resistance in ovarian cancer.
- Chemotherapeutic agents which aim to destroy and eliminate neoplastic cells that grow and proliferate quite rapidly compared to normal cells in the proliferative period have negative side effects on many healthy tissues.
- Vital organs such as blood cells, cells in the gastrointestinal tract, hair follicles, sperm, heart, bladder, kidneys, lungs and nervous system organs are mostly affected by the side effects.
- Chemotherapeutic agents possess poor pharmacokinetic characteristics with a narrow therapeutic window. These agents immediately reach the maximum tolerated concentration and are then eliminated from the blood. An ideal drug formulation that provides maximum benefit for patients should be released at the minimum effective concentration over a period of time. Nanotechnology-based therapeutics have been shown to play an important role in meeting these aspects and increase drug efficacy, reduce toxicity in healthy tissue, and improve patient compatibility.
- Nanocarriers increase the delivery of drugs to tumor sites through passive or active targeting, thereby reducing negative side effects on healthy tissues in the treatment of all types of cancer. Furthermore, the bioavailability of the tumor site is enhanced by the improved permeability and retention (EPR) mechanism.
- EPR improved permeability and retention
- Nanomedicine promises more effective systems with less side effects than standard therapies, taking advantage of nanosized materials.
- Nanosystems used in cancer treatment are miniature carrier systems that aim to increase the therapeutic effect by combining existing chemotherapeutics with nanosized carriers. It is aimed to increase the performance of anticancer drugs in terms of bioavailability, safety, and selectivity in oncology, which is one of the most common uses of nanomaterials.
- the most important advantage of oncological nanosystems is that they create a more effective and selective treatment by increasing the selectivity of the existing anticancer drugs in terms of reaching their areas of action. This is a direct consequence of the size and surface properties of nanosized drug carrier systems that increase their penetration into the tissue.
- Nanotechnology-based chemotherapy has advantages over conventional chemotherapy: They increase the efficacy of drug substances while reducing their toxic effects. In particular, they expand the therapeutic indexes of anticancer drug substances. They maintain the steady state concentration for a longer time. They increase the accumulation of drug substance in the tumor tissue. They improve the pharmacokinetic properties of the drug substances without changing their molecular structure. They increase the solubility of poorly soluble drug substances. They prolong the circulatory half-life. They increase the stability of drug substances. They enable the development of multifunctional systems. They provide tissue, cell and molecular targeting. They allow the simultaneous transport of drug substances with different physicochemical properties.
- Combination therapy is based on grounds that tumor cells which are resistant to one drug can be sensitive to another drug with different action and resistance mechanisms, that there can be a biochemical synergy between the two drugs, and that a single drug can provide a limited clinical to for treatment due to tumor heterogeneity and drug resistance.
- the main object of combination therapy is to increase the effectiveness of cancer treatment without increasing systemic toxicity and also to prevent drug resistance. Synergistic effects of two or more agents targeting different pathways, genes or cellular events in cancer development are utilized in combination therapy. There are a number of principles to consider to form an effective combination. For example, different phases of the cell cycle should be targeted, they should have different mechanisms of action in order to obtain an additive or synergistic effect, the toxicity profiles should not overlap with each other. In this way, it is possible to increase the effects and reduce the cytotoxic effects of the drug substances by using them at lower doses. In practice, it was observed that combination therapy prolongs the average life span compared to treatment with a single drug.
- the amount of nanoparticles that can enter a cell is limited.
- a nanoparticulate drug carrier system that carries the combination of carboplatin and decitabine, an epigenetic drug substance that will increase the efficacy of carboplatin by modulating the platinum resistance, and can be targeted to tumorous tissues without damaging healthy tissues has been prepared with the new nanotechnology-based drug carrier system, in order to successfully modulate the drug resistance that is frequently encountered in the treatment of ovarian cancer and treat ovarian cancer.
- a lipid-coated nanoparticulate drug carrier system which carries the combination of carboplatin and decitabine, a demethylation agent that will provide the re-expression of tumor suppressing genes silenced by carboplatin methylation has been prepared by passive targeting to increase uptake into ovarian cancer cells in order to achieve success in the treatment of ovarian cancer and modulation of drug resistance that is frequently encountered in ovarian cancer.
- the preparation process of drug carrier systems was carried out in two phases. Core nanoparticles containing carboplatin were produced and then these nanoparticles were coated with a lipid layer containing carboplatin and decitabine in the first step of the invention.
- bovine serum albumin BSA
- ethanol by continuously stirring at constant speed in a magnetic stirrer and albumin aggregates were formed.
- the formed aggregates were stabilized by cross-linking with heat or glutaraldehyde application.
- the resulting nanoparticle dispersion was centrifuged and purified, then frozen at -20°C and lyophilized for 24 hours.
- the concentration of the carrier material used in the preparation of all matrix structured drug carrier systems affects the properties of the nanoparticulate systems obtained, especially the particle size and encapsulation efficiency. Therefore, the effect of BSA concentration on the prepared nanoparticles was investigated by using different concentrations of BSA solution in the range of 2% and 5% within the scope of the invention.
- the solubility of albumin molecules in the dissolution medium in the desolvation process is reduced using a desolvation agent, and nanoparticles are formed.
- the effects of the amount of desolvation agent used were examined by using three different ratios of ethanol as 2:1 , 3:1 , and 4:1 , in this process step.
- Albumin molecules should be stabilized by various methods after forming the albumin aggregates with the desolvation process.
- Albumin nanoparticles were prepared using BSA solution at different pH values (pH 5,0, pH 7,2, and pH 11 ,0) based on this information and their in vitro properties were examined.
- the presence of surfactants is one of the parameters that affect the loading of drug substances into matrix structured systems and the dissolution rate.
- albumin nanoparticles were prepared using different concentrations of poloxamer 188, and the effect of this surfactant on carboplatin encapsulation and dissolution rate was evaluated.
- Particle sizes of nanoparticulate drug carrier systems used in cancer treatment are one of the most important characteristics that enable their accumulation in the target tissue.
- the core albumin nanoparticles produced were coated with a lipid shell layer in order to increase the interaction with cells, to increase their biocompatibility due to their structure similar to the cell membrane, to prolong the duration of circulation, and to prevent the leakage of drug substances having high water solubility.
- the optimum carboplatin-loaded albumin nanoparticle formulation was coated with a shell material consisting of different lipid components, and carboplatin and the second drug substance, decitabine, were loaded into this layer.
- the lipid-coated albumin nanoparticles with optimum particle size, particle size distribution and zeta potential that can reach the desired tissue were obtained by passive targeting in the cancer treatment.
- the lipids to be used according to the lipid film hydration method were dissolved in 2 ml of chloroform and taken into a 50 ml flask.
- the organic solvent was vaporized in the rotavapor (Buchi Rotavapor RII) at a constant rotational speed of 60 rpm at 40°C, in order to obtain a smooth lipid film on the flask wall.
- the lipid film obtained was sonicated and hydrated for 10 minutes at 5°C above the phase transition temperatures of the lipids used in the ultrasonic bath with the decitabine solution in 30 mg carboplatin-loaded albumin nanoparticle and Phosphate Saline buffer (PBS pH 7.4).
- the lipid-coated albumin nanoparticles were centrifuged at 30000 rpm at 4°C for 1 hour after the lipid film was restored on the surface of the nanoparticles with the help of ultrasound.
- the separated particles were dispersed in distilled water, frozen at -20°C and lyophilized for 24 hours.
- the lipid coating process was tried to be optimized by using different lipid: nanoparticle ratios as 1 :1 and 0,5:1 (w/w) and different lecithin: cholesterol ratios as 1 : 1 and 1 : 0,5 (w/w) during lipid coating.
- lipid-coated albumin nanoparticles having the optimum particle size, particle size distribution, and zeta potential by using different dispersion medium volumes in the range of 2-5 ml and different lipid compositions including lecithin; 1 ,2-dipalmitoyl-sn-glysero-3- phosphotidylcholine (DPPC), 1 ,2-dimyristoyl-sn- glysero-3-phosphotidylcholine (DMPC) and 1 ,2-disteraoyl-sn-glysero-3-phosphotidylcholine (DSPC).
- DPPC dioyl-sn-glysero-3- phosphotidylcholine
- DMPC ,2-dimyristoyl-sn- glysero-3-phosphotidylcholine
- DSPC ,2-disteraoyl-sn-glysero-3-phosphotidylcho
- the final optimal carboplatin- and decitabine-loaded lipid-coated BSA nanoparticle formulation obtained is provided in Table 3.
- the physicochemical properties of the final formulation are also given in Table 4.
- Table 3. Optimum carboplatin- and decitabine-loaded, lipid-coated BSA nanoparticle formulation and its physicochemical properties.
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Abstract
The object of this invention is to modulate the platinum resistance with the combined nanoparticulate drug carrier system, which is applied by encapsulating carboplatin, used in the standard treatment of ovarian cancer together with decitabine, a DNA methyl transferase inhibitor, in a nanoparticulate drug carrier system. Within the scope of the invention, decitabine and carboplatin-loaded lipid-coated albumin nanoparticle formulations were prepared, the optimum formulation was determined by determining the in vitro properties of the prepared formulations; and the cytotoxic effects of the free drugs and drug substance-loaded nanoparticulate drug carrier systems, cellular involvement levels and changes in apoptotic pathway proteins and MLH1 protein expression were evaluated with cell culture studies on the platinum-sensitive A2780 and platinum-resistant A2780cis cell lines.
Description
A NEW DRUG CARRIER SYSTEM FOR TREATMENT OF OVARIAN CANCER WHICH IS RESISTANT TO PLATINUM
Technical field of the invention
The invention relates to nanotechnology-based alternative drug carrier systems in the treatment of cancer.
Prior art
Ovarian cancer is the 7th most common and the 8th most fatal type of cancer among women. All over the world, 240000 women are diagnosed with ovarian cancer every year, causing the death of 150000 women annually with a 5-year survival period of less than 45%. With ovarian cancer being less common in women under the age of 40, more than 90% of ovarian cancers seen over the age of 40 are epithelial tumors. The risk of disease increases with age. Even though ovarian cancer is one of the most susceptible tumors with a treatment respond rate of approximately 60-80%, even in advanced stages, it is still the most fatal gynecological cancer.
In ovaries, cancer occurs in 3 types of tissues: epithelial tissue surrounding the egg, stromal cells responsible for hormone production, and germ cells. 90% of ovarian cancers are of epithelial origin whereas 10% are of germ and stromal cell origin. Epithelial ovarian cancer is classified in different ways such as high- and low-grade serous, mucinous, clear cell and endometrioid ovarian cancers localized in the intraperitoneal cavity with different morphologies and clinical appearances. Low-grade serous tumors develop slowly and are resistant to chemotherapy whereas high-grade serous ovarian cancers are cancers that spread rapidly to the peritoneal cavity but are sensitive to chemotherapy. Endometrioid and mucinous cancers are generally low-grade tumors and are limited in the ovaries.
Treatment of ovarian cancer mainly consists of surgery, radiotherapy, chemotherapy, immunotherapy, and combinations thereof. All or some of the tumor is removed by surgery. Radiotherapy is performed by placing the source of radiation in or near the tumor or by intravenous delivery of the liquid radiation source to the patient through a device that targets certain parts of the body, from outside the body. The most commonly known cancer
treatment is chemotherapy. Chemotherapy is used to kill cancer cells or to shrink the tumor, to prevent its growth or spread.
Ovarian cancer and fallopian tube cancers are generally divided into 4 different stages (FIGO system). Staging in ovarian cancer is important in terms of determining how common cancer is; that is because cancer shows different prognosis at different stages and requires a different treatment method.
First stage ovarian cancer includes cases in which the tumor is located in one or both ovaries and has not spread to the organs, lymph nodes or outside of the abdomen in the pelvic or lower abdominal region. The majority of patients recover through appropriate surgical interventions in stage I ovarian cancers. Surgical intervention in early-stage ovarian cancer is defined as “staging surgery” since the tumor is removed and all areas having the possibility of spreading are sampled. Survival is between 80-95% when staging surgery is performed according to the procedure. However, there is a risk of recurrence and related death even in this group of patients. Chemotherapy given to prevent possible recurrences as a result of staging surgery is called “Adjuvant Chemotherapy”. The combination of paclitaxel and carboplatin is used in patients with high risk, with carboplatin being recommended as the standard treatment in adjuvant chemotherapy in stage I ovarian cancer. However, the prolonged use of this treatment causes a serious increase in toxicity.
Second stage ovarian cancer is limited to the ovaries and other lower abdominal organs. The cancer has not yet spread to the upper abdomen, lymph nodes, or out of the abdomen. The tumor spreads to the uterus and/or fallopian tubes in stage IIA cancers. The tumor spreads to other intra-pelvic organs and is limited to the pelvis in stage IIB. The standard treatment of second stage ovarian cancer consists of chemotherapy following surgical intervention. The likelihood of recurrence of cancer in patients with stage IIA is 30-40%. However, this rate increases even more in patients with later stage IIB. A combination of six cycles of intravenous taxane and carboplatin is recommended as standard treatment for this stage according to the National Comprehensive Cancer Network (NCCN) guidelines.
Ovarian cancer spreads to the abdominal membrane or lymph nodes in the upper abdominal region other than the ovary in the third stage; however, it has not yet shown spreading to outside of the abdominal region or to the liver. The standard of care for stage three ovarian cancer is chemotherapy consisting of a combination of platinum and taxane administered following surgical intervention. However, less than 40% of the patients receiving standard
treatment can have a life span of more than 10 years. This is because the entire cancer tissue cannot be removed with surgical intervention and the chemotherapy applied afterwards is not sufficient in killing the remaining cancer cells alone.
Surgical treatment in Stage III requires advanced surgical procedures in the form of clearing all tumor foci beyond staging surgery. One of the combinations of cisplatin/docataxel, docataxel/carboplatin, paclitaxel/carboplatin, pegylated liposomal doxorubicin/carboplatin can be used in the cases where tumor is removed suboptimally. Intraperitoneal treatments can be added to intravenous treatments in patients whose tumors have been removed optimally and more successful results are obtained. Intravenous paclitaxel is administered on the first day, intraperitoneal cisplatin on the second day, and intraperitoneal paclitaxel on the eighth day in this standard treatment. However, the long duration of this treatment causes a very serious increase in toxicity, affecting the success of the treatment.
The disease is called “platinum-resistant disease” and “unresponsive ovarian cancer” if the patient does not respond to chemotherapy clinically after the completion of chemotherapy cures. In this case, targeted treatment and immunotherapy are applied to patients with recurrent ovarian cancer, such as angiogenesis inhibitors, angiopoietin inhibitors, PARP inhibitors, EGFR tyrosine kinase inhibitors, folate receptor alpha inhibitors, in order to reinforce treatment, rather than the first-line treatment.
Stage IV ovarian cancer is a systemic involvement condition in which cancer extends out of the intraabdominal cavity or organ metastases occur. The fourth stage consists of surgery and subsequent chemotherapy if the standard treatment of ovarian cancer is appropriate. It has been observed that the use of paclitaxel in combination with platinum in the chemotherapy of advanced stage ovarian cancer prolongs the life span. Response rates have increased in recent years, with the addition of Bevacizumab (Avastin®), a monoclonal antibody that acts by binding to the human vascular endothelial growth factor (VEGF) on the surface of blood and lymph vessels, to this dual chemotherapy. Sustained treatment is recommended as the possibility of recurrence of the disease is inevitable in stage IV. However, the overall survival advantage with topotecan, anthracycline or platinum did not provide very high results for this purpose.
Today, it is impossible to talk about the existence of a single and definitive treatment method in ovarian cancer, because each method has its own advantages and disadvantages, and because the treatments differ from person to person. The effect expected from the treatment
with conventional chemotherapies has still not been fully achieved, despite all technological developments. It is necessary to apply a more aggressive, high-dose chemotherapy to achieve success in standard treatments. However, one of the biggest problems in this regard is the toxic and side effects such as neurotoxicity, nephrotoxicity and bone marrow depression in healthy cells and tissues due to dosage. These side effects prevent the success of the treatment.
Technical problems the invention aims to solve
Most of the chemotherapeutic drugs used in the treatment of standard ovarian cancer prevent the growth and proliferation of malignant cells and lead to their death with their cytotoxic effects. A radical treatment is possible with the destruction of all cells without a single malignant cell remaining in the body. However, such a situation cannot be achieved with existing drugs, apart from a small number of exceptions. An important factor limiting the therapeutic efficacy of anticancer drugs is the reduced sensitivity of tumor cells to the drug, in other words, the development of resistance to the drug.
Platinum-based drugs such as cisplatin and carboplatin are one of the most important chemotherapeutics in the treatment of ovarian cancer. The anticancer activity of these alkylating agents is based on their interaction with DNA and the formation of intra-chain and inter-chain cross-links. The side effects and pharmacokinetic profile of the second-generation platinum compound carboplatin are different from cisplatin, even though cisplatin and carboplatin have similar mechanisms of action. The nephrotoxic effect, gastrointestinal side effects, and neurotoxicity of carboplatin are less than those of cisplatin; therefore, carboplatin is the most commonly used platinum agent in ovarian cancer chemotherapy. Carboplatin is used in first-line treatment; however, it has some important hematological side effects and leads to limited high dose requirement therapeutic activity due to low cellular intake of carboplatin.
Carboplatin, which is frequently used in the stages of ovarian cancer, initially responds to chemotherapy, but drug resistance develops in the treatment procedure in the long run. Drug resistance to chemotherapeutics is the cause of cancer treatment failure, and death, due to metastatic disease in 90% of patients. One of the most important causes of drug resistance development in ovarian cancer is the change in the DNA repair mechanisms due to silencing tumor suppressor genes through epigenetic changes, and the increase in the tolerance of cancer cells to chemotherapeutics and changes in the uptake of chemotherapeutics into
cancer cells. DNA methylation is one of the basic epigenetic mechanisms that enables gene silencing. Methylation-dependent silencing in the hMLH1 tumor suppressor gene in ovarian cancer cells is a process that develops during treatment and is determining in the sensitivity to platinum compounds. Therefore, it is thought that ensuring the re-expression of tumor suppressing genes with DNA methyl transferase inhibitors can make ovarian cancer cells sensitive to chemotherapeutics, and the combined application of these inhibitors with carboplatin will be a new method for overcoming drug resistance in ovarian cancer.
Chemotherapeutic agents, which aim to destroy and eliminate neoplastic cells that grow and proliferate quite rapidly compared to normal cells in the proliferative period have negative side effects on many healthy tissues. Vital organs such as blood cells, cells in the gastrointestinal tract, hair follicles, sperm, heart, bladder, kidneys, lungs and nervous system organs are mostly affected by the side effects.
Chemotherapeutic agents possess poor pharmacokinetic characteristics with a narrow therapeutic window. These agents immediately reach the maximum tolerated concentration and are then eliminated from the blood. An ideal drug formulation that provides maximum benefit for patients should be released at the minimum effective concentration over a period of time. Nanotechnology-based therapeutics have been shown to play an important role in meeting these aspects and increase drug efficacy, reduce toxicity in healthy tissue, and improve patient compatibility.
Nanocarriers increase the delivery of drugs to tumor sites through passive or active targeting, thereby reducing negative side effects on healthy tissues in the treatment of all types of cancer. Furthermore, the bioavailability of the tumor site is enhanced by the improved permeability and retention (EPR) mechanism.
Nanomedicine promises more effective systems with less side effects than standard therapies, taking advantage of nanosized materials. Nanosystems used in cancer treatment are miniature carrier systems that aim to increase the therapeutic effect by combining existing chemotherapeutics with nanosized carriers. It is aimed to increase the performance of anticancer drugs in terms of bioavailability, safety, and selectivity in oncology, which is one of the most common uses of nanomaterials. The most important advantage of oncological nanosystems is that they create a more effective and selective treatment by increasing the selectivity of the existing anticancer drugs in terms of reaching their areas of action. This is a direct consequence of the size and surface properties of nanosized drug carrier systems that
increase their penetration into the tissue. Nanotechnology-based chemotherapy has advantages over conventional chemotherapy: They increase the efficacy of drug substances while reducing their toxic effects. In particular, they expand the therapeutic indexes of anticancer drug substances. They maintain the steady state concentration for a longer time. They increase the accumulation of drug substance in the tumor tissue. They improve the pharmacokinetic properties of the drug substances without changing their molecular structure. They increase the solubility of poorly soluble drug substances. They prolong the circulatory half-life. They increase the stability of drug substances. They enable the development of multifunctional systems. They provide tissue, cell and molecular targeting. They allow the simultaneous transport of drug substances with different physicochemical properties.
Description of the invention
Combination therapy is based on grounds that tumor cells which are resistant to one drug can be sensitive to another drug with different action and resistance mechanisms, that there can be a biochemical synergy between the two drugs, and that a single drug can provide a limited clinical to for treatment due to tumor heterogeneity and drug resistance. The main object of combination therapy is to increase the effectiveness of cancer treatment without increasing systemic toxicity and also to prevent drug resistance. Synergistic effects of two or more agents targeting different pathways, genes or cellular events in cancer development are utilized in combination therapy. There are a number of principles to consider to form an effective combination. For example, different phases of the cell cycle should be targeted, they should have different mechanisms of action in order to obtain an additive or synergistic effect, the toxicity profiles should not overlap with each other. In this way, it is possible to increase the effects and reduce the cytotoxic effects of the drug substances by using them at lower doses. In practice, it was observed that combination therapy prolongs the average life span compared to treatment with a single drug.
Nanosystems that have been investigated for the treatment of ovarian cancer until today have generally focused on the transport of a single therapeutic agent even though the standard treatment of ovarian cancer consists of several drug substance combinations. However, it has been shown in the literature that the amount of nanoparticles that can enter a cell is limited. As a result, only half of the drug substances can be introduced into the cell with a single agent transport strategy, when the nanoparticle application carrying multiple agents is compared with the simultaneous application of different nanoparticles carrying a
single agent. For this reason, future nanosystems should focus on the transport of a synergistic combination of multiple drugs with optimum distribution within the tumor.
In this invention, a nanoparticulate drug carrier system that carries the combination of carboplatin and decitabine, an epigenetic drug substance that will increase the efficacy of carboplatin by modulating the platinum resistance, and can be targeted to tumorous tissues without damaging healthy tissues has been prepared with the new nanotechnology-based drug carrier system, in order to successfully modulate the drug resistance that is frequently encountered in the treatment of ovarian cancer and treat ovarian cancer.
Detailed description of the invention:
Within the scope of this invention, a lipid-coated nanoparticulate drug carrier system, which carries the combination of carboplatin and decitabine, a demethylation agent that will provide the re-expression of tumor suppressing genes silenced by carboplatin methylation has been prepared by passive targeting to increase uptake into ovarian cancer cells in order to achieve success in the treatment of ovarian cancer and modulation of drug resistance that is frequently encountered in ovarian cancer.
The preparation process of drug carrier systems was carried out in two phases. Core nanoparticles containing carboplatin were produced and then these nanoparticles were coated with a lipid layer containing carboplatin and decitabine in the first step of the invention.
In this invention, primarily, the solubility of bovine serum albumin (BSA) in water was reduced by adding ethanol by continuously stirring at constant speed in a magnetic stirrer and albumin aggregates were formed. The formed aggregates were stabilized by cross-linking with heat or glutaraldehyde application. The resulting nanoparticle dispersion was centrifuged and purified, then frozen at -20°C and lyophilized for 24 hours.
Formulation and process variables that play key roles during the formation of albumin nanoparticles in the preparation of albumin nanoparticle formulations were examined separately and the results were evaluated. The effects of nanoparticles obtained by using glutaraldehyde: BSA ratios in the range of 47.04-1.56 pg/mg on the particle size and carboplatin encapsulation efficiency were examined. In vitro properties of protein nanoparticles in the literature have been reported to be significantly affected by the
dispersion medium used. For this reason, carboplatin-loaded albumin nanoparticles were prepared using water and sodium chloride solution as the dispersion medium in the invention and the obtained nanoparticulate systems were evaluated. The concentration of the carrier material used in the preparation of all matrix structured drug carrier systems affects the properties of the nanoparticulate systems obtained, especially the particle size and encapsulation efficiency. Therefore, the effect of BSA concentration on the prepared nanoparticles was investigated by using different concentrations of BSA solution in the range of 2% and 5% within the scope of the invention. The solubility of albumin molecules in the dissolution medium in the desolvation process is reduced using a desolvation agent, and nanoparticles are formed. The effects of the amount of desolvation agent used were examined by using three different ratios of ethanol as 2:1 , 3:1 , and 4:1 , in this process step. Albumin molecules should be stabilized by various methods after forming the albumin aggregates with the desolvation process. One of the main variables affecting the solubility and surface charge of protein molecules is the pH of their solution. Albumin nanoparticles were prepared using BSA solution at different pH values (pH 5,0, pH 7,2, and pH 11 ,0) based on this information and their in vitro properties were examined. The presence of surfactants is one of the parameters that affect the loading of drug substances into matrix structured systems and the dissolution rate. In this invention, albumin nanoparticles were prepared using different concentrations of poloxamer 188, and the effect of this surfactant on carboplatin encapsulation and dissolution rate was evaluated. Particle sizes of nanoparticulate drug carrier systems used in cancer treatment are one of the most important characteristics that enable their accumulation in the target tissue. The mixing rate at which albumin nanoparticles were prepared was changed between 600 and 1200 rpm, the particle sizes were examined and the results were evaluated in the invention. As a result of all evaluations, the optimum carboplatin-loaded BSA core nanoparticle formulation given in Table 1 was determined. The physicochemical properties of the final nanoparticle formulation are also given in Table 2.
Table 1. Carboplatin-loaded BSA core nanoparticle formulation.
Table 2. Physicochemical properties of carboplatin-loaded BSA nanoparticle core formulation
The core albumin nanoparticles produced were coated with a lipid shell layer in order to increase the interaction with cells, to increase their biocompatibility due to their structure similar to the cell membrane, to prolong the duration of circulation, and to prevent the leakage of drug substances having high water solubility. For this purpose, the optimum carboplatin-loaded albumin nanoparticle formulation was coated with a shell material consisting of different lipid components, and carboplatin and the second drug substance, decitabine, were loaded into this layer. Finally, the lipid-coated albumin nanoparticles with optimum particle size, particle size distribution and zeta potential that can reach the desired tissue were obtained by passive targeting in the cancer treatment.
The lipids to be used according to the lipid film hydration method were dissolved in 2 ml of chloroform and taken into a 50 ml flask. The organic solvent was vaporized in the rotavapor (Buchi Rotavapor RII) at a constant rotational speed of 60 rpm at 40°C, in order to obtain a smooth lipid film on the flask wall. The lipid film obtained was sonicated and hydrated for 10 minutes at 5°C above the phase transition temperatures of the lipids used in the ultrasonic bath with the decitabine solution in 30 mg carboplatin-loaded albumin nanoparticle and Phosphate Saline buffer (PBS pH 7.4). The lipid-coated albumin nanoparticles were centrifuged at 30000 rpm at 4°C for 1 hour after the lipid film was restored on the surface of the nanoparticles with the help of ultrasound. The separated particles were dispersed in distilled water, frozen at -20°C and lyophilized for 24 hours. The lipid coating process was tried to be optimized by using different lipid: nanoparticle ratios as 1 :1 and 0,5:1 (w/w) and different lecithin: cholesterol ratios as 1 : 1 and 1 : 0,5 (w/w) during lipid coating. After determining the rates at which the lipid coating process is successfully performed, it is aimed to reduce the rate of carboplatin leaking from the core albumin nanoparticles into the dispersion medium; to increase the amount of drug substance loaded into the lipid coating, to prepare lipid-coated albumin nanoparticles having the optimum particle size, particle size distribution, and zeta potential by using different dispersion medium volumes in the range of 2-5 ml and different lipid compositions including lecithin; 1 ,2-dipalmitoyl-sn-glysero-3- phosphotidylcholine (DPPC), 1 ,2-dimyristoyl-sn- glysero-3-phosphotidylcholine (DMPC) and 1 ,2-disteraoyl-sn-glysero-3-phosphotidylcholine (DSPC). The final optimal carboplatin- and decitabine-loaded lipid-coated BSA nanoparticle formulation obtained is provided in Table 3. The physicochemical properties of the final formulation are also given in Table 4.
Table 3. Optimum carboplatin- and decitabine-loaded, lipid-coated BSA nanoparticle formulation and its physicochemical properties.
Table 4. Physicochemical properties of the optimal carboplatin- and decitabine-loaded, lipid- coated BSA nanoparticle formulation.
It was determined that the lipid-coated albumin nanoparticle drug carrier systems loaded with the combination of decitabine and carboplatin produced 8 times lower anticarcinogenic effects in the platinum-sensitive A2780 cell line compared to pure carboplatin, and 16 times lower anticarcinogenic effects in the platinum-resistant A2780cis cell line. It was determined in the protein analysis that the expression of MLH1 protein, whose expression decreased in case of platinum resistance, increased with the administration of decitabine released from nanoparticulate systems, and the effectiveness of carboplatin was increased by breaking the platinum resistance in the A2780cis cell line.
Using the decitabine and carboplatin-loaded albumin nanoparticle formulation developed as a result of all the in vitro characterization and cell culture studies provided successful results for the treatment of platinum-resistant ovarian cancer, in accordance with the objectives of the study.
Claims
CLAIMS Nanoparticulate drug carrier system for use in the treatment of ovarian cancer which is resistant to platinum, characterized in that it has a carboplatin- and decitabine-loaded, lipid-coated bovine serum albumin (BSA) nanoparticle formulation. Formulation according to claim 1 , characterized in that it is prepared with 120 mg core BSA nanoparticles, 5 mg carboplatin, glutaraldehyde having 7,80 pg/mg glutaraldehyde: BSA ratio and 16 ml ethanol; and the lipid layer is prepared with 20 mg carboplatin, 1 mg decitabine, 10 mg lecithin, and 5 mg cholesterol. A drug carrier system according to claim 1 , characterized in that it comprises the following preparation stages:
- Reducing the solubility of BSA in water in the range of 2% to 5% by adding ethanol by continuously stirring at constant speed in a magnetic stirrer, and stabilizing the formed aggregates with glutaraldehyde having a glutaraldehyde: BSA ratio in the range of 47,04-1 ,56 pg/mg,
- Reducing the solubility of albumin molecules in the dissolution medium in the desolvation process by using three different ratios of ethanol as 2:1 , 3:1 , and 4:1 , and ensuring the formation of nanoparticles. A drug carrier system according to claim 1 , characterized in that it comprises the following preparation stages:
- The lipids to be used according to the lipid film hydration method are dissolved in 2 ml of chloroform,
- The lipid: nanoparticle ratio is 0,5:1 or 1 :1 (w:/w),
- Use of lecithin/DPPC/DMPC/DSPC as lipid,
- Lipid: cholesterol ratio is 1 :1 or 1 :0,5 (w/w),
- The organic solvent is vaporized in the rotavapor in a 50 ml flask, at a constant rotational speed of 60 rpm at 40°C in order to obtain a smooth lipid film on the wall,
- Hydrating the lipid film obtained in the ultrasonic bath with 30 mg carboplatin-loaded albumin nanoparticle and decitabine and carboplatin solution in 2-5 ml PBS pH 7,4, by sonicating the phase transition
temperatures of the lipids used for 10 minutes above 5°C.
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| TR2020/18770A TR202018770A2 (en) | 2020-11-23 | 2020-11-23 | A New Drug Delivery System for Platinum Resistant Ovarian Cancer Treatment |
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| CN115025118A (en) * | 2022-06-20 | 2022-09-09 | 浙江大学医学院附属妇产科医院 | Application of composition of gallium nano-drug and platinum compound with pH response release characteristic in preparation of drug resistant ovarian cancer treatment drug |
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| WO2011156119A1 (en) * | 2010-06-07 | 2011-12-15 | Abraxis Bioscience, Llc | Combination therapy methods for treating proliferative diseases |
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| WO2011156119A1 (en) * | 2010-06-07 | 2011-12-15 | Abraxis Bioscience, Llc | Combination therapy methods for treating proliferative diseases |
Non-Patent Citations (5)
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| ERIC A. BENSON, TODD C. SKAAR, YUNLONG LIU, KENNETH P. NEPHEW, DANIELA MATEI: "Carboplatin with Decitabine Therapy, in Recurrent Platinum Resistant Ovarian Cancer, Alters Circulating miRNAs Concentrations: A Pilot Study", PLOS ONE, vol. 10, no. 10, pages e0141279, XP055717748, DOI: 10.1371/journal.pone.0141279 * |
| ESMIN O., MEHMET GUMUSTAS, CANAN HASCICEK, SIBEL A OZKAN: "A novel stability-indicating analytical method development for simultaneous determination of carboplatin and decitabine from nanoparticles", JOURNAL OF SEPARATION SCIENCE, WILEY, DE, vol. 43, no. 17, 9 August 2020 (2020-08-09), DE , pages 3491 - 3498, XP055940353, ISSN: 1615-9306, DOI: 10.1002/jssc.202000320 * |
| HASSANIN ISLAM, ELZOGHBY AHMED: "Albumin-based nanoparticles: a promising strategy to overcome cancer drug resistance", CANCER DRUG RESISTANCE, vol. 3, no. 4, 3 November 2020 (2020-11-03), pages 930 - 946, XP055940367, DOI: 10.20517/cdr.2020.68 * |
| NOORANI, L. ET AL.: "Albumin nanoparticles increase the anticancer efficacy of albendazole in ovarian cancer xenograft model", JOURNAL OF NANOBIOTECHNOLOGY, vol. 13, no. 1, 2015, pages 1 - 12, XP021214971, DOI: 10.1186/s12951-015-0082-8 * |
| ROUDSARI MAJID HASANZADEGAN, NASIM SAEIDI , NAHID KABIRI , AFROOZ AHMADI , MARAL MAZLOUMI TABRIZI , HASAN EBRAHIMI SHAHMABADI , A: "Investigation of Characteristics and Behavior of Loaded Carboplatin on the, Liposomes Nanoparticles, on the Lung and Ovarian Cancer: An In-Vitro Evaluation", ASIAN PACIFIC JOURNAL OF CANCER BIOLOGY, vol. 1, no. 1, 25 April 2016 (2016-04-25), pages 9 - 13, XP055940361, ISSN: 2538-4635, DOI: 10.31557/APJCB.2016.1.1.9-13 * |
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| CN115025118A (en) * | 2022-06-20 | 2022-09-09 | 浙江大学医学院附属妇产科医院 | Application of composition of gallium nano-drug and platinum compound with pH response release characteristic in preparation of drug resistant ovarian cancer treatment drug |
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