Technical Field of the Invention

The invention relates to drug delivery system that has a large surface area, is biodegradable and suitable for contact with the food, and comprises nanographene and triblock copolymer for use in the pharmaceutical industry, in the fields of biotechnology and biomedicine, in the treatment of cancer, especially in the treatment of breast, prostate, lung, bladder, esophagus and brain cancer, and a method of preparing this delivery system. Said triblock copolymer comprises polylactic acid (PLA), polycaprolactone (PCL) and polyglycolic acid (PGA). By means of the drug delivery system that is the subject of the invention, the therapeutic efficacy of the chemotherapy drugs used is increased compared to the existing liposomal drug delivery systems, possible side effects as a result of chemotherapy are prevented and a controlled drug release is provided.

State of the Art

Cancer is the leading cause of death all over the world, right after cardiovascular diseases. In Western societies, one in every 250-350 people is diagnosed with cancer every year. In the group over the age of 60, the incidence of cancer increases even more, reaching around 4-5 per 300 people [1], World Health Organization-International Agency for Research on Cancer (IARC) 2020 world cancer statistics show that in 2020 an estimated 19.3 million new cancer cases and approximately 10.0 million cancer deaths occurred worldwide. When the rates reported as 19.3 million new cases and 10.0 million deaths in 2020 are compared with the rates of 18.1 million cases and 9.6 million deaths in 2018, it is estimated that the cancer burden in the world has increased [2].

In the state of the art, the treatment methods commonly used in cancer are surgery, radiotherapy and chemotherapy. In cancer treatment, hormone therapies, biological therapy methods and targeted therapies are used less frequently. These treatment methods are applied alone or together. The first treatment, which is often referred to as first-line treatment, is surgery. The treatment applied after surgical treatment is chemotherapy [3], Chemotherapy means treating the tumour with drugs and is a very important part of tumour treatment, along with surgery and radiotherapy (radiation therapy). With chemotherapy, tumour cells are killed or the growth of the tumour is tried to be stopped. Chemotherapy is applied by giving a single, sometimes several drugs to cancer patients in various ways. Chemotherapy can be applied for different reasons, depending on the tumour type and the characteristics of the patient. Chemotherapy is applied to completely destroy the tumour and cure the patient, to prevent the spread of the tumour, to stop or slow the growth of the tumour, and to eliminate the symptoms caused by the tumour. In cancer treatment, chemotherapy is applied sequentially or simultaneously with other treatments (surgery and radiation therapy). For example, chemotherapy can be applied to shrink the tumour before surgery or to prevent its spread after surgery, and the same applications can be performed before and after radiation therapy, as well as simultaneously with radiation therapy [4], As a result, chemotherapy is an indispensable part of cancer treatment. Surgery or radiation therapy alone is insufficient in the treatment of cancer.

In the state of the art, various drugs are used in chemotherapy, some of which are chemotherapeutic drugs (cytotoxic) to destroy tumour cells, some are drugs that prevent the development and proliferation of the tumour by affecting the biology of the tumour (cytostatic), and others are drugs used to reduce or destroy the side effects of hormones and immunity. The drugs used in chemotherapy are administered intravenously (the most commonly used), orally or by giving them into the body cavities. Serious side effects are seen in chemotherapy drugs in the state of the art. Examples of these side effects are skin changes, mouth sores, easy bruising, fatigue, infection or flu-like symptoms, nausea, vomiting, diarrhoea and hair loss. The incidence and seventy of side effects vary between patients. In addition, the interactions between chemotherapy drugs and other drugs increase the side effects [5], In some patients receiving chemotherapy, the drugs used cause permanent organ damage and secondary cancer types depending on the patient's pre-treatment health status [6], Chemotherapy can cause side effects on the heart for some people. These side effects are irregular heart rhythm, high blood pressure, congestive heart failure, valvular heart disease and stroke. In some people, chemotherapy brings about lung problems. These problems are decreased capacity in the lung, increase in scar tissue called pulmonary fibrosis, inflammation of the lung and difficulty in breathing (shortness of breath). Lung problems may be more likely when treatment is targeted to the lung area, such as with specific drugs or chest radiotherapy for lung cancer. In addition to all these, a group of cognitive difficulties known as chemo-brain may occur as a late side effect of chemotherapy in some people. Cognitive problems include problems with memory, concentration, or focus. For example, the person may lose their keys and have difficulty multitasking or performing daily activities that require attention. Hair loss is another common side effect of chemotherapy. A study conducted in 2017 states that approximately 65% of people who receive chemotherapy experience hair loss. This percentage may also increase depending on the drug. In some cases, hair loss can be permanent, for example, when the person has to undergo intensive chemotherapy for a long time. Infertility can also be seen in people receiving chemotherapy. Nerve damage or peripheral neuropathy is a potential side effect of various cancer types and their treatments and some chemotherapy (especially taxane group) treatments. Although nerve damage can heal over time, it can cause permanent damage in some people [5], [7],

Due to the problems such as all these side effects encountered in the state of the art, improving the therapeutic profile and effectiveness of therapeutic agents used in chemotherapy applications and the development of effective drug delivery systems have become one of the most studied subjects in modem cancer treatment.

In the state of the art, liposomes are used as a drug delivery system that is widely used in cancer treatment. Since their discovery by Bangham et al. in 1965, liposomes have been extensively studied in order to increase the therapeutic effects of active substances, reduce their side effects and increase their stability by protecting them from chemical degradation, and are among the most promising and widely applied drug delivery systems [8], For liposomes to enter the pharmaceutical market, they must be stable throughout their shelf life and remain intact until they reach their target sites to produce the desired effect. However, liposomes are low stability colloidal systems with various chemical and physical stability problems. Physical stability problems relate to changes in vesicle size resulting from vesicle aggregation and fusion, and leakage of encapsulated material out of the vesicle. Chemical stability problems arise as a result of the hydrolysis of the ester bonds connecting the fatty acids to the glycerol backbone and the peroxidation of the unsaturated acyl chains in phospholipids. These problems accelerate the degradation of liposomes and change their drug release properties. They also affect the in vivo performance and storage conditions of liposomes [9], Therefore, special storage conditions are needed for liposomes. In addition to stability problems, the purity of natural phospholipids used in liposome formulations can vary. During the manufacture of liposomes, problems such as inappropriate solvent use and insufficient hydration of the formed lipid film can also be observed [10], As a result, the use of oversized materials in existing liposomal drug delivery systems causes problems such as in vivo instability, poor bioavailability, poor solubility, poor absorption in the body, problems with targeted delivery, and possible adverse effects of drugs. In addition, the need for innovative drug systems is inevitable due to leakage and fusion of encapsulated drug molecules, phospholipid hydrolysis and high production cost experienced in liposomal drug delivery systems.

Due to reasons such as limitations and inadequacies of drug delivery systems in the state of the art, inability to reach a drug delivery system in the state of the art with an efficiency that will eliminate or minimise the side effects of chemotherapy drugs used especially in cancer treatment, the emergence of in vivo instability, harmful bioavailability, poor solubility, poor absorption in the body, targeted delivery and side effects problems due to the use of large-size materials in the liposomal drug delivery systems in the state of the art, the problem of leakage, fusion and phospholipid hydrolysis of drug molecules encountered in liposomal drug delivery systems, and the high cost problem of these liposomal drug delivery systems, introdcing a drug delivery system in which all these problems are eliminated has become necessary.

Brief Description and Aims of the Invention

In the invention, a drug delivery system comprising nanographene and triblock copolymer for use in cancer treatment and a method of preparing this delivery system is explained. Said triblock copolymer comprises polylactic acid (PLA), polycaprolactone (PCL) and polyglycolic acid (PGA). By means of the drug delivery system that is the subject of the invention, the therapeutic efficacy of the chemotherapy drugs used is increased compared to the existing liposomal drug delivery systems, possible side effects as a result of chemotherapy are prevented and a controlled drug release is provided.

An aim of the invention is to provide a drug delivery system with enhanced therapeutic effectiveness for use in the treatment of breast, prostate, lung, bladder, oesophageal and brain cancer. A drug delivery system with enhanced therapeutic efficiency is achieved by using a large surface area nanomaterial comprising nanographene and PLA:PCL:PGA triblock copolymer in the drug delivery system. By means of the use of graphene nanomaterial and biocompatible PLA:PCL:PGA triblock copolymer in the drug delivery system that is the subject of the invention, the therapeutic effectiveness of chemotherapy drugs used in cancer treatment is increased compared to existing liposomal drug delivery systems.

Another aim of the invention is to provide a drug delivery system that minimises the side effects of chemotherapeutic agents used in cancer treatment in the state of the art. A drug delivery system that prevents said side effect is provided with the use of graphene nanomaterial and biocompatible PLA:PCL:PGA triblock copolymer in the drug delivery system of the invention.

The invention provides a drug delivery system with controlled drug release for use in cancer treatment. A drug delivery system in which drug release can be controlled is provided by the drug delivery system of the invention comprising nanographene and PLA:PCL:PGA triblock copolymer. PGA in said triblock copolymer has an important place in the realisation of controlled drug release.

Another aim of the invention is to provide a low-cost drug delivery system. The provision of said low-cost drug delivery system is provided by a single-step synthesised PLA:PCL:PGA triblock copolymer in the drug delivery system of the invention.

Another aim of the invention is to provide a drug delivery system in which the problems of in vivo instability, harmful bioavailability, poor solubility, poor absorption in the body, targeted delivery and side effects encountered in drug delivery systems due to the use of large-size materials are prevented. Providing a drug delivery system in which these problems are prevented is provided by the PLA:PCL:PGA triblock copolymer synthesised in different ratios and weights in the drug delivery system of the invention. Another aim of the invention is to provide a drug delivery system that prevents the leakage, fusion and phospholipid hydrolysis problems of drug molecules experienced in drug delivery systems. The provision of a drug delivery system with said feature is achieved by using a nanomaterial with a large surface area, comprising nanographene and PLA:PCL:PGA triblock copolymer, in the drug delivery system.

In the invention, a biodegradable drug delivery system suitable for contact with food is provided. A drug delivery system suitable for contact with the food and biodegradable is provided by nanographene and PLA:PCL:PGA triblock copolymer the drug delivery system of the invention comprise. While PLA is an FDA-approved polymer, it is biodegradable and compostable. Also, PLA can be easily processed because it has a lower melting point than many fossil-based polymers. PLA requires little energy to be converted. Likewise, PCL is FDA-approved and is a biodegradable polymer. PCL can be easily broken down by lipase and esterase enzymes. In short, PCL is used in the drug delivery system of the invention due to its features such as high biocompatibility, low degradation rate and less acidic degradation and high drug transport potential compared to other polyesters. PGA in the drug delivery system that is the subject of the invention is used in the drug delivery system that is the subject of the invention, due to its biocompatibility, biodegradability and high mechanical properties.

Detailed Description of the Invention

The invention relates to drug delivery system that has a large surface area, is biodegradable and convenient for contact with the food, and comprises nanographene and triblock copolymer for use in the pharmaceutical industry, especially in the treatment of breast, prostate, lung, bladder, oesophagus and brain cancer, and a method of preparing this delivery system. Said triblock copolymer comprises polylactic acid (PLA), polycaprolactone (PCL) and polyglycolic acid (PGA). By means of the drug delivery system that is the subject of the invention, the therapeutic efficacy of the chemotherapy drugs used is increased compared to the existing liposomal drug delivery systems, possible side effects as a result of chemotherapy are prevented and a controlled drug release is provided.

The drug delivery system that is the subject of the invention, developed for use in cancer treatment comprises, per 100 mg, 5-8 mg of nanographene, 22-35 mg of triblock copolymer (polylactic acid:polycaprolactone:polyglycolic acid triblock copolymer in a ratio of 73: 12:15, respectively) and 5.5-10 mg of anticarcinogenic agent.

PLA, PGA and PCL are the most common synthetic biodegradable polymers used in medical applications. Polylactic acid (PLA) is a biodegradable, biocompatible, nontoxic and environmentally friendly polymer. Because of its bioabsorbability and biocompatibility in the human body, PLA is used in dermatology and cosmetics to manufacture tissue engineering scaffolds, drug delivery systems, orthopaedic devices, and different bioabsorbable medical implants and sutures.

Polyglycolic (PGA) acid is a linear, aliphatic polyester. PGA is a biodegradable material with high crystallinity, insoluble in most organic solvents, and whose fibres exhibit high strength and modulus. PGA is often produced in mesh form and has been used as a scaffold for bone, cartilage, tendon, tooth, intestinal, lymphatic and spinal regeneration.

PLGA is a copolymer of poly-lactide (PLA) and poly-glycolide (PGA). Therefore, PLGA properties are highly dependent on the chemical structure and molar ratio of the main component polymers. PLGA is one of the best-known carriers used in the biomedical field for continuous, controlled and targeted delivery due to its excellent biocompatibility, ease of manufacture, versatile degradation kinetics, good mechanical strength and regulatory approval for in-vivo applications.

Polycaprolactone (PCL) is a synthetic, biodegradable, aliphatic semi-crystalline, FDA- approved polymer widely used in biomedical applications, especially in controlled drug release systems.

Graphene is a single-atom-thick honeycomb layer composed of carbon atoms and is one of the most promising nanomaterials due to its unique combination of properties. Charge carriers in graphene behave like massless relativistic particles or Dirac fermions due to the compression of conduction and valence bands at the Brillouin region comers, resulting in a linear distribution of the energy spectrum. Also, graphene displays the unusual semi-integral quantum Hall effect for both electrons and holes at room temperature. The synthesised graphene has an extraordinarily fine nanostructure, very high specific surface area, high thermal conductivity, high impermeability and chemical inertness. The method of preparing the drug delivery system that is the subject of the invention comprises the process steps of: i. Synthesising the nanographene using acetylene gas at a temperature of 900-1200°C and a pressure of 0.5-2 atm in a chemical vapour deposition reactor, ii. Synthesising the polylactic acid: polycaprolactone (PLA:PCL) copolymer with two hydroxyl groups at both ends, by ring-opening polymerisation of caprolactone using oligomeric PLA diol at 170 - 200 °C under nitrogen for 30 - 45 minutes, followed by the formation of PLA:PCL:PGA triblock chains in 73: 12: 15 ratios, respectively, using glycolic acid (GA) of the final extension step of polycaprolactone-polyglycolic acid (PCL-PGA), iii. after adding distilled water, 1-3% sodium chloride (NaCI) and 5-8% synthesized nanographene into the reactor, shaking the substances added into the balloon in an ultrasonic bath at 25-40°C for 30-45 minutes and ensuring the homogeneous distribution of the nanographene in the mixture, iv. adding 20-30% PLA:PCL:PGA triblock copolymer to the resulting mixture and keeping the polymer-added mixture mixed at 25°C for 40-60 hours, v. purifying the solid phase to be used as a drug delivery system by filtering the mixture obtained with the help of a filter, vi. adding 55-65% distilled water and 7-10% anticarcinogenic agent in powder form to the separated solid phase at once and mixing the resulting mixture for 40-60 hours, vii. separating the solid phase by filtering the obtained mixture comprising nanocamer and anticarcinogenic agent with the help of a filter, and viii. adding 55-65% distilled water to the separated solid phase and filling and packaging the resulting mixture into medicine bottles.

The anticarcinogenic agent mentioned in the method is paclitaxel. The drug delivery system comprising the obtained anticarcinogenic agent is administered by intravenous injection using the main vein or peripheral venous line. REFERENCES

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