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Back to Journal »International Journal of Nanomedicine» Volume 16

Current trends and challenges in the pharmacoeconomics of nanocarriers as cancer therapeutic drug delivery systems

Author Milewska S, Niemirowicz-Laskowska K, Siemiaszko G, Nowicki P, Wilczewska AZ, Car H

Published on September 28, 2021, the 2021 volume: 16 pages 6593-6644

DOI https://doi.org/10.2147/IJN.S323831

Single anonymous peer review

Editor approved for publication: Professor Israel (Rudi) Rubinstein

Sylwia Milewska,1 Katarzyna Niemirowicz-Laskowska,1 Gabriela Siemiaszko,2 Piotr Nowicki,1 Agnieszka Z Wilczewska,2 Halina Car1 1 Department of Experimental Pharmacology, Bialystok Medical University, Bialystok, Poland 15-361 2 Department of Chemistry, Bialystok University, Bialystok, 15-245, Poland Corresponding author: Katarzyna Niemirowicz-Laskowska; Halina Car Department of Experimental Pharmacology, Bialystok Medical University, Szpitalna 37, Bialystok , 15-361, Poland Phone 48602749149; 48604831512 Email [email protection]; [email protection] Abstract: Nanotherapy is a part of nanomedicine, involving nanoparticles as carriers to deliver drugs to target locations. It has been found that this new targeting method can solve various problems, especially those related to cancer treatment. In nanotherapy, carriers play a vital role in coping with many existing challenges, including the protection of drugs before the early degradation of active substances, so that they can reach target cells and overcome cell resistance mechanisms. This review includes the following parts: The first part introduces pharmacoeconomics as a branch of medical economics, and the second part covers various beneficial aspects of the use of nanocarriers for in vitro, in vivo, pre-phase and clinical research, such as and on the issue of drug resistance. Discuss and propose solutions to overcome it. The third part discusses the progress of drug preparation and the optimization of nanoparticle synthesis technology. Finally, the pharmacokinetic and toxicological properties of nano-formulations produced by the latest research are summarized. In this review, the latest developments in the economic impact of nanotechnology are introduced, especially its beneficial applications in medicine. The main focus is on cancer treatment, but other application areas closely related to cancer epidemiology and treatment are also discussed. In addition, it also introduced the current limitations of nanomedicine and its huge potential in improving and developing the healthcare system. Keywords: nanotechnology, pharmacology, pharmacoeconomics analysis, pharmacoeconomics, nanomaterial synthesis, clinical trials

Nowadays, more and more evidences show that nanomedicine may have completely changed the treatment and diagnostic procedures, especially cancer treatment. This new technology provides a new tool set that affects disease prevention through the application of new molecular diagnostic disease markers, early diagnosis of tumor lesions in molecular imaging, and precise and effective therapies based on personalized medication regimens. 1,2 In addition, there is evidence that combining nanomedicine with pharmacoeconomic evaluation can help reduce the cost of managing cancer patients, for example, by shortening the length of hospital stay or reducing the number of tests that need to be performed. Another important fact worth mentioning is that the efficacy of drugs used with nanocarriers can significantly reduce cytotoxicity, preventing side effects by reducing the dose and reducing the accumulation of therapeutic compounds in healthy body parts. 3,4 The above considerations provide a good foundation to master nanotechnology in the future medical development and be able to provide efficient and safe products. These new methods should be provided at a reasonable cost and help limit healthcare costs while maintaining clinical efficacy. 3,5

From the perspective of pharmacoeconomics, the development of new drug substances and products (such as nanosystems) and their introduction into the pharmaceutical market can help provide more affordable care. Specifically, the potential to reduce adverse events plays an important role in new encapsulation therapies, thereby reducing medical procedures and reducing personnel costs. It also provides greater opportunities for relief and enables patients to return to professional life. 5,6

In addition, it should be emphasized that the application of nanotechnology in the medical field has many advantages, because nanoparticles have made significant contributions as drug delivery systems due to their unique characteristics such as small size and large surface area. 7-9 The nanoformulation of the drug increases the efficacy by enhancing the cellular uptake of the drug in the cell target; therefore, it achieves a better biodistribution. Compared with traditional forms of drugs, nano-scale preparations show better drug release kinetics control, thereby increasing the active concentration and bioavailability. Another important factor is that nanomedicine can significantly inhibit tumor growth, prolong the overall survival time and targeted delivery of cancer patients, which may enhance the cytotoxic effect on tumor cells and limit systemic adverse reactions. 10,11 All of the above advantages make nanotechnology much cheaper than traditional therapies. This can also be reflected in pharmacoeconomics, that is, reducing or completely avoiding medical (hospitalization, medical equipment, monitoring and treatment) and non-medical procedures (accommodation, transportation). ) Related costs or informal care).

It is worth noting that an extensive literature review was conducted. This article introduces the existing evidence that proves the effectiveness of commonly used chemotherapy drugs to replace different types of cancer and the expected economic benefits of drugs. Some factors may affect the outcome of the applied treatment plan, such as the patient's age, disease stage, treatment start, duration of benefit, and time to relapse. Pharmacoeconomic analysis of alternative treatment options will improve decision-making and help optimize the use of already limited medical resources allocated to cancer patient care. 12 This article aims to determine the potential benefits of applying pharmacoeconomics to the rapidly evolving field of nanotechnology, especially in the field of cancer treatment drug development, as shown in Figure 1. Figure 1 The impact of pharmacoeconomics in biomedical nanotechnology.

Figure 1 The impact of pharmacoeconomics in biomedical nanotechnology.

Pharmacoeconomics is considered a branch of health economics, which identifies, measures and compares the costs and consequences of drug treatments on the healthcare system and society. 13-15 In addition, it provides necessary guidance for the management of limited medical resources and medical practices. Given the limited financial resources, health economics, especially pharmacoeconomics analysis, is becoming a commonly used decision-making standard in modern healthcare policies. 16,17 Therefore, finding a new type of treatment that is characterized by high efficiency and limited side effects is still an urgently needed goal.18

Pharmacoeconomics applies the principles of health economics to the field of drug policy. In addition, it uses a wide range of health economic assessment techniques in the specific context of drug management. 19,20 In fact, the introduction of new forms of drugs (such as drugs encapsulated in carriers) is for pharmacoeconomic purposes.

If we consider pharmacoeconomic analysis, we should follow a clearly defined step-by-step approach: a) Define pharmacoeconomics problems-we should state the problem and choose goals; b) determine the research perspective-the most popular are: patients, Providers, payers and society; c) Identify relevant interventions-we need to answer an important question: "Has all relevant interventions (including non-pharmaceutical interventions) been identified?"; Use decision trees or treatment models; d) Select the appropriate pharmacoeconomics method-CEA, CMA, CUA, CBA; e) Select the main data source and research design-retrospective/prospective clinical trial data, economic (natural) trial data; f) Select secondary data Sources-such as databases, literature, clinical expertise; g) selection of appropriate analytical techniques-modeling, meta-analysis; h) determination of alternative intervention measures and results-beneficial and adverse health outcomes and resource outcomes; i) Use analytical methods-determine the probability of outcome events and answer research questions-such as efficiency, incidence of adverse drug reactions and decision trees; j) estimate costs and effectiveness-reduce costs and results; perform incremental costs Analysis; k) Conduct sensitivity analysis—determine the impact of changing uncertain variables on a series of results/hypotheses; l) Interpret and present results—describe hypotheses, methods, and data sources; research limitations, including major omissions in statements; Interpret the result 21

There are four most popular analyses to estimate the results, and each method is related to a different type of pharmacoeconomic analysis, as shown in Table 1. Table 1 Types of pharmacoeconomics research. 21-24

Table 1 Types of pharmacoeconomics research. 21-24

In pharmacoeconomics analysis, cost is a key factor that should be considered. They can be divided into direct (medical and non-medical), indirect and intangible costs. Financial costs involve monetary payments related to the prices of goods or services traded in the market. Economic costs match the broader concept of resource consumption, regardless of whether these resources are traded in the market. 13,24 In Table 2, we summarize and detail the types of costs considered in pharmacoeconomics. These costs and the expected pharmacoeconomic efficacy measurements when applying nanocarriers in cancer treatment are shown in Table 3. Table 2 Types of costs in pharmacoeconomic analysis. 13,22,24 Table 3 The efficacy of the selected drugs and the expected pharmacoeconomic benefits due to their nano-formulations. 115,140–167

Table 2 Types of costs in pharmacoeconomic analysis. 13,22,24

Table 3 Efficacy of selected drugs and expected drug economic benefits due to their nano-formulations. 115,140–167

For any pharmacoeconomic analysis, the perspective is important because it determines which costs and benefits are to be measured: 1. Society-all costs and consequences that occur during treatment, 2. Third-party payers-insurance companies, employers , Or government; including direct costs, but can also include indirect costs, 3. Hospitals/doctors (health care providers)-providers include hospitals, private practitioners or managed care organizations; from this perspective, including direct Medical expenses, 4. Patient-all expenses borne by the patient for any product or service are not included in any insurance coverage; there are direct, indirect and intangible costs (out of pocket). Based on the above, if we are considering the safe application of nanocarriers in modern treatments, these costs/analysis should be considered. 13,25

The National Cancer Institute defines cancer as a group of abnormal cells that divide uncontrollably and can spread to various tissues. Cancer can manifest in different parts of the body-leading to a range of different cancer types. 26 According to available data, it is estimated that cancer is one of the main causes of death. In 2018, an estimated 9.6 million people died from various forms of cancer. Globally, WHO roughly estimates that 1 in 6 people will die from cancer. Consider income—about 70% of cancer deaths occur in low- and middle-income countries. In terms of frequency and number of deaths, the most common cancers are lung cancer, breast cancer, and colorectal cancer. 27

The cancer burden is related to the risk factors belonging to three main groups. They are: socioeconomic, lifestyle and genetic/health predispositions, including long-term and chronic inflammation caused by microbial infections. In addition to the fact that microorganisms may induce chronic inflammation, there is evidence that they can produce carcinogenic bacterial metabolites, which can lead to mutations in genetic material. 28 This means that interference from one of these groups triggers the cascading process leading to development. cancer. Researchers have discovered several risk factors that may increase the risk of lung cancer, breast cancer, and colorectal cancer (Figure 2).

As far as lung cancer is concerned, the number one risk factor is smoking. Smokers are 15 times more likely to develop or die of lung cancer than non-smokers, and even as high as 30 times. Smoking only a few cigarettes a day or occasionally smoking a few cigarettes can increase the risk of lung cancer. The longer a person smokes and the more cigarettes smoked each day, the greater the risk. It is misleading to think that smoking will only cause lung cancer. Smoking can also cause several other tumors, such as oral and throat cancer, esophageal cancer, gastric cancer, colon and rectal cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, and even acute myeloid leukemia. 29 In addition, it should be emphasized that tuberculosis, pneumonia, and chronic bronchitis are examples of pathology, and they have a profound role in the emergence of cancer. In fact, as far as lung cancer is concerned, persistent microbial infection is the main inflammation-inducing factor, which is known to be the cause of cancer development. 30

The risk factors of breast cancer can be divided into changeable and unchangeable. 31 In order to reduce the risk of breast cancer, every woman should actively exercise and maintain a normal weight, if possible-avoid taking birth control pills and hormone replacement therapy, get pregnant for the first time before the age of 30, breastfeed, and have enough Month pregnancy. Smoking, exposure to chemicals, alcohol, and other hormone changes due to night work may also increase the risk of breast cancer. 31 Unchangeable risk factors include age, genetic mutations, reproductive history, dense breasts, personal and family history of breast cancer, and previous treatment with radiation therapy. Importantly, there is evidence that chronic inflammation that may be caused by microbial infections is associated with the risk, development, and progression of breast cancer. 32 For example, it is determined that breast cancer is an example of the other 15 cancers. Compared with the general population, the risk of occurrence of Staphylococcus aureus bacteremia (SAB) is significantly increased one year after. 33 Screening for cancer in people with SAB infection may allow earlier detection of the disease. In addition, the presence of chronic infections can also affect the human microbiota. Recent studies have found that people who respond well to immunotherapy to treat cancer appear to have a different microbiome composition than people who do not respond well. 34 Figure 2 The burden of cancer: risk factors and frequency of confirmed cases and deaths (at center 35).

Figure 2 Cancer burden: risk factors and frequency of confirmed cases and deaths (at center 35).

As the patient gets older, the risk of colorectal cancer also increases. 36 Approximately 90% of cases occur in people in their 50s or older. Other risk factors include inflammatory bowel disease (Crohn’s disease, ulcerative colitis), personal or family history of colorectal cancer or colorectal polyps, and genetic syndromes such as hereditary non-polyposis colorectal cancer (Lin Odd syndrome). 36 In addition, the published literature has accumulated information on the link between CRC and microbial infections in recent decades. It has been announced that both viruses and bacteria can induce colorectal cancer through long-term infection and accompanying inflammation and mutagenesis to induce epithelial cell proliferation out of control. According to clinical and laboratory test data, among the above-mentioned microbial preparations, Streptococcus bovis, Helicobacter pylori, Escherichia coli, Klebsiella pneumoniae and Fusobacterium have a key role. 37

It should be remembered that lifestyle factors may also increase the risk of colorectal cancer, such as lack of regular physical exercise, low fruit and vegetable diets, a low-fiber and high-fat diet or diet of processed meats, overweight and obesity, alcohol and alcohol consumption. The proportion of smoking is high. 36

It is worth noting that by avoiding risk factors and implementing existing evidence-based prevention strategies, 30% to 50% of cancers can be prevented. Early detection of cancer and management of cancer patients can also reduce the burden of cancer. Many cancers can be cured if they are diagnosed early and treated appropriately. 38 In addition, it should be emphasized that inflammation is often associated with the development and progression of cancer. 39 Chronic inflammations that increase the risk of cancer include bacterial infections. In fact, the application of nanotechnology products with proven antibacterial properties may have important implications for cancer prevention (Table 4). Table 4 Examples of nanotechnology-based applications with proven antibacterial properties

Table 4 Examples of nanotechnology-based applications with proven antibacterial properties

Adequate preventive measures and early detection and treatment may greatly reduce cancer mortality. Effective detection has two components: 1. Early diagnosis-cancer diagnosed at an early stage, when it is not too large and has not spread, is more likely to respond better to effective treatment and can lead to greater improvement Survival rate, mortality reduction and treatment costs are lower; 2. Screening-aims to detect cancer before symptoms appear. This definition means that it is the presumptive identification of unidentified diseases or defects through tests, inspections or other procedures that can be quickly applied. 60

However, due to the failure of the systematic approach, in most cases, the implementation of the above preventive measures cannot be completed.

Recently, more and more evidences have shown that nanoparticle-based targeting strategies are effective and promising at the diagnostic and therapeutic level, and may include a variety of cancers, such as colorectal cancer, breast cancer, ovarian cancer, or lung cancer. 61,62 Nanotechnology can be used for disease prevention, diagnosis and treatment, especially by realizing early disease detection and diagnosis as well as precise and effective treatment, which is essential for formulating personalized treatment strategies. In fact, the implementation of the above-mentioned new concept of personalized medicine may provide an effective treatment method for almost any type of malignant tumor. Figure 3 shows the various applications of nanotechnology in the field of prevention, diagnosis and treatment. Figure 3 Application of nanotechnology 1

Many types of nanodevices can be used clinically for different types of detection, such as imaging contrast agents, immunoassays, or targeted drug delivery systems. Table 5 lists commonly used nano-devices and their main application areas. Table 5 Types of Nano Devices in Clinical Applications

Table 5 Types of Nano Devices in Clinical Applications

Accurate cancer diagnosis is essential for fully effective treatment, because each type of cancer requires a specific treatment plan that includes one or more actions, such as surgery, radiation therapy, and chemotherapy. Determining treatment goals and palliative care is an essential first step, and health services should be integrated and patient-oriented. The fundamental purpose is to cure cancer or prolong life. Improving the quality of life of patients is not trivial. This can be achieved through supportive or palliative care, as well as minimizing drug side effects and psychosocial assistance. 73

The size of nanocarriers used in drug delivery systems is generally below 500 nm. They are made of organic (lipids, liposomes, dendrimers, polymers) or inorganic (carbon nanotubes, iron oxides, metals) materials and mixtures of their different sizes, shapes and surface characteristics. 74 Examples of the most widely used anti-cancer drugs as part of a drug delivery system, specify nanocarriers and cancer types, as shown in Figure 4. Figure 4 The use of nanocarriers. 73

In order to achieve targeted drug delivery with maximum pharmacokinetic activity at the pathological site, continuous advancements in drug delivery systems using nanotechnology strategies have been noted. The use of drug carriers provides multiple benefits in terms of the chemical and biological properties of the drug. From a chemical point of view, the application of nanocarriers has an impact on the solubility and permeability of drugs. In addition, the surface characteristics, the immobilization of homing molecules and the sensitivity of the carrier to different stimuli determine specific site delivery, regulate drug release, affect the biodistribution and retention process, and affect the immunomodulatory properties of the carrier. The above characteristics indicate that there is a strong correlation between physical chemistry and biological characteristics.

The most critical goal of nano-encapsulation is to solve the problem of poor drug solubility. 74 Most of the drugs currently in use are molecules with poor water solubility, which is why various methods of immobilizing and encapsulating drugs in nanoparticles are used to improve their bioavailability. Drugs can be increased by adding additives (DMSO) Solubility, however, may be toxic even at low doses. 75 From a pharmacoeconomics point of view, insoluble drug delivery technology has many benefits, including reduced dosage and related toxicity, improved formulation, reduced costs, patent protection, or patient compliance. 76

Nanocarriers used for hydrophobic drug delivery are usually composed of biodegradable monomers or prefabricated polymers (polymer nanoparticles), and amphiphilic building blocks. Due to their organizational structure, the drug is located in a hydrophilic carrier (polymer glue). The hydrophobic interior of bundles, liposomes), or structures that exhibit guest characteristics (dendrimers, carbon nanotubes).

Polymer nanoparticles can be divided into (1) nanospheres, in which the drug is captured or dispersed in a polymer matrix, and (2) nanocapsules, composed of drugs dissolved or dispersed in an oily or aqueous core, according to their organization. The core is surrounded by a solid polymer film. A large number of drugs, including anticancer drugs (paclitaxel, 5-fluorouracil), anti-inflammatory drugs (ibuprofen, diclofenac) and antibiotics (rifabutin, benzathine penicillin G) are described as preparations based on polymer nanoparticles. Many PNPs with hydrophobic anticancer drugs are in different stages of clinical trials. 73,74

In another strategy involving the use of polymer micelles, water-insoluble drugs exhibit an affinity for the hydrophobic regions of micelles formed by diblock hydrophobic-hydrophilic polymers. Because the drug is encapsulated, hydrophilic nanocarriers are produced, and because the critical micelle concentration is usually low, it can remain stable even after being diluted by body fluids. Drug-containing polymer micelles already exist on the market, such as Genexol PM® containing paclitaxel. 76

Another example of the delivery of poorly soluble drugs is liposome formulations, in which lipophilic drugs can be dissolved in the lipid fragments of the phospholipid bilayer membrane. Liposome carriers are very flexible in terms of their structure and function. Lipid formulations of anticancer drugs have been successfully marketed, such as Endo®-TAG-1, which is a product containing paclitaxel that uses positively charged phospholipid vesicles to treat pancreatic cancer. 77,78

Finally, hydrophilic dendrimers are considered suitable carriers because drugs can be encapsulated inside them. The configuration of the polymer can be influenced by changing the pH value, the type of solvent, and the design of the polymer structure itself, thereby controlling the existence of cavities. At the same time, the encapsulation mechanism can utilize electrostatic, hydrophobic, acid-base interaction or hydrogen bonding between the drug and the polymer. Although there are no dendrimer-based products on the cancer drug market, studies have shown that some known dendrimer carriers are good drug candidates. For example, it is reported that in addition to better drug solubility, polyamidoamine branched polymers with hydrophobic paclitaxel also show 10 times higher anticancer activity than free drugs, which is attributed to better tumor cells. Absorption. 79

Interestingly, in the latest literature, there are similar bio-inspired drug delivery solutions, such as the use of amphiphilic proteins to stabilize hydrophobic drugs and induce biosilicidation on their surfaces, thereby forming drug-core silicon-shell nanoparticles. 80

Other interesting examples are hydrogels, biocompatible cross-linked hydrophilic polymer networks, which are known to be a good hydrophilic drug delivery system, which can be modified to encapsulate hydrophobic drugs, for example, by having a hydrophilic part or Molecules with cavities in their structure even contain polymer micelles or nanoparticles and encapsulated drugs. 81

A key factor in the effectiveness of the drug is the successful entry of the diseased site. This can be improved or achieved through the use of nano-scale drug delivery systems, which can themselves pass through biological barriers or allow encapsulated drugs to pass through them to achieve maximum effect on the target. Depending on the method of administration (intravenous, oral or inhalation), nanocarriers must pass through various obstacles in the process of reaching tissues or organs and then reaching cells or organelles. This is done through two modes of transportation, "passive" and "active" of". Targeted drug delivery systems (TDDS) have many advantages, including (1) reducing the exposure of healthy cells to cytotoxic compounds, (2) overcoming the increasingly common drug resistance of tumors, and (3) reducing the side effects of treatment, directly from drugs From an economic perspective, it translates into profit. 82

"Passive", non-specific targeting is related to reduced nanoparticle size and surface properties, such as hydrophobicity, surface charge, or non-specific adhesion, which may lead to organs with porous endothelial capillaries (liver, spleen) and help For example, in the case of cancer, an increase in permeability and retention (EPR effect) can be observed, which is based on the size of nanoparticles that selectively penetrate into cancer cells compared to normal tissues. This is caused by the leaky nature of tumor blood vessels lined with 100 to 700 nm endothelial cells, which is 10 to 70 times that of normal endothelial cells. This, combined with the weak drainage system typical of solid tumors, leads to the accumulation of drug-loaded nanoparticles in the tumor.

In addition, due to the increased metabolism of tumor cells, the surrounding environment is characterized by acidic pH and slightly elevated temperature, which can be used to design stimulus-responsive nanocarriers. Finally, tumors will release specific enzymes (such as metalloproteinases) into their surrounding environment. In addition to being tumor markers, these enzymes can also be recognized by functionalized drug delivery systems. 73

Unfortunately, for some organs, the use of nanosystems for passive drug delivery is significantly hindered due to the poor permeability of biological barriers, such as the blood-brain barrier (BBB). In these cases, "active" transport methods can improve the ability to pass through the membrane. 84 "active targeting" relies on the increased selectivity of drug-loaded nanocarriers through its surface functionalization, and the ligands show affinity for pathological sites. These ligands, including antibodies, peptides, proteins, glycoproteins, growth factors, nutritional compounds, vitamins, or nucleic acids, are bound by receptors that are overexpressed on cancer cells. Then, receptor-mediated endocytosis ensures that the cells take up the nanocarrier, thereby providing a higher drug concentration in the cytoplasm. An interesting example of a ligand is folic acid, whose receptor (FR) is overexpressed in many types of cancer, such as breast, lung, ovarian, and colorectal tumors. 85 Among the classic targets, there are transferrin receptor (TfR) or nicotinic acetylcholine receptors, which are typical features of the vascular system of brain tumors. 86

In addition, targeting many parts of the tumor endothelium, such as vascular endothelial growth factor (VEGF) or vascular cell adhesion molecule (VCAM), can be a supplementary strategy for drug delivery because it involves the destruction of the endothelial wall, thereby cutting off oxygen and nutrients. Get to cause cell death. 73

Another advantage of nanocarrier functionalization is the combination of carrier and fluorescent label, which allows tracking of carrier and drug in in vitro and in vivo studies, which can be used in therapeutic diagnostics. 87

Today, most clinical trials using nanocarriers use "passive" transport,85 and the use of EPR effects in drug delivery system design has become the standard. Some of these products are commercially available, such as Doxil®, a liposomal formulation of cytotoxic doxorubicin, or Caelyx®, a pegylated liposomal formulation of the drug. In addition, many studies are using the "active" mechanism of cell permeation to record the anti-tumor activity of nanosystems in vivo, some of which are undergoing clinical trials, including lipids containing doxorubicin and scFv antibodies as ligands that target human epidermal growth Body Nanoplatform Factor (HER2) receptor in advanced breast cancer, and polymer nanoplatform with docetaxel and nucleic acid-based protein ligand (ACUPA), targeting prostate-specific membrane antigen (PSMA) in solid tumors . 86

Compared with the use of free drugs, the drug delivery system (DDS) has many advantages. Generally, one type of carrier significantly improves a given therapy by improving several chemical properties of the formulation, thereby increasing the stability of the formulation and the drug during storage, the in vivo stability of the formulation, and also allowing the prolonged release of the drug.

It can be very helpful to maintain the unchanged properties of the drug during storage and expand its applicability in drug delivery systems. For example, it is reported that a carrier made of cyclodextrin can improve thermal stability and reduce drug volatility. 88 Hsiao and colleagues described another case where they showed that chlorophyll is a valuable biologically active compound known for being sensitive to oxygen. It has high temperature and light and has been encapsulated in polycaprolactone for higher stability. Sex, so it’s easier to store. 86

The drug delivery system can improve the stability of the drug in the body and protect it from degradation before and after entering the systemic circulation by reducing the metabolic clearance rate in the blood and gastrointestinal tract (GIT) or the renal reticuloendothelial system (RES) clearance rate. However, it is very important to maintain constant nanoparticle parameters, such as size, morphology, size distribution, porosity, or crystallinity, because their interference can cause changes in the pharmacological properties of the drug-loaded nanosystem. Some active parts, such as DNA or siRNA, have unfavorable physicochemical properties (molecular weight, charge, sensitivity to enzymatic degradation), and must be used clinically together with appropriate nanocarriers. 88,89 Especially when enzymes are immobilized on nanocarriers, in addition to improving stability, they also have advantages such as reduced protein degradation, resistance to mass transfer, high mechanical strength and minimal diffusion problems. 90 One should also mention the "stealth" technology used for liposomes, which involves attaching the synthetic polymer poly(ethylene glycol) (PEG) to the liposome structure. This modification prolongs the presence of intact PEGylated nanocarriers in the blood by reducing the uptake of the mononuclear phagocyte system (MPS). 91

The preparation must be stable to external factors that mimic the conditions in the body, so the nanomaterials cannot be used clinically without evaluation. 83 For example, Villamizar-Sarmiento et al. conducted a comprehensive study and confirmed that the prepared poly(styrene)-based nano-pharmaceutical sulfonate) polymer can be maintained for more than ten days under different salt concentration (NaCl), pH value and temperature. Constant hydrodynamic size and zeta potential, and durable despite freeze-drying and re-dissolving in water. 92 Similarly, Kanwar et al. studied structural changes in nanostructured lipid carriers (NLC) under pressure conditions, such as changing electrolyte concentration, pH, and stabilizing polymer additions. Interestingly, NLC can resist environmental changes, which is important for its pharmaceutical applications. 93

The immobilization of hydrophobic and hydrophilic drugs helps ensure their controlled and sustained release and avoid burst effects, which is impossible without a carrier. 94 Due to slow-controlled drug release, the active substance has a prolonged circulation in the body and is released at the pathological target site. In one of the strategies, due to the specific chemical properties of the designed nanocarrier, its durability can be controlled in the body by local stimuli, such as abnormal pH, 95 temperature, 96 or ionic strength 97 (so-called stimulus response materials). For example, Guo et al. reported the synthesis of a carrier composed of cationic liposomes coated with carboxymethyl chitosan, which is stable under physiological conditions, but rapidly transforms into a tumor-specific acidic environment (pH=6.5). Cationic form, which helps tumor-specific cellular uptake. In addition, in the presented study, the use of a dual drug delivery system can synergistically use two active molecules, namely an anticancer drug (doxorubicin) and an oncogenic protein inhibitor (MDM2). 98 Recently, Razavi et al. described the multi-stimulus response based on poly(N-(2-(dimethylamino)ethyl)-methacrylate) (PDMAEMA) and poly(methyl methacrylate) (PMMA) chains. The sexual block copolymer is terminated with spiropyran, where the size of the nanoparticles, and doxorubicin are controlled by pH, light and temperature. 99

From a pharmacological point of view, it is important to ensure effective drug encapsulation to avoid the side effects of excessive use of nanocarriers in the body, such as clumps that cause immune system excretion, high blood pressure, renal failure, or systemic toxicity . 100 Unfortunately, most currently known drug delivery systems are characterized by low loading efficiency (less than 10%), which is related to the use of a large number of carriers. 101 In order to achieve good loading efficiency, the types of materials used (mainly characterized by large surface areas) and their surface modification and drug encapsulation/immobilization methods are important. Generally speaking, drug loading mechanisms through non-covalent interactions most often lead to low drug loading, while covalent bonds or coordination bonds have high drug loading efficiency. This non-covalent bond is the electrostatic interaction between the drug and the carrier surface, π-π stacking, hydrogen bonding, or hydrophobic/hydrophilic interaction. For example, the most popular carrier liposomes, depending on their morphology, are characterized by hydrophobic or hydrophilic drug-carrier interactions. In the case of polymer nanoparticles or dendrimers, they can form structures that allow drugs to be encapsulated in micelles or hollow structures, respectively, or bind drugs through chemical linkers. Generally, enzymatic or chemically cleavable linkers are used, such as amides, esters, disulfide bonds or phosphate esters. There are also examples of specific linkers that are sensitive to stimuli or enzymes typical of the tumor environment. For example, disulfide bonds can be broken by glutathione, an enzyme that is overexpressed on cancer cells. 102,103

Due to the structure of nanocarriers, the following types of high drug loading nanomedicine can be distinguished: 1. Inert porous materials as carriers (silica, carbon or protein nanoparticles); 2. Polymer-drug conjugates (PDCs) ; 3. Coordination polymer nanoparticles (metal organic framework); 4. Carrier-free nano-drugs (drug nanocrystals, amphiphilic drug-drug conjugates). 103 The PDC system used is a solid dispersion of a drug in a hydrophilic polymer, and a nanoconjugate of an amphiphilic or hydrophilic polymer and a drug. Recently, various PDC carrier improvement strategies have been introduced to improve loading efficiency, such as the use of: 1. Multi-arm polymers coupled with drugs; 104 2. Hydrophobic 105 and hydrophilic 106 drugs as part of the core-shell carrier structure; 3. Two drugs with opposite hydrophilicity are connected by a hydrophilic carrier (spacer); 107 4. Encapsulated in the core cross-linked polymer. 108,109

Another type of nanomaterial that overcomes the problem of low drug loading is nanocages (protein, gold, carbon, silica or DNA NCs), which have a hollow structure and can contain up to thousands of drug particles. 97 A different way to increase the effectiveness of drug loading lies in surface modification. For example, porous iron oxide nanoparticles (IONP) coated with materials such as silica, surfactants, carbon, and polymers can be used as drug carriers. In addition, the introduction of functional groups on the surface can be further modified, such as modification with proteins, which further increases the affinity for drugs. 103 Another example describes calcium phosphosilicate nanoparticles (CPSNPs) as phosphorous drug nanocarriers (5-fluorouracil), where effective drug encapsulation is possible due to the metal ligand complex between the phosphate group and calcium . 99

Facts have proved that the effectiveness of the encapsulation procedure depends on many factors. In the literature, a comprehensive analysis of specific carriers combined with various drugs and encapsulation methods can be found. For example, Krakiewicz et al. described the fact that the fixation route should be selected according to the type of drug, in which two different loading methods have been tested with two different active substances. For quercetin, the highest loading was achieved by immobilizing on the polypyrrole matrix during the electropolymerization process, while in the case of the second test drug, ciprofloxacin, it was incorporated during the post-modification (polymer oxidation) process. Entry efficiency is higher. 110 In addition, Perotto et al. reported that in addition to drug properties such as hydrophilicity and molecular weight, the charge of the drug may have the most significant impact on its encapsulation. For example, positively charged methylene blue achieves up to 88% in keratin nanoparticles. % Encapsulation efficiency. 111 In addition, Nagy and colleagues used the Box-Behnken experimental design to study the encapsulation of curcumin into polyε-caprolactone NP, where the variables in the encapsulation process are the initial amount of the drug and the volume ratio of organic matter to organic matter. The composition of the water phase, as well as the organic phase. The results indicate that the volume of the organic phase containing the drug for polymer nanoprecipitation is critical for effective drug loading. 112

In the latest literature, you can also find reports of encapsulating drugs in high-load carriers through environmentally friendly methods. In other words, due to the aromatic-aromatic interaction and the formation of ion pairs, hydrophilic and aromatic low molecular weight drugs (HALMD) are encapsulated in poly(styrene sulfonate) (PSS), and the yield is about 50%. 113

Doxorubicin (DOX) is commonly used in various types of malignant tumors, such as sarcoma, leukemia, lymphoma, breast cancer, lung cancer, and ovarian cancer. There are two different mechanisms of action: doxorubicin intercalates into DNA and inhibits topoisomerase II leading to changes in chromatin structure; the generation of free radicals and oxidative damage to biomolecules. Repeated use of doxorubicin can lead to drug-resistant cancer cells; it also increases the cytotoxicity of the drug. The interaction between signaling pathways can promote drug resistance by inducing proliferation, cell cycle progression, and preventing cell apoptosis. Doxorubicin-induced drug resistance and tumor growth can occur through the adaptive role of the MAPK/ERK pathway in protecting tumor cells. The resistance mechanism of the Anatomical Therapeutic Chemistry Classification System (ATC) is related to the expression of the multidrug resistance 1 (MDR1) transporter. The MDR1 transporter pumps Dox molecules out of the cell, reducing the intracellular drug concentration and inhibiting the efficacy of chemotherapy. 114,115

5-Fluorouracil (5-FU) can be used to treat solid tumors of the gastrointestinal tract, breast, head and neck, and pancreas. The mechanism of action includes blocking DNA synthesis and replication by inhibiting thymidylate synthase and incorporating 5-FU metabolites into RNA and DNA. 5-FU resistance eliminates the anticancer effect of Chk1's inhibition of amplification, even in p53-deficient cancer cells. Chk1 inhibition may effectively sensitize 5-FU-resistant cancer cells to 5-FU, because Chk1 activation is reported to be related to chemotherapy resistance. It was also observed that in p53-deficient colon cancer cells with or without 5-FU resistance, the synergistic cytotoxic potential of Chk1 inhibition during 5-FU treatment. 116,117

Paclitaxel (PTX) is used to treat a variety of cancers, such as ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. The mechanism of action is related to the targeting of microtubules-it destroys the main function of microtubules, that is, the production of mitotic spindles during cell division, and the maintenance of cell structure, movement, and cytoplasmic movement within the cell. The weakened mitotic checkpoint only confers short-term resistance to mitotic arrest, but also confers activation of the mitotic checkpoint, followed by mitotic slippage leading to optimal cell killing. There are some established markers of resistance or sensitivity to paclitaxel, such as proteasome subunits, cyclin-G1 (CCNG1), and solute carrier genes. Using tamarind seed polysaccharide and paclitaxel through epichlorohydrin cross-linking (PST-PTX) nanoparticles in cancer cell lines and drug-resistant cancer cell lines cytotoxicity was determined by MTT method. Quantitative analysis of cell death was determined by Annexin V dead cell assay, caspase 3/7 assay and the expression of pro-apoptotic protein Bax. Overexpression of ABCB1 gene makes urothelial cancer cells resistant to albumin-bound paclitaxel. 118,119

Each of these drugs has different application areas, mechanisms of action, and various explanations for resistance. Cells develop resistance to different drugs through a variety of mechanisms, including modification of drug targets, changes in drug metabolism, and genetic changes in the pathways of cells against targets. 120 However, it is worth noting that despite these differences, drug resistance remains a major problem in oncology, affecting most cancer patients.

At present, the main treatment methods for cancer treatment include cytotoxic chemotherapy, surgery, targeted therapy, radiotherapy, endocrine therapy and immunotherapy. Although many efforts and achievements have been made in the treatment of cancer in the past few decades, resistance to classic chemotherapeutic drugs and new targeted drugs is still a major problem in cancer treatment. 121 Drug resistance, which is also the drug resistance (acquired) before treatment (intrinsic) or after treatment, is the cause of most cancer recurrences, and this is the main cause of death from this disease. The heterogeneity between the patient and the tumor and the comprehensiveness of cancer bypass treatment make drug resistance more difficult to deal with. There is a need to better understand the mechanisms of drug resistance, provide guidance for future cancer treatments and achieve better results. 121 The complexity of the development of drug resistance suggests that combined and personalized treatments may provide better methods and higher efficacy for combating cancer drug resistance. 122

Cancer presents daunting challenges and will benefit the uniting of experts from a wide range of related and unrelated fields. Combining existing methods with new methods may help solve this challenging health problem, enabling the development of treatments to prevent disease progression and prolong patients’ lives. 122 Regardless of the research method, based on the results of clinical trials and research publications, the application of nanoparticles as a drug delivery system for cancer treatment has the main benefits of enhancing the permeability of blood vessels and gastrointestinal tract and the selectivity of drugs/compounds to tumor cells. Abdifetah et al., 123 pointed out in their review summary that due to the application of nanoparticles, improvements in permeability and selectivity lead to overall improvements in cellular drug uptake, inhibition of first-pass liver metabolism and P-gp efflux, drug solubility and The stability increases and the drug excretion rate decreases. Therefore, the dose can be reduced without affecting the efficacy, thereby minimizing potential drug toxicity. Nevertheless, regardless of the progress made in treatment and research, some challenges in cancer treatment, such as multidrug resistance (MDR), are still under further research to better understand the molecular mechanism and optimize the efficacy and safety treatment method. According to El-Readi et al., 124 due to the peculiarities of tumor tissues, such as abnormal blood vessels and pathological processes that hinder effective cancer chemotherapy, it is important to design and apply new drug delivery methods (such as NP). As we all know, MDR is the result of a coordinated process that occurs directly in cancer tissues and tumor cells. In Figure 5, the different synergistic mechanisms that lead to multidrug resistance (MDR) are summarized. Figure 5 Multidrug resistance in an overview of cancer mechanisms. 125

Figure 5 Multidrug resistance in an overview of cancer mechanisms. 125

The effect on membrane transport is one of the most important mechanisms for the development of anticancer drug resistance. The reduction of drug concentration can be achieved by reducing drug uptake or increasing molecular extrusion. Overexpression of P-glycoprotein is responsible for efflux. It has been proved that the use of nanoparticles loaded with docetaxel (PLGA-PEG) can effectively overcome the MDR mentioned in the article. 126 The author also lists other advantages of using NPs in therapy over standard dosage forms; for example, nano-sized drug carriers minimize the elimination of molecules through the liver or kidneys. Other properties, such as increased permeability and accumulation of drug-loaded nanoparticles, passively target tumor tissues, thereby reducing systemic toxicity.

In the article, Radu et al. introduced another successful application of targeted anti-cancer nanocarriers using biological carriers. 127 Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) carrier was obtained by emulsification-diffusion method, loaded with 5-fluorouracil and its therapeutic potential was studied on human adenocarcinoma cells. As a result, it was observed that the drug-loaded carrier can significantly reduce cell viability, showing a high potential for destroying human adenocarcinoma cells. Overall, nanocarriers have made significant progress in the field of cancer treatment, thereby improving pharmacokinetic properties, enhancing anti-tumor efficacy, and reducing the risks associated with adverse drug effects. There is still a need to study the physicochemical properties and pathophysiological tumor characteristics of therapeutic nanocarriers to gain a deeper understanding of the mechanisms that allow effective and safe cancer treatment. Arranja et al. reported a series of clinically used nanomedicines, mainly including liposomes, polymer-drug conjugates and polymer micelles. 128 Compared with traditional chemotherapy, nanomedicine is characterized by prolonged circulating half-life, increased bioavailability and better tumor treatment; however, they mainly rely on the EPR effect. In order to increase our understanding of actively targeted nanomedicine, the authors suggest and discuss the application of therapeutic diagnostic strategies. The main purpose of this method is to integrate molecular imaging properties into therapeutic formulations to monitor tumor accumulation and therapeutic effects of nanomedicine at the same time of application. More controllable targeted drug delivery should further optimize the therapeutic effect and minimize unwanted cytotoxicity in off-target tissues.

The multidrug resistance (MDR) of cancer to chemotherapy is a key obstacle to effective treatment of malignant tumors, which may lead to the failure of treatment programs. Nanotechnology ensures a novel and unconventional way to circumvent MDR. In Table 6, the latest literature examples of applying nanocarriers to overcome MDR are introduced. The mechanisms and advantages of various types of nanocarriers and potential methods to overcome these limitations are discussed below. Table 6 Mechanisms to overcome drug resistance and the benefits of using nanocarriers

Table 6 Mechanisms to overcome drug resistance and the benefits of using nanocarriers

Compared with traditional anti-tumor drug delivery systems, the establishment of a practical nanotechnology-based drug delivery system may help improve the bioavailability and therapeutic effects of anti-tumor drugs in the future, while providing better accumulation at the target site.

Due to the equivalence in nanocarriers, the efficacy of selected drugs may have an impact on reducing or minimizing the cost of pharmacoeconomic analysis, especially in terms of shortening the length of hospital stay or reducing the number of tests performed. We can also avoid some intangible costs, such as pain, pain or anxiety-if the patient stays in the ward for less time, and the time at home can be faster. In addition, we can reduce the number of days in hospital, thereby reducing the risk of infection and drug side effects, improving the quality of treatment, and increasing hospital profits through more effective bed management. 133

Due to the use of drug carriers, we can observe the following benefits: 1. The economic benefits come from savings associated with more cost-effective medical procedures; 2. The clinical benefits are defined as the direct positive effects of the applied therapy, measured by primary or secondary endpoints . The size of the clinical benefit is a measure of the clinical effectiveness of the medical procedure examined; 3. The unmeasured benefit involves reducing pain, anxiety and improving the comfort of life and its duration.

Comparing the use of traditional therapies with alternative therapies (such as nanocarrier-based therapies), we can evaluate examples of systemic treatment parameters in oncology, such as evaluation of response to treatment (%); percentage of corresponding patients (%); accounted for Percentage of total remission (%); Relapse time (months, years); Percentage of reduced risk of recurrence (%); 5-year survival rate (%); Percentage of response to treatment (%); Percentage of total pathological remission (% ); overall survival time (months); median survival time (months); indicators of quality of life and symptom reduction, such as VAS procedures. 134

Clinical studies have demonstrated the effect of using pegylated liposomal adriamycin in adjuvant chemotherapy for advanced and metastatic breast cancer (Table 7). The results are reflected in Table 7, which reviews the clinical application of PLD in adjuvant chemotherapy for breast cancer, and illustrates the therapeutic effect of pegylated liposomal doxorubicin in various treatment options. These clinical studies have proposed treatment strategies for applying the listed drugs to this type of adjuvant chemotherapy, indicating that the treatment results have significantly improved survival time and progression-free survival time. These two indicators are essential for effective treatment of cancer patients. Table 7 The effect of adjuvant chemotherapy using pegylated liposomal doxorubicin (PLD) on advanced and metastatic breast cancer

Table 7 The effect of adjuvant chemotherapy using pegylated liposomal doxorubicin (PLD) on advanced and metastatic breast cancer

In the past ten years, the application of nanomaterials in cancer treatment has the characteristics of high sensitivity, specificity and effectiveness. Nanomaterials can be used to target cancer cells in a predictable manner using specific ligands and effectively provide encapsulated load capacity. In addition, nanomaterials can be created by changing the size, composition, morphology, and surface area of ​​nanomaterials to increase drug loading, prolong the half-life in the body, slow release and selective distribution. For example, carbon-based materials, polymer nanomaterials, metal nanoparticles, dendrimers, and liposomes have been developed as smart drug delivery systems for cancer treatment. Due to their nanometer size and individual physical and chemical properties, Develop better pharmacokinetic and pharmacodynamic parameters than standard formulations.

The data in Table 3 indicate that nanotechnology will provide new opportunities for cancer management. In addition, a series of nanoparticles have shown significant efficacy in anti-cancer therapy, and their applications can also be discussed in the context of pharmacoeconomics. Considering that all the benefits of using nanomaterials make nanotechnology much cheaper than traditional treatments, this can also be reflected in the expected pharmacoeconomics. This may result in the reduction or avoidance of cancer patient management costs, especially by reducing intervention costs, shortening hospital stays or avoiding disease expenditures, thereby reducing medical procedures, thereby reducing personnel costs and allowing patients to return to professional life.

The website Clinicaltrials.gov was searched on December 9, 2020. The search was conducted using keywords: cancer and nanoparticles. The start and end dates of the study are determined from 01.01.2015 to 09.12.2020. It also defines the status of the study—only studies with a "completed" status are considered. As a result of this search, 13 studies that met the above criteria were found. The search strategy is shown in Table 8. Table 8 Terms and synonyms searched in the clinical trial database

Table 8 Terms and synonyms retrieved in the clinical trial database

In summary, in Table 9, all studies are interventional (clinical trials) and these studies are available on the clinical trials.gov website. Each study involved a different number of patients, ranging from 2 to 146 participants. Different types of cancer are studied, and the severity is considered, regardless of whether it is metastatic cancer or not. Each study describes the experimental group or placebo group, and treatment/other interventions. According to the agreement, selected endpoints—primary, secondary, or other—are included in the study. Table 9 Features of retrieved clinical studies

Table 9 Features of retrieved clinical studies

Unfortunately, so far, none of these 13 studies have published any results, so we cannot draw any conclusions, but we can say that the use of nanoparticles in medicine to treat cancer is becoming more and more important. It's getting more and more popular.

In the manufacturing process of pharmaceutical dosage forms, different methods should be considered. The choice of manufacturing method usually depends on the clinical efficacy requirements of the final product, including size distribution, chemical composition and drug release characteristics, which determine the pharmacokinetic proof of adsorption, distribution, metabolism and elimination (ADME). 181

It is estimated that the development of a new nanomedicine will only take about 3-4 years and 20-50 million US dollars. In contrast, it takes more than 10 years to discover a new active molecule, and the average cost is about 500 million U.S. dollars. 182

In order to perform the procedure to obtain an industrial-scale laboratory-designed drug delivery system, the synthesis must be carefully optimized to reduce production costs. For example, Ding et al. optimized the synthesis of polymers for protein therapy by changing the time, solvent, and reagent equivalents. As a result, in accordance with the principles of green chemistry, the cost of polymers prepared on a scale of several hundred grams has been reduced by nearly 90%. 183

In addition, in industrial-scale production, synthesis time is directly converted into cost; therefore, it is important to choose the most time-saving and inexpensive production method. 185 Finally, affordable, non-toxic and commonly used solvents, such as water, are most needed. 111 Interestingly, to reduce the time and cost of formulation development, calculation methods are used to predict the in vitro/in vivo characteristics of the carrier, such as stability, solubility, and potential toxicity. 186

It is also worth noting that multifunctional carriers with targeting and imaging properties, multi-step synthesis and greater regulatory barriers are worth the price due to their many advantages, such as reduced side effects, frequency of administration, use in therapeutic diagnosis, and even fewer drugs Toxicity, as demonstrated by Cheng et al. 187 Despite the high production costs, recent analysis shows that the use of targeted drug delivery systems for cancer patients will lead to long-term reductions in the utilization and cost of healthcare. 188

Although interest in nanomedicine has increased in recent years, the transfer of methods to the market is still a challenge due to difficulties in industrial transfer. 189,190 Generally speaking, the reaction conditions and properties of nanomaterials (size, charge, shape, morphology and dispersion) are easily disturbed by the process of nanocarrier synthesis due to amplification, so the formulation and effectiveness of nanomedicine may change . 191 In addition, these parameters are very important for the in vivo stability and toxicity of nanocarriers. 192

In industrial plants, particle size is affected by the available chemical reactor volume, stirring speed and time, and the energy used in the synthesis process. The fluctuation of these characteristics may further reduce the drug loading efficiency. 193,194 One of the difficult examples related to large-scale production is Doxil, which was the first nanomedicine approved in 1995. As a result of production and 195, the literature describes how scale-up produces new trace impurities. These impurities are It was found to be cytotoxic and changed the colloidal and structural properties of the nanoparticles. 196

Another challenge regarding the transfer of the nanomedicine industry is the insufficient number of guidelines on the safety and non-toxic characterization of nanoparticles, and the lack of strict legal regulations. 188,197 In view of the listed challenges to obtain the required characteristics during the synthesis of pharmaceutical formulations, the Food and Drug Administration (FDA) introduced a quality by design method in the 2000s that provides at every stage of the process Product quality control (through the use of pH or ionic strength sensors). In this way, the key parameters for the synthesis of drug carriers must be obtained through standardized procedures and scalable chemical equipment. Since the synthesis conditions in the factory are different from those in the laboratory, each stage of the synthesis must be based on chemistry, manufacturing and control (CMC) and follow the requirements of Good Manufacturing Practice (GMP). 191,198 However, since it does not take into account the many parameters required by nanoparticles, it is easy to control the process, so repeatability problems arise. 195 Therefore, each batch of materials must be thoroughly tested to ensure its characteristics, safety and non-toxicity. 190 Some researchers have suggested that large-scale preparations need to be routinely tested in animal models. 191

One may notice that the simple industrial procedure for synthesizing nanomaterials is flawed due to the limited possibilities of industrial plants. 199 The nanomaterial synthesis methods described in the literature have many limitations, such as difficulty in removing toxic organic solvents (in the solvent emulsification diffusion technology applied to lipids) or challenges to maintain product sterility. 185,191,200 In addition, some methods of producing nano-formulations, such as freeze-drying and spray-drying for the manufacture of nanocapsules in powder form, are expensive and may affect the particle size. 201 Large-scale preparation of nanocarriers that are biodegradable in the body is another challenge. 201,202 Therefore, top-down processes (including mechanical fragmentation of products) are still more common than bottom-up methods (generating nanoparticles from molecules or atoms). 203 However, some production methods seem to be more useful than others For large-scale applications, such as supercritical reverse phase evaporation or microfluidic mixers. 191,192

In addition, since the creation of a new drug delivery system is usually a reformulation of previously known drugs, pharmaceutical companies generally believe that this process is not worth the time and cost compared with profit, and is more willing to simply screen small drug libraries. Invest in new drugs. Compound. 188,199

"Green Nanomedicine" is a new field of drug delivery systems based on nanomaterials, which provides tools for more economical synthesis of nanocarriers. However, only a few literature examples can be found at present, which satisfy at least a few of the dozens of "green chemistry" hypotheses. In the synthesis of drug carriers such as nanometal compounds, polymer nanocomposites and quantum dots, it is possible to find the use of safer reagents, solvents or auxiliaries, safer design, atom-economic synthesis methods, application of renewable energy or synthesis Biodegradable carrier. In the described nanosystems, protein and lipid compounds are the safest known drug carriers. 204,205

A very important aspect is the choice of synthesis method among the available methods. 206 Another group of non-toxic reactions in nanomedicine is the use of plant extracts as reagents. For example, Palai et al. describe the synthesis of decorative graphene nanocomposites, in which neem leaf extract is used to reduce graphene oxide, while the synthesis procedure is modified to reduce the amount of toxic gases and impurities produced. 207

Uthappa et al. provided one of the latest examples of the use of environmentally friendly reagents. They described the green synthesis of natural diatoms modified with polydopamine as a drug delivery system, which additionally shortened the synthesis time and no toxic reagents. 87 In addition, Hasan et al. Describes the eco-friendly synthesis of silver nanoparticles, in which the reduction process of chemical compounds has been replaced by the reduction of biopolymers (dextrins). 208 An alternative to green solvents may be the use of ionic liquids. 209

Although there are more adaptable technologies, such as reversed-phase evaporation or thin-film hydration, Khan et al. chose a green technology, namely the energy-saving probe ultrasound method that uses only water as a solvent to produce niosomes. 113 Next, the Ca2 cross-linked Fe-guanosine monophosphate (Fe-GMP) hydrogel for doxorubicin delivery was prepared by easily mixing appropriate components under ambient conditions. 210 Finally, it’s important to start with the available polymers (poly(sodium) 4-styrene sulfonate), PSS) and ensure that simple green methods are used to encapsulate the drug, for example, mixing the polymer and the drug separately Of the two water phases. 92 From the perspective of the manufacturer, the "greener" the process, since it does not contain toxic impurities, the cheaper and safer the final product.

Pharmacokinetics, usually described as the effect of organisms on drugs, is a branch of pharmacology that studies the activity of compounds in the body over a period of time, focusing on the process of pharmaceutical products and drugs being absorbed, distributed, metabolized and finally excreted ( ADME). Pharmacokinetics depends on many factors related to the physical and chemical properties of complex substances and patient-related conditions (such as gender, age, individual physiology or genetics). Knowledge of pharmacokinetics is essential for the targeted and safe application of drugs to achieve the maximum therapeutic effect and the minimum risk associated with adverse reactions.

The ideal drug should be highly specific to pathological processes and changes, without any toxicity to healthy organs, tissues or cells. The most desirable properties of the active compound should directly lead to proper absorption and drug distribution, low metabolism, proper elimination, and low toxicity.

The key pharmacokinetic parameters used to define and describe the ADME process include bioavailability (by determining the area under the plasma concentration-time curve), elimination half-life (t1/2), volume of distribution (Vd), and clearance (CL) .123 These factors play a crucial role in determining the in vivo drug concentration of a specific therapeutic target. Pharmacokinetics are used to estimate exposure and the most important parameters, and to determine the best dosage form and dosing regimen in clinical practice to achieve maximum efficacy and minimum toxicity. 211

From being administered in a specific dosage form to reaching the target of therapeutic molecules, drugs encounter many obstacles in the organism. Technological advancements have allowed us to make structural changes to significantly improve drug properties and help overcome the limitations of reduced drug efficacy and potential safety issues. The advancement of nanotechnology in the past few decades has indeed revolutionized the drug delivery system by improving the pharmacokinetic and pharmacodynamic properties of the drug delivery system, such as higher solubility, exposure duration, and delivery of targeted sites. 212

The following table briefly summarizes the main differences between the pharmacokinetic properties of small drug molecules and ideal drug-loaded nanoparticles (Table 10). Table 10 Comparison of pharmacokinetic properties of small molecule drugs and drug-loaded nanoparticles

Table 10 Comparison of pharmacokinetic properties of small molecule drugs and drug-loaded nanoparticles

There are many different types of nanoparticles used as carriers for therapeutic compounds, as shown in Figure 6, each with different characteristics. Figure 6 Classification of nanocarriers for drug delivery.

Figure 6 Classification of nanocarriers for drug delivery.

As mentioned in the previous sections, nanoparticles have differences in surface charge, particle size and shape, efficiency, loading capacity, and stability, leading to great differences in pharmacological effects and safety of different nanocarriers. In their review, Petschauer et al. summarized the main factors affecting the pharmacokinetics (PK) and pharmacodynamics (PD) properties of anticancer carrier-mediated drugs in patients. 213 The discussion included the following elements: uptake by the mononuclear phagocyte system; delivery of the compound in the tumor: Due to the leakage of the vascular system, nanoparticles (NPs) can enter the tumor tissue, thereby enhancing permeability and retention. Particle size and shape: It has been observed that NPs between 100 and 200 nm are most effectively absorbed by tumors; conversely, particles smaller than 50 nm have a short circulation time, and NPs larger than 300 nm prevent particles from using the EPR effect, thereby reducing tumor accumulation; Surface modification and charge (conjugation of PEG and NPs surface increases cycle time and bioavailability—measured by the area under the curve—AUC; uncharged particles have less mononuclear phagocyte systemic uptake, resulting in longer Circulation time); Concentration of NPs given: A higher concentration of particles per dose will increase drug exposure in plasma and tumors.

In addition, the author emphasizes the fact that there is a relationship between the NP clearance rate and the patient’s age, sex, liver or kidney damage and other diseases or concomitant drugs. Another point to consider is the possibility of predicting the pharmacokinetic properties of PEGylated liposomal NPs based on the functions of monocytes and dendritic cells.

Advances in computational science over the past decade have allowed researchers to focus on mathematical and statistical methods. Dogra et al. describe a new modeling method aimed at predicting the pharmacokinetics of systemic nanoparticles and their tumor delivery. 214 The main factors that control the dynamics of nanoparticles in the tumor stroma are the size of the nanoparticles, tumor vascular fraction, tumor vascular porosity, nanoparticle degradation rate, and tumor blood viscosity. Since the number of potential factors that affect the ADME process in organisms is inherently huge, it is recommended to perform mathematical modeling in this parameter space as an effective alternative to traditional experiments.

The authors discussed the influence of parameters and specific values ​​to optimize the delivery of NPs to tumor tissues. Garofalo et al. proposed another method that combines computer-aided drug design and drug delivery technology in the field of computational chemistry. 215 The multidisciplinary approach has achieved promising results in overcoming some of the main challenges, such as poor target selectivity or poor ADME characteristics. The author discussed the selected application of the new method, which aims to provide insights into the rational design of new anti-cancer therapies. The authors believe that computer-aided drug delivery system design should be combined with "wet" laboratory technology to better predict in vivo drug delivery systems and help design drug molecules that increase therapeutic targeting and reduce optimal doses .

Although nanoparticles show excellent potential as drug delivery agents, it has been found that nanoprotein interactions and the formation of protein corona can interfere with the delivery of nanoparticles. In a recently published study, Zhang et al. briefly summarized the latest developments in nanoprotein interactions between NPs and digestive enzymes, and launched a fascinating discussion on the possibility of digestive enzyme corona for targeted delivery. 216 The author described the physical and chemical properties closely related to the oral absorption of NP, including size, zeta potential, and surface molecules. These properties are greatly affected by nanoenzyme interaction and enzymatic cap formation. In addition, it has been shown that the uptake of NPs by epithelial cells increases significantly after the formation of the enzyme corona. Therefore, the interaction of nanoenzymes is the main challenge for oral administration of nanoparticles and may have an impact on the pharmacological properties. On the other hand, nanoenzyme interaction can also be applied to advanced oral administration. Since the epithelial absorption of NPs is inhibited by enzyme corona, there is a high chance that a large amount of NPs will enter the colon in the form of NP-corona complex. Later, in the colon, the enzyme caps and nanoparticles can be degraded and metabolized in the largest microbiota in the organism, resulting in the loaded drugs being released directly to the colon area. Peng et al. discussed the same issue before. 217 They synthesized cationic NPs (CNPs) based on poly(3-hydroxybutyrate-co-3-hydroxyhexanoate), and studied the interaction of CNPs with digestive enzymes and their effects on cellular uptake. The author's research The results showed for the first time the formation of enzyme corona and its inhibitory effect on the uptake of CNP by epithelial cells. In another paper, Peng et al. evaluated the interaction between proteins and nanomaterials, and the results showed that the performance of nanomaterials in vivo is significantly different from that in vitro. It has been shown that protein-nanomaterial interactions may cause significant changes in the properties of nanomaterials and related proteins. 218 Changes in these properties will eventually lead to undesirable consequences, including: 1. The blood quickly clears opsonin due to the following reasons; 2. The increase in volume after serum protein adsorption leads to the risk of capillary blockage; 3. The original surface ligand is protein. The crown covering leads to the loss of targeting ability; 4. The possible toxicity due to the conformational change of the binding protein. On the one hand, the above-mentioned interactions are the main challenge for the safe and effective use of nanomaterials in clinical practice, but on the other hand, these interactions may become the possibility of decorating nanomaterial-based drug delivery systems. Therefore, the in vivo transportation and subsequent behavior of protein-nanomaterial complexes are more controlled, and in fact this complex is more likely to be transferred to the actual product. In fact, it can be assumed that in the near future, these new smart products will be put on the market for clinical use.

Even if nanoparticles are used as drug carriers, toxicity is still a challenge. The highly complex interactions between molecules, cells and the host environment are affected by nanoparticles, and there are many questions about their long-term safety.

Khan et al. described some potential NPs toxicity, depending on various factors and types of particles used. 219 As the author points out, one of them is the ability to organize around protein concentration. This particular characteristic depends on the particle size, curvature, shape and surface charge, functional groups and free energy. Based on these characteristics, NPs may at least produce unfavorable and unexpected results through protein unfolding, cross-linking, or loss of enzyme activity.

Obviously, although NPs loaded with anticancer drugs have achieved promising results and improved pharmacokinetic properties, long-term research and further research must be carried out to better understand the complex interactions at the molecular level in the body.

In view of this article, the application of nanotechnology in practice may face some challenges. The most worrying thing is that regulators have not yet addressed the health and safety impact of specific properties of nanoparticles. The new European chemicals policy REACH does not consider side effects. Nanoparticles have caused many safety and regulatory issues that governments are now beginning to address. It is necessary to review recent regulations and continuous monitoring by the authorities. 220 In addition, when considering the application of nanomedicine in routine clinical practice, some issues cannot be ignored, such as the toxicity exhibited by certain nanoparticles. Recently, nanoparticles are mostly used with natural products to reduce toxicity issues. The green chemical approach in the design of drug-containing nanoparticles is being widely promoted because it minimizes harmful components in the biosynthesis process. Therefore, the use of "green" nanoparticles to deliver drugs can potentially reduce the side effects of drugs. 189

The use of the best nanoparticle drug delivery system mainly depends on the biophysical and biochemical characteristics of the targeted drug selected for treatment, which helps to improve the successful delivery of the nanosystem and optimize the pharmacoeconomic impact. 189

Recently, various nanotechnology-based drug delivery solutions in the medical field have attracted great interest. Nevertheless, unfortunately, there are still many concerns about the safety application of nanoparticles as drug delivery systems. 221

Research on nanotechnology has proven that each type of nanoparticle has some limitations in practical applications. The toxic effects of NPs are usually related to the poor biocompatibility of the nanomaterials used to develop them. Carbon nanotubes (CNT) are the type of NPs that have been observed to have a higher toxicity potential. They have been found to be carcinogenic to lung cancer, but they are also toxic to the central nervous system, blood and gastrointestinal tract. Heavy metals may accumulate in the liver and kidneys and cause toxicity to the central nervous system and gastrointestinal tract. Silicate also has a great potential to accumulate in the liver and lungs and cause fibrosis. The direct toxicity of liposomes may be mainly caused by their size, charge or composition. For example, cationic liposomes may interact with lipoproteins, serum proteins and even extracellular matrix, leading to the aggregation or release of reagents loaded before they reach target cells, causing systemic toxicity. At much higher doses (multiple injections of ≥100 mg/kg lipids), liposomes have been shown to cause RES damage, granulomas, hepatomegaly, and even splenomegaly. In addition, it has been shown that an increase in lipid dose consumes plasma of different proteins. Although the identification and importance of all missing proteins are still unclear, their loss may lead to impaired normal homeostasis. Metal nanoparticles can cause peribronchitis, granulomas, interstitial fibrosis, collagen deposition, adenocarcinoma, and pleural lesions. Nanoemulsions may interfere with the tight connections and direct cytotoxicity in GIT. Carbon nanoparticles exhibit oxidative stress, glutathione depletion, increased number of dermal cells, and thickening of the skin and rash. Dendrimers and gold nanoshells show toxicity caused by macrophages, plasma protein consumption, and platelet aggregation, and their synthesis pathways are complex. 222,223

In view of the above, it is essential for workers and exposed patients to understand the level of particles that may have an impact on their health. 222

Nanomedicine uses nanotechnology for highly specific medical interventions to prevent, diagnose, and treat diseases, all of which are described in this article. The development of nanomedicine tends to improve the therapeutic effect, reduce the therapeutically effective dose, and reduce the risk of side effects. 224 nanocarriers as DDS are designed to reduce the cost of drug delivery, improve compliance and help patients recover as soon as possible. All of these aspects are reflected in pharmacoeconomics, the discipline of which aims to provide reliable information about the cost of treatment and to select the best treatment method, while considering its effectiveness at the lowest possible cost. In the aforementioned papers, nanotechnology solutions and standard therapies are discussed, as well as their cost and effectiveness. 224

The clinical development of nanomedicine involves many aspects, and there are some key issues that need attention: biological development (appropriate in vivo structural stability after nanomedicine application); manufacturing process (large-scale production according to GMP standards, including: reproducibility, technology, and foundation The cost of facilities, experience, and the entire process; tests used to control the quality of characterization, including: charge, size, morphology, dispersion, encapsulation, surface modification, stability and purity); biocompatibility and safety issues (for nanomedicine Develop more targeted toxicological analysis; properly understand the interaction between nanocarriers and cells and tissues; reduce the accumulation level of nanoparticles in target cells, tissues or organs); intellectual property (understand the complexity of nanomedicine patents); Government regulations (developing clear regulatory guidelines for nanomedicine); and total cost-effectiveness compared to standard treatment options (limited understanding of the biological interactions between nanomedicine and the patient’s biological environment, making it impossible to apply pharmacoeconomics methods) 225-229 .

Although nanomedicine has therapeutic efficacy, these determinants may be major obstacles that limit the emergence of the nanomedicine market.

Evidence obtained by applying pharmacoeconomics can be used in health policy decisions. It can be applied by healthcare professionals, such as decision makers, primary healthcare providers, healthcare administrators, and health managers.

Pharmacoeconomics can certainly help in decision-making when assessing affordability and obtaining the right medicines for the right patients at the right time, comparing alternative medicines from the same treatment category or medicines with similar mechanisms of action, and determining liability for claims The manufacturer's view of the drug is reasonable. The correct application of pharmacoeconomics will enable pharmacists and managers to make better and more informed decisions about products and services.

According to published literature, the participation of nanomorphs in different stages, including prevention, diagnosis, and treatment, may provide significant benefits from an economic and therapeutic perspective. These factors include, but are not limited to, faster diagnosis, improved survival of patients during anti-tumor therapy, overcoming the drug resistance mechanism of tumor cells, or improving the therapeutic effect through synergistic or additive interactions.

The use of drug nanocarriers is a unique opportunity to make economically attractive improvements to known drugs because the development of new nanoformulations is much cheaper and faster than the discovery of new drugs. Although production costs are higher, regulatory obstacles are greater, and industry transfer is difficult, they are worth the price due to their many advantages.

Nano-encapsulation can improve the bioavailability of poorly soluble drugs. By improving the crossing of biological barriers and increasing the selectivity of drug-loaded nanocarriers, it promotes access to the site of pathological changes, provides better storage and in vivo stability, and enables the drug to stay in the body Release slowly and in a controlled manner. The human body. From a pharmaceutical and economic point of view, all these benefits can reduce dosage and related toxicity, dosing frequency, side effects and costs, improve formulations, protect patents, and increase patient compliance. In addition, the use of drug nanocarriers has been widely used in therapeutic diagnostics.

However, there are doubts about the risks associated with the use of excessive nanocarriers in the use of drug carriers, such as hypertension or systemic toxicity. These side effects can be offset by selecting appropriate carrier materials and appropriate drug-carrier combination to ensure that the ratio of drug to carrier in the formulation is low. In addition, due to careful optimization of synthesis, including product control at each stage of its production, and preparation guidelines for nanomaterial synthesis, it is possible to avoid changes in carrier stability and toxicity associated with industrial production.

It is difficult to say which is better: discover new drug nanocarriers or search for new and more effective active substances. However, from the perspective of pharmacoeconomics, it is certainly ideal and cost-effective to use nano-formulations to improve well-known drugs with serious side effects.

Today, nanotechnology has many advantages, including: good bioadhesion, high biocompatibility, low toxicity, high encapsulation efficiency and large drug loading. Analyzing the above-mentioned characteristics of nanoformulations, it can be concluded that nanoparticles have great potential as drug delivery systems, imaging agents, and phototherapy. Despite these advantages, there are still many issues that need to be resolved before nanoparticles can be used in a safe and comprehensive clinical manner. Some aspects need further research, such as: generating nanoparticles of the required size; controlling the thickness of each layer of nanoparticles and its influence on the therapeutic effect; developing more stable nanoparticles; optimizing the drug release curve of nanomaterials; currently, the release rate The difference is very large, depending on how the drug is integrated into the nanomaterial (mainly through: surface adsorption, binding or encapsulation); safety and clinical application; their biodistribution and long-term toxicity characteristics. Finally, in vivo studies understand the metabolism, accumulation and biodegradation mechanisms of nanoparticles; discover the interaction of nanoparticles with other materials, substances, drugs and organisms.

In addition, the current research is limited to the in vitro stage and does not show in-depth toxicological and pharmacokinetic parameters. However, over time, the science and publishing are expanding, and we have obtained more data, allowing us to evaluate and predict the effects of nanocarrier formulations.

In addition, from a manufacturing point of view, optimization of synthesis parameters, encapsulation efficiency, and improved stability of nano-products will also provide a better understanding of its mode of action, and may predict the risk of end-use. In fact, this may be a major achievement in reducing the direct and indirect costs of treatment.

There is no doubt that the implementation of new treatment options, such as nanotherapy, will bring risks that have not yet been known; however, the expansion and development of current research will therefore eliminate our use of nanotechnology in drug development and related costs. Existing gaps in knowledge and understanding of related mechanisms.

In view of the above situation, more attention should be paid to the pharmacoeconomics aspect of nanocarriers in order to correctly assess the risk and benefit balance of the very promising technology proposed in this review.

5-FU, 5-fluorouracil; p53, cellular tumor antigen p53; ABCB1, ATP binding cassette subfamily B member 1; ACUPA, acid-based protein ligand; ADME, absorption, distribution, metabolism and excretion; AE, adverse events; AgNPs, silver nanoparticles; AGuIX NPs, nanoparticles based on polysiloxane gadolinium chelate; ALK, anaplastic lymphoma kinase; ALT, alanine aminotransferase; ANG 1005, Angiopep-2 paclitaxel conjugate; AST, aspartate aminotransferase; ATC, anatomical therapeutic chemistry classification system; ATC, undifferentiated thyroid cancer; AUC, area under the curve; BBB, blood-brain barrier; BCL2L12, BCL-2 related proline-rich protein; BCRP, breast cancer resistance protein; BiOBr NPs, polyethyleneimine grafted bismuth oxybromide nanosheets and Fe3; BNPs, bioadhesive nanoparticles; BSA, bovine serum albumin; C1-PNPs, pyridinium amphiphile loaded PLGA ( Poly(lactic acid-glycolic acid copolymer) nanoparticles; CA, cancer antigen; CBA, cost-benefit analysis; CCNG1, cyclin-G1; CD NPs, cyclodextrin nanoparticles; CEA, cost-benefit analysis; Chk1, check Point kinase 1; CL, clearance; CMA, cost minimization analysis; Cmax, maximum concentration; CMC, chemistry, manufacturing and control; CNF, carbon nanofibers; CNS, central nervous system; CNT, carbon nanotubes; CPSNP, phosphorous silicon Calcium acid nanoparticles; CR, complete clinical response; CRC, colorectal cancer; [email protection] 2, chitosan-assisted MoS2; CSC, cancer stem cells; CTC, circulating tumor cells; CTCAE, general terminology criteria for adverse events; CUA, cost-effectiveness analysis; CuS NP, copper sulfide nanoparticles; DDS, drug delivery system; DKK4, Dickkopf WNT signaling pathway inhibitor 4; DMSO, dimethyl sulfoxide; DNA, deoxyribonucleic acid; DOX, doxorubicin ; DPYD, dihydropyrimidine dehydrogenase; DLT, dose-limiting toxicity; dvPtNPs, bivalent platinum nanoparticles; electrocardiogram, electrocardiogram; EGF, epidermal growth factor; EORTC QLQ-C30, European cancer research and treatment organization quality of life 30 items Questionnaire; EPR effect, enhanced permeability and retention; Eudragit S100, an anionic copolymer based on methacrylic acid and methyl methacrylate; FACT-G, functional evaluation of cancer treatment-general questionnaire; FDA, food and drug management Bureau; FFPE, formalin fixed paraffin embedding; FKBP5, FKBP prolyl isomerase 5; FR, folate receptor; GBM, glioblastoma multiforme; GC, gastric cancer; GIT, gastrointestinal tract ; GMP, good manufacturing practices; [email protection] NPs, poly(ethylene glycol) (PEG) modified core Shell [email protection] (gold nanorods) layered double hydroxide nanoparticles; GNSs, gold nanospheres; GO, graphene oxide; GR, glucocorticoid receptor; GS, glioblastoma stem cell-like cells Culture; GSH, glutathione; GSH-AgNPs, glutathione stabilized silver nanoparticles; Gy, Gray (SI unit); HA, hyaluronic acid; HAAH, human aspartyl (asparaginyl) ) Β-hydroxylase; (HA)-PBCA-NPs, hyaluronic acid-coated poly(butyl cyanoacrylate) nanoparticles; HALMD, hydrophilic and aromatic low molecular weight drugs; HER2, human epidermal growth factor 2; HIF-1α, hypoxia inducible factor 1-α; HO-GC, hydrophilic oligomer-conjugated glycol chitosan; HPG, hyperbranched polyglycerol; HPG-C10-PEG, hyperbranched poly Glycerol-C10-poly(ethylene glycol); ICER, incremental cost-benefit ratio; ICPMS, inductively coupled plasma mass spectrometer; IONPs, iron oxide nanoparticles; iv, intravenous; MDCK-MDR1, Madin darby with MDR1 gene Canine kidney (MDCK) cells; MDM2, mouse bipartite 2 homolog; MDR, multidrug resistance; MDR1, multidrug resistance 1 transporter; Mg(OH)2 NPs, magnesium hydroxide nanoparticles; MIC, Minimum inhibitory concentration; MnO2 NPs, manganese oxide nanoparticles; MNP, magnetic nanoparticles; molybdenum disulfide/PDA-RGD, molybdenum disulfide/polydopamine-arginine-glycine-aspartic acid; mPEG-CHO-shell Glycan nanoparticles, methoxypoly(ethylene glycol) coupled chitosan nanoparticles; MPS, mononuclear phagocyte system; MRI, magnetic resonance imaging; MRSA, methicillin-resistant Staphylococcus aureus; MTD, maximum Tolerated dose; MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazole reduction assay; mTOR, the mechanical target of rapamycin Dots; NaCl, sodium chloride; NCI's CTCAE, National Cancer Institute General Terminology Standards for Adverse Events; NCs, new carcinogens; NCQDs, nitrogen-doped carbon quantum dots; NIH, National Institutes of Health; NIR, near-infrared radiation NK 105, micellar nanoparticle formulations incorporating paclitaxel; NLC, nanostructured lipid carrier; NPs, nanoparticles; NRS-11, numerical rating scale; ORR, overall response rate; OSA, octyl modified bovine serum Albumin; OS, overall survival; PBCA-NPs, poly(butyl cyanoacrylate) nanoparticles; PCE, perchloroethylene; PCL, poly(ε-caprolactone); PCMB-Dox NPs, PEGylation Carborane-conjugated amphiphilic copolymer doxorubicin nanoparticles; PD, pharmacodynamics; PD, progressive disease; PDA-PEG-Van NPs, polydopamine-based nanoparticles, modified with PEG and vancomycin; PDCs, polymerization Drug-drug conjugate; PDL1, programmed death ligand 1; PDMAEMA, poly(N-(2-(dimethylamino)ethyl)-methacrylate); PEG, poly(ethylene glycol); PEG , Polyaspartic acid micellar nanoparticles; PEG-PCL, poly(ethylene glycol)-poly(ε-caprolactone); PEG-PE, poly(ethylene glycol) phosphatidylethanolamine; PEI-C18-HPG , Polyethyleneimine (PEI)-C18-HPG; PET, positron emission tomography; PFS, progression-free survival; PG, pharmacogenomics; P-gp, permeability glycoprotein; pH, hydrogen potential; PIPAC, Pressurized intraperitoneal aerosol chemotherapy; PK, pharmacokinetics; PLA, polylactic acid; PLD, pegylated liposomal adriamycin; PLGA, poly(lactic-glycolic acid copolymer); PLGA-PEG, Poly(lactic acid-co-glycolic acid)-poly(ethylene glycol); PLMB-Dox NPs, carborane-coupled polymer nanoparticles loaded with doxorubicin; PMMA, poly(methyl methacrylate); po , Per os; PR, partial response; PSMA, prostate specific membrane antigen; PSS, poly(4-styrene sulfonate); PST-PTX, poly(styrene)-paclitaxel; PTX, paclitaxel; evaluation of the efficacy of solid tumors Standard RECIST; RES, renal reticuloendothelial system; rGO-Au NPs, reduced graphene oxide functionalized with gold nanoparticles; RNA, ribonucleic acid; ROS, reactive oxygen species; RP2D, the recommended phase II dose (in clinical trials ); SAB, Staphylococcus aureus bacteremia; SAE, serious adverse event; sc, subcutaneous injection; scFv, single-stranded fragment variable; SD, stable disease; siRNA, small interfering RNA; SLNs, solid lipid nanoparticles; SNA , Spherical nucleic acid; SNPs/SiNPs, silica nanoparticles; SPF, sun protection factor; t1/2, half-life; TDDS, targeted drug delivery system; TFAP2E, transcription factor AP-2 epsilon; TfR 1, transferrin receptor 1; Tmax, the time required to reach Cmax; Tri-Ag NPs, citrate-coated triangular nanoparticles; Tv-Ag NPs, Toxicodendron vernicifluum silver nanoparticles; UPLC-MS/MS, ultra-high performance liquid chromatography-tandem Mass spectrometry; ultraviolet, ultraviolet; VAS, vasectomy; VCAMs, vascular cell adhesion molecules; VEGF, vascular endothelial growth factor; Vd, volume of distribution; VOI, amount of interest; QALYs, quality-adjusted life years.

Polish National Science Center, authorization number. NCN/2016/21/B/ST5/01365 (AZW).

The author declares that there is no conflict of interest in this work.

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