rus
Issue #1/2019
N.M.Murashova, E.S.Trofimova, Е.V.Yurtov
Dynamics of scientific publications on the using of nanoparticles and nanostructures for targeted drug delivery
Dynamics of scientific publications on the using of nanoparticles and nanostructures for targeted drug delivery
Publications dynamics based on the ScienceDirect scientific database for the period from 1997 to 2016 was analyzed for the areas related to the use of nanoparticles and nanostructures for targeted drug delivery. The most dynamically developing areas of research were identified.
According to the data presented in the article, most popular nowadays (i.e. characterized by the rapid growth of the number of publications and the large total number of applications) there are such areas of research as the application for targeted drug delivery of magnetic nanoparticles, silica nanoparticles, polymer nanoparticles, solid lipid nanoparticles, dendrimers, polymeric micelles and micelles of surfactants. It can be predicted that in the nearest 10 to 20 years these areas of research will develop further and probably with the lower speed growth of the number of publications which is indicative of the areas of research from the first group.
According to the data presented in the article, most popular nowadays (i.e. characterized by the rapid growth of the number of publications and the large total number of applications) there are such areas of research as the application for targeted drug delivery of magnetic nanoparticles, silica nanoparticles, polymer nanoparticles, solid lipid nanoparticles, dendrimers, polymeric micelles and micelles of surfactants. It can be predicted that in the nearest 10 to 20 years these areas of research will develop further and probably with the lower speed growth of the number of publications which is indicative of the areas of research from the first group.
Теги: development trends of scientific fields drug delivery nanoparticles nanostructures nanotechnology number of publications scientometrics доставка лекарственных веществ наноструктуры нанотехнология наночастицы наукометрия тенденции развития научных направлений число публикаций
The actual problem of the contemporary medicine is the development of precise drug delivery systems or targeted drug delivery. Under the term of precise drug delivery it is meant to understand the targeted delivery of the drug to the indicated part of the body, organ or a cell. The using of nanoparticles or nanostructured systems for creating new drugs is supposed to solve such tasks as ensuring optimal pharmacological effect, targeted delivery and the controlled release of the drug, minimal side effects and the convenience of use. Nanostructures of the biological origin such as lipids, polysaccharides, proteins, as well as synthetic polymers and inorganic nanoparticles can be used as carriers for precise drug delivery [1–3]. Many specialized international journals are dedicated to this problem. These journals are: Advanced Drug Delivery Reviews (impact factor 11,764), Journal of Controlled Release (impact factor 7,786), Nanomedicine, Nanotechnology, Biology and Medicine (impact factor 5,720) etc.
One of the instruments that gives possibility to sort out great amount of information on the researched topic and highlight the promising fields of research is the analysis of scientific publications dynamics for a rather extended period of time (not less than 15 years). The analysis of the scientific publications dynamics may serve as the complementary means to the other methods of assessment of the trends of development of the scientific areas of research – reviews in national and foreign scientific journals, the analysis of the results of scientific conferences and also the analysis of the patent information [4]. The advantages of this method are its speed and the possibility to embrace the wide variety of scientific fields of study. The analysis of scientific publications dynamics was previously implemented to identify the trends in the development of scientific areas of research in the fields of science connected with nanotechnology and liquid extraction [5].
The aim of this paper is to identify the most promising and rapidly developing approaches of the use of nanoparticles and nanostructures for targeted drug delivery on the basis of analysis of scientific publications dynamics.
To assess the dynamics of publications we used resources of the scientific database ScienceDirect and the Internet. The number of publications where target notions were included in the title, keywords and annotation from the scientific database ScienceDirect for the period from 1997 to 2016 was analyzed. The methodological approaches which were implemented for the analysis of publications dynamics are described more fully in the article [5].
RESULTS AND DISCUSSION
Among nanomaterials and nanostructures which are reviewed as carriers for precise drug delivery it is possible to distinguish the following groups:
1. self-organizing (i.e. thermodynamically stable) nanostructures of surface-active agents – microemulsions, micelles, organogels of cylindrical micelles (such as lecithin organogel[6], lyotropic liquid crystals);
2. thermodynamicly unstable structures with surface-active agents – nanoemulsions, multiple emultions, solid lipid nanoparticles, liposomes, niosomes, hexosomes, cubosomes;
3. polymer nanoparticles and nanostructures – polymeric micelles, polymer nanoparticles, polymeric nanocapsules, polymer conjugates – medicinal substance, dendrimers, protein conjugates with medicinal substances;
4. inorganic nanoparticles – magnetic nanoparticles, gold nanoparticles, silica nanoparticles, titanium dioxide nanoparticles, calcium phosphate nanoparticles;
5. carbon nanoparticles – fullerens, carbon nanotubes, nanodiamonds, graphene;
6. objects of supramolecular chemistry – calixarenes, cucurbiturils, cyclodextrines, DNA-nanocontainers.
The given below list is not exhaustive, we wanted to review the most widely known nanostructures offered for precise drug delivery and evaluate the perspectives of their application.
For the analysis of the interest of scientists to the use of self-organising nanostructures of surface-active agents (surfactants) for precise drug delivery we studied the publications dynamics by the combination of two keywords: drug delivery and the names of self-organising structures of surfactants – microemulsion, micelle and liquid crystal. Due to the thermodynamic stability of such nanostructures there are advantages from the point of view of technology – simpler methods of manufacture, correspondence of the properties only to the composition of the system and their independence of the conditions of mixing of the components, the long-term storage capacity [6]. The above-mentioned advantages of self-organising nanostructures of surfactants make them promising systems for precise drug delivery. The results of the analysis of publications dynamics on this topic for the period from 1997 to 2016 are given in Fig.1.
The annual number of publications for all reviewed nanostructures of surfactants has been increasing (see Fig.1). The greatest number of publications is connected with the use for precise drug delivery such self-organizing nanostructures of surfactants as micelles. In recent years the annual quantity of publications on this topic has surmounted 150 entries in the database. The second in the number of publications topic is the use of microemulsions, during several recent years the annual number of publications is dozens of entries in the base. The interest to the use for precise drug delivery such systems as liquid crystals is not sufficient, the annual number of publications consists of about a dozen entries in the database.
Thermodynamicly unstable nanostructures with surface-active agents also are offered as carriers for precise drug delivery. Among such systems it is possible to single out two groups – derivatives of emulsions and derivatives of the liquid crystal phase. The first group comprises nanoemulsions (emulsions with the droplet size less than 200 nm [7]), multiple emulsions (droplets of one dispersed phase, for example, an aqueous phase, are dispersed in drops of a different dispersed phase, for example, an oil phase, and these drops in their turn are dispersed in the continuous phase, an aqueous phase, for example), and solid lipid nanoparticles. Solid lipid nanoparticles are obtained via emulsification of the lipid melt under the elevated temperature, and while cooling of the emulsion the droplets of lipids become crystallized thus forming solid lipid nanoparticles. The derivatives of the liquid crystal phase comprise well known liposomes, which can be regarded as nanoscaled particles of the lamellar liquid crystal phase, and less known hexosomes and cubosomes – nanoscaled particles of the hexagonal and cubic phases respectively. Niosomes also belong to this group, they are the analogues of liposomes formed by bilayers of non-ionogenic surface-active agents which are esters of polyethylene glycol and polydimethylsiloxanes.
Fig.2 represents the results of the analysis of the dynamics of publications by the combination of two keywords: drug delivery and the names of the nanostructures: nanoemulsion, multiple emulsion, solid lipid nanoparticles, liposomes, niosomes, hexosomes and cubosomes.
As it becomes clear from the presented data (see Fig.2), the greatest number of publications is connected with the use of liposomes for precise drug delivery. In recent years the annual number of publications on this topic has exceeded 200 which is larger comparing to the number of the top-runners of the first group that was reviewed – micelles. Liposomes have been studied since 60s of the 20th century, the first suggestions on their use as carriers for precise drug delivery appeared at the end of the 60s. A large amount of scientific data on the use of liposomes for targeted drug delivery has been accumulated, the total number of publications for the indicated period has surpassed 2 300. Nowadays there exists a range of medicinal preparations in the liposomal form, approved for the clinical use, for example AmBisome (liposomal amphotericin B), Doxil (Doxorubicin hydrochloride liposome), Daunoxome (Daunorubicin Liposomal) etc. As a rule, anticancer drugs are manufactured in the form of liposomes, as namely the drugs for chemotherapy have the most severe side effects, and it was necessary to decrease their manifestation and improve the efficacy of the used medicinal substances [8].
The next topics according to the number of publications in the studied group of nanostructures are the use of solid lipid nanoparticles and nanoemulsions. In recent years the annual number of publications on these topics comprises dozens which is comparable to the application of microemulsions. The annual number of publications on the use for precise drug delivery of such systems as niosomes, multiple emulsions, hexosomes, cubosomes is drastically lower than the use of solid lipid nanoparticles and nanoemulsions.
Yet another group of nanostructured carriers of drugs are the structures based on biocompatible polymers. Biologically compatible are those polymers the application of which causes no harmful influence on people or animals as the consequence of their total elimination, gradual dissolution or degradation in the body. Among the used polymers there are substances of biological origin, for example proteins and polysaccharides, as well as synthetic biocompatible polymers, for example poly-L-lactic acid, poly-D-lactic acid, copolymer of lactic and glycolic acids, poly-β-benzyl-L-aspartat, polylysine and the other polyaminoacids, polyethylene glycol and a variety of others [9].
For the analysis of the interest of scientists to the use of polymeric nanostructures for precise drug delivery we have studied the publications dynamics by the combination of two keywords: drug delivery and the names of nanostructures based on polymers: polymer nanoparticles, polymeric micelles, polymeric nanocapsules, polymer conjugate, protein conjugats and dendrimers. The obtained results are shown in Fig.3.
In all reviewed polymeric nanostructures there has been an increase in the number of publications, but the speed of the growth and the annual number of publications are different (see Fig.3). The largest amount of publications is connected with the use of nanoparticles of polymers for the precise drug delivery. In recent years the annual number of publications on this topic has exceeded 200 which is comparable with the number of micelles, but is slightly lower than of liposomes.
The succeeding in number of publications topics in the studied group of nanostructures are the use of polymeric micelles, polymer conjugates, protein conjugates and dendrimers. In recent years the annual number of publications has fallen between 50 and 100. The number of publications with the keyword "polymeric nanocapsules" is insignificant, not more than 10 in a year. Generally, large volumes of the scientific data on the use of polymeric nanostructures for precise drug delivery have been accumulated, for example the number of publications between 1997 and 2016 by combination of words drug delivery and polymer nanoparticles exseeds 1400. Nowadays there are several medicinal preparations based on polymeric carriers approved for the clinical use, for example Vivitrol (the drug is immobilized on the carrier of the copolymer of lactic and glycolic acids by means of noncovalent interactions), Pegasys (conjugate formed by the chemical bond between polyethylene glycol and alpha interferon) and so on.
The next method for the development of carriers for precise drug delivery comprises the use of inorganic nanoparticles. Such particles must be chemically inert and non-toxic, they must be eliminated of the body without accumulation in the liver, kidneys, spleen and other organs. If the substance in the form of macroparticles corresponds to these conditions then in the nanoparticles there might appear toxic effects which depend on the dose, ways of administration and the size of the particles. On the cellular level most often nanoparticles of metals and oxides cause oxidative stress (a damage of the cell as a result of the processes of oxidation of biomolecules), on the level of tissues and the whole body the inflammatory reactions are observed [10]. The second problem in the application of inorganic nanoparticles for precise drug delivery consists of the prevention of particle aggregation. For this purpose inorganic nanoparticles are covered with a layer of a stabiliser – a surface-active agent or hydrophilic polymer.
We have studied the dynamics of the scientific publications by the combination of two keywords: drug delivery and the names of the groups of inorganic nanoparticles: magnetic nanoparticles, gold nanoparticles, silica nanoparticls, calcium phosphate nanoparticles, titanium dioxide nanoparticls. The results of the analysis of publications dynamics are given in Fig.4.
From the given in the fig.4 data it is seen that the annual number of publications for most studied nanoparticles has been increasing taking into account that the quantity of publications drastically differs. The largest number of publications is connected to the use of magnetic nanoparticles for precise drug delivery. In recent years the annual number of publications on this topic has exceeded 130 which is lower than the front-runners in the number of publications from the other reviewed groups – micelles surfactants, liposomes and nanoparticles of polymers.
The next in the number of publications topics in the studied group of nanostructures are the use of gold nanoparticles and silica nanoparticles. In recent years the annual number of publications has fallen between 50 to 100. The number of publications on the use of calcium phosphate nanoparticles for precise drug delivery is insufficient, not more than 20 in a year, on the use of titanium dioxide nanoparticles there are only isolated cases of publications.
It should be noted that the significant number of publications (more than 15 in a year) on the use of inorganic nanoparticles for precise drug delivery appears only after 2005 for magnetic nanoparticles and after 2009 for gold nanoparticles and silica nanoparticles. In the clinical use the medicinal preparations where inorganic nanoparticles as carriers for precise drug delivery are used were not included. Nowadays superparamagnetic nanoparticles of iron oxide are used as contrast agents for magnetic resonance imaging, for example preparations Resovist and Endorem.
Into the separate group we allocated the publications where for precise drug delivery carbon nanoparticles are offered – fullerenes, carbon nanotubes, nanodiamonds and graphene. Requirements for carbon nanoparticles as carriers for precise drug delivery are analogous to the requirements for inorganic nanoparticles. We have studied the dynamics of publications by the combination of two keywords: drug delivery and the names of carbon nanostructures: carbon nanotube, graphene, fullerenes, nanodiamonds. The obtained results are given in Fig.5.
The annual number of publications of the reviewed carbon nanoparticles has been increasing but the number of publications and their speed growth differ (see Fig.5). The interest to the use of such nanostructures for precise drug delivery has appeared recently. The substantial number of publications (more than 15 a year) for carbon nanotubes appears only after 2008, and for the graphene only after 2013. Such dynamics is connected with the great interest of scientists of different specialities to the new structures of carbon. Despite the fact that both monolayered and multilayered carbon nanotubes are toxic [10], the number of publications on the use of carbon nanotubes for precise drug delivery has recently comprised more than 40 entries for a year and is still growing. The newly discovered graphene is held accountable for the interest of scientists and the sharp increase in the quantity of publications by the combination of words: drug delivery and graphene, the mean time of doubling of the number of publications makes 2,1 years. The number for publications on the use of nanodiamonds and fullerenes for precise drug delivery is insufficient, not more than 10 a year. None of the reviewed nanostructures of carbon is adopted into the practical medicine.
The last of the studied groups includes the objects of supramolecular chemistry. The examples of the objects of supramolecular chemistry offered as the carriers of drugs are massive organic molecules which have an inner cavity and are capable of forming inclusion complexes as "host-guest", such as calixarenes, cucurbiturils, cyclodextrines. These molecules serve as "nanocontainers" which under certain conditions can release the molecule of the drug from their inner cavity into the environment. To this group we also allocated "nanocontainers" formed of short strands of DNA, which are obtained by the "DNA-origami" method [11]. In figure 6 the dynamics of publications by the combination of keywords: drug delivery and words: cyclodextrins, calixarenes, cucurbiturils, DNA-nanocontainers, DNA origami is shown.
As seen from the depicted data (see Fig.6), only on the use of cyclodextrins for targeted drug delivery there is a substantial number of publications, more than 680 entries totally. The annual number of publications on this topic has been increasing, in recent years 70 papers have been published each year. Cyclodextrenes are the cyclic oligomers of glucose, they are derived from starch and are used in the food and cosmetic industry. Separate publications mainly after 2011 can be observed for the remaining studied combinations of the keywords. Thus with the exception of cyclodextrins the use of the objects of supramolecular chemistry for the precise drug delivery is an insufficiently researched field. It is possible to be attributed to the complexity of the synthesis of such organic molecules.
To elicit the most favorable and rapidly developing approaches on the application of nanoparticles and nanostructures for precise drug delivery the comparison of the dynamics of scientific publications has been conducted by the two parameter – the mean time of doubling of publications and the total number of publications for the indicated period (see Table 1). The total number of publications (N) provides opportunity to assess the amount of accumulated scientific information on the researched problem, and the mean time of doubling (t2 years) characterizes the interest of scientist to the chosen research area. For example the mean time of doubling of the number of publications for the keyword drug delivery reaches 6,3 years, and for the research area drug nanocarriers (nanostructured carriers of drugs) – 1,9 years. The mean number of t2 for the chosen research areas makes 4,1 years. The mean number of publications N for all reviewed in the Table 1 areas of research makes 410. Based on these values the research areas can be allocated into 4 groups:
1. the slow growth, large number of publications (t2 > 4,1; N > 400);
2. the rapid growth, large number of publications,(t2 ≤ 4,1; N > 400);
3. the rapid growth, small number of publications (t2 ≤ 4,1; N < 400);
4. the slow growth, small number of publications (t2 > 4,1; N < 400).
The first group, which is characterized by the relatively slow growth and the large number of publications comprises nanostructures which were offered for precise drug delivery more than 30 years ago, such as liposomes, micelles, microemulsions, conjugates of drugs with polymers, including proteins.
CONCLUSIONS
According to the data presented in Table 1, most popular nowadays (i.e. characterized by the rapid growth of the number of publications and the large total number of applications) there are such areas of research as the application for targeted drug delivery of magnetic nanoparticles, silica nanoparticles, polymer nanoparticles, solid lipid nanoparticles, dendrimers, polymeric micelles and micelles of surfactants. It can be predicted that in the nearest 10 to 20 years these areas of research will develop further and probably with the lower speed growth of the number of publications which is indicative of the areas of research from the first group.
For the range of research areas from the third group (the rapid growth, small number of publications) in the nearest 10–20 years it is possible to expect the significant growth of the total number of publications, i.e. transfer to the second group. It will be preconditioned by obtaining new significant results, development of the breakthrough methods and technologies. The other areas of research from this group might no longer attract attention and the annual number of publications on them will rise slowly or decrease.
Majority of areas of study allocated into the fourth group are just the reseach ones, they are connected to the use of insufficiently studied nanostructures for precise drug delivery. In the nearest 10 to 20 years a part of them probably will cease to attract the attention of scientists and researches on them will be stopped. Another part of the research areas from the forth group will continue to develop, but relatively slowly, without the boost in growth, indicative of the third group. Some of the reseach studies that belong to the forth group will lead to the production of interesting and significant results, which attract the attention of the scientists. It will lead to the rapid growth of the number of publications in these areas of research and their transfer to the third group. ■
One of the instruments that gives possibility to sort out great amount of information on the researched topic and highlight the promising fields of research is the analysis of scientific publications dynamics for a rather extended period of time (not less than 15 years). The analysis of the scientific publications dynamics may serve as the complementary means to the other methods of assessment of the trends of development of the scientific areas of research – reviews in national and foreign scientific journals, the analysis of the results of scientific conferences and also the analysis of the patent information [4]. The advantages of this method are its speed and the possibility to embrace the wide variety of scientific fields of study. The analysis of scientific publications dynamics was previously implemented to identify the trends in the development of scientific areas of research in the fields of science connected with nanotechnology and liquid extraction [5].
The aim of this paper is to identify the most promising and rapidly developing approaches of the use of nanoparticles and nanostructures for targeted drug delivery on the basis of analysis of scientific publications dynamics.
To assess the dynamics of publications we used resources of the scientific database ScienceDirect and the Internet. The number of publications where target notions were included in the title, keywords and annotation from the scientific database ScienceDirect for the period from 1997 to 2016 was analyzed. The methodological approaches which were implemented for the analysis of publications dynamics are described more fully in the article [5].
RESULTS AND DISCUSSION
Among nanomaterials and nanostructures which are reviewed as carriers for precise drug delivery it is possible to distinguish the following groups:
1. self-organizing (i.e. thermodynamically stable) nanostructures of surface-active agents – microemulsions, micelles, organogels of cylindrical micelles (such as lecithin organogel[6], lyotropic liquid crystals);
2. thermodynamicly unstable structures with surface-active agents – nanoemulsions, multiple emultions, solid lipid nanoparticles, liposomes, niosomes, hexosomes, cubosomes;
3. polymer nanoparticles and nanostructures – polymeric micelles, polymer nanoparticles, polymeric nanocapsules, polymer conjugates – medicinal substance, dendrimers, protein conjugates with medicinal substances;
4. inorganic nanoparticles – magnetic nanoparticles, gold nanoparticles, silica nanoparticles, titanium dioxide nanoparticles, calcium phosphate nanoparticles;
5. carbon nanoparticles – fullerens, carbon nanotubes, nanodiamonds, graphene;
6. objects of supramolecular chemistry – calixarenes, cucurbiturils, cyclodextrines, DNA-nanocontainers.
The given below list is not exhaustive, we wanted to review the most widely known nanostructures offered for precise drug delivery and evaluate the perspectives of their application.
For the analysis of the interest of scientists to the use of self-organising nanostructures of surface-active agents (surfactants) for precise drug delivery we studied the publications dynamics by the combination of two keywords: drug delivery and the names of self-organising structures of surfactants – microemulsion, micelle and liquid crystal. Due to the thermodynamic stability of such nanostructures there are advantages from the point of view of technology – simpler methods of manufacture, correspondence of the properties only to the composition of the system and their independence of the conditions of mixing of the components, the long-term storage capacity [6]. The above-mentioned advantages of self-organising nanostructures of surfactants make them promising systems for precise drug delivery. The results of the analysis of publications dynamics on this topic for the period from 1997 to 2016 are given in Fig.1.
The annual number of publications for all reviewed nanostructures of surfactants has been increasing (see Fig.1). The greatest number of publications is connected with the use for precise drug delivery such self-organizing nanostructures of surfactants as micelles. In recent years the annual quantity of publications on this topic has surmounted 150 entries in the database. The second in the number of publications topic is the use of microemulsions, during several recent years the annual number of publications is dozens of entries in the base. The interest to the use for precise drug delivery such systems as liquid crystals is not sufficient, the annual number of publications consists of about a dozen entries in the database.
Thermodynamicly unstable nanostructures with surface-active agents also are offered as carriers for precise drug delivery. Among such systems it is possible to single out two groups – derivatives of emulsions and derivatives of the liquid crystal phase. The first group comprises nanoemulsions (emulsions with the droplet size less than 200 nm [7]), multiple emulsions (droplets of one dispersed phase, for example, an aqueous phase, are dispersed in drops of a different dispersed phase, for example, an oil phase, and these drops in their turn are dispersed in the continuous phase, an aqueous phase, for example), and solid lipid nanoparticles. Solid lipid nanoparticles are obtained via emulsification of the lipid melt under the elevated temperature, and while cooling of the emulsion the droplets of lipids become crystallized thus forming solid lipid nanoparticles. The derivatives of the liquid crystal phase comprise well known liposomes, which can be regarded as nanoscaled particles of the lamellar liquid crystal phase, and less known hexosomes and cubosomes – nanoscaled particles of the hexagonal and cubic phases respectively. Niosomes also belong to this group, they are the analogues of liposomes formed by bilayers of non-ionogenic surface-active agents which are esters of polyethylene glycol and polydimethylsiloxanes.
Fig.2 represents the results of the analysis of the dynamics of publications by the combination of two keywords: drug delivery and the names of the nanostructures: nanoemulsion, multiple emulsion, solid lipid nanoparticles, liposomes, niosomes, hexosomes and cubosomes.
As it becomes clear from the presented data (see Fig.2), the greatest number of publications is connected with the use of liposomes for precise drug delivery. In recent years the annual number of publications on this topic has exceeded 200 which is larger comparing to the number of the top-runners of the first group that was reviewed – micelles. Liposomes have been studied since 60s of the 20th century, the first suggestions on their use as carriers for precise drug delivery appeared at the end of the 60s. A large amount of scientific data on the use of liposomes for targeted drug delivery has been accumulated, the total number of publications for the indicated period has surpassed 2 300. Nowadays there exists a range of medicinal preparations in the liposomal form, approved for the clinical use, for example AmBisome (liposomal amphotericin B), Doxil (Doxorubicin hydrochloride liposome), Daunoxome (Daunorubicin Liposomal) etc. As a rule, anticancer drugs are manufactured in the form of liposomes, as namely the drugs for chemotherapy have the most severe side effects, and it was necessary to decrease their manifestation and improve the efficacy of the used medicinal substances [8].
The next topics according to the number of publications in the studied group of nanostructures are the use of solid lipid nanoparticles and nanoemulsions. In recent years the annual number of publications on these topics comprises dozens which is comparable to the application of microemulsions. The annual number of publications on the use for precise drug delivery of such systems as niosomes, multiple emulsions, hexosomes, cubosomes is drastically lower than the use of solid lipid nanoparticles and nanoemulsions.
Yet another group of nanostructured carriers of drugs are the structures based on biocompatible polymers. Biologically compatible are those polymers the application of which causes no harmful influence on people or animals as the consequence of their total elimination, gradual dissolution or degradation in the body. Among the used polymers there are substances of biological origin, for example proteins and polysaccharides, as well as synthetic biocompatible polymers, for example poly-L-lactic acid, poly-D-lactic acid, copolymer of lactic and glycolic acids, poly-β-benzyl-L-aspartat, polylysine and the other polyaminoacids, polyethylene glycol and a variety of others [9].
For the analysis of the interest of scientists to the use of polymeric nanostructures for precise drug delivery we have studied the publications dynamics by the combination of two keywords: drug delivery and the names of nanostructures based on polymers: polymer nanoparticles, polymeric micelles, polymeric nanocapsules, polymer conjugate, protein conjugats and dendrimers. The obtained results are shown in Fig.3.
In all reviewed polymeric nanostructures there has been an increase in the number of publications, but the speed of the growth and the annual number of publications are different (see Fig.3). The largest amount of publications is connected with the use of nanoparticles of polymers for the precise drug delivery. In recent years the annual number of publications on this topic has exceeded 200 which is comparable with the number of micelles, but is slightly lower than of liposomes.
The succeeding in number of publications topics in the studied group of nanostructures are the use of polymeric micelles, polymer conjugates, protein conjugates and dendrimers. In recent years the annual number of publications has fallen between 50 and 100. The number of publications with the keyword "polymeric nanocapsules" is insignificant, not more than 10 in a year. Generally, large volumes of the scientific data on the use of polymeric nanostructures for precise drug delivery have been accumulated, for example the number of publications between 1997 and 2016 by combination of words drug delivery and polymer nanoparticles exseeds 1400. Nowadays there are several medicinal preparations based on polymeric carriers approved for the clinical use, for example Vivitrol (the drug is immobilized on the carrier of the copolymer of lactic and glycolic acids by means of noncovalent interactions), Pegasys (conjugate formed by the chemical bond between polyethylene glycol and alpha interferon) and so on.
The next method for the development of carriers for precise drug delivery comprises the use of inorganic nanoparticles. Such particles must be chemically inert and non-toxic, they must be eliminated of the body without accumulation in the liver, kidneys, spleen and other organs. If the substance in the form of macroparticles corresponds to these conditions then in the nanoparticles there might appear toxic effects which depend on the dose, ways of administration and the size of the particles. On the cellular level most often nanoparticles of metals and oxides cause oxidative stress (a damage of the cell as a result of the processes of oxidation of biomolecules), on the level of tissues and the whole body the inflammatory reactions are observed [10]. The second problem in the application of inorganic nanoparticles for precise drug delivery consists of the prevention of particle aggregation. For this purpose inorganic nanoparticles are covered with a layer of a stabiliser – a surface-active agent or hydrophilic polymer.
We have studied the dynamics of the scientific publications by the combination of two keywords: drug delivery and the names of the groups of inorganic nanoparticles: magnetic nanoparticles, gold nanoparticles, silica nanoparticls, calcium phosphate nanoparticles, titanium dioxide nanoparticls. The results of the analysis of publications dynamics are given in Fig.4.
From the given in the fig.4 data it is seen that the annual number of publications for most studied nanoparticles has been increasing taking into account that the quantity of publications drastically differs. The largest number of publications is connected to the use of magnetic nanoparticles for precise drug delivery. In recent years the annual number of publications on this topic has exceeded 130 which is lower than the front-runners in the number of publications from the other reviewed groups – micelles surfactants, liposomes and nanoparticles of polymers.
The next in the number of publications topics in the studied group of nanostructures are the use of gold nanoparticles and silica nanoparticles. In recent years the annual number of publications has fallen between 50 to 100. The number of publications on the use of calcium phosphate nanoparticles for precise drug delivery is insufficient, not more than 20 in a year, on the use of titanium dioxide nanoparticles there are only isolated cases of publications.
It should be noted that the significant number of publications (more than 15 in a year) on the use of inorganic nanoparticles for precise drug delivery appears only after 2005 for magnetic nanoparticles and after 2009 for gold nanoparticles and silica nanoparticles. In the clinical use the medicinal preparations where inorganic nanoparticles as carriers for precise drug delivery are used were not included. Nowadays superparamagnetic nanoparticles of iron oxide are used as contrast agents for magnetic resonance imaging, for example preparations Resovist and Endorem.
Into the separate group we allocated the publications where for precise drug delivery carbon nanoparticles are offered – fullerenes, carbon nanotubes, nanodiamonds and graphene. Requirements for carbon nanoparticles as carriers for precise drug delivery are analogous to the requirements for inorganic nanoparticles. We have studied the dynamics of publications by the combination of two keywords: drug delivery and the names of carbon nanostructures: carbon nanotube, graphene, fullerenes, nanodiamonds. The obtained results are given in Fig.5.
The annual number of publications of the reviewed carbon nanoparticles has been increasing but the number of publications and their speed growth differ (see Fig.5). The interest to the use of such nanostructures for precise drug delivery has appeared recently. The substantial number of publications (more than 15 a year) for carbon nanotubes appears only after 2008, and for the graphene only after 2013. Such dynamics is connected with the great interest of scientists of different specialities to the new structures of carbon. Despite the fact that both monolayered and multilayered carbon nanotubes are toxic [10], the number of publications on the use of carbon nanotubes for precise drug delivery has recently comprised more than 40 entries for a year and is still growing. The newly discovered graphene is held accountable for the interest of scientists and the sharp increase in the quantity of publications by the combination of words: drug delivery and graphene, the mean time of doubling of the number of publications makes 2,1 years. The number for publications on the use of nanodiamonds and fullerenes for precise drug delivery is insufficient, not more than 10 a year. None of the reviewed nanostructures of carbon is adopted into the practical medicine.
The last of the studied groups includes the objects of supramolecular chemistry. The examples of the objects of supramolecular chemistry offered as the carriers of drugs are massive organic molecules which have an inner cavity and are capable of forming inclusion complexes as "host-guest", such as calixarenes, cucurbiturils, cyclodextrines. These molecules serve as "nanocontainers" which under certain conditions can release the molecule of the drug from their inner cavity into the environment. To this group we also allocated "nanocontainers" formed of short strands of DNA, which are obtained by the "DNA-origami" method [11]. In figure 6 the dynamics of publications by the combination of keywords: drug delivery and words: cyclodextrins, calixarenes, cucurbiturils, DNA-nanocontainers, DNA origami is shown.
As seen from the depicted data (see Fig.6), only on the use of cyclodextrins for targeted drug delivery there is a substantial number of publications, more than 680 entries totally. The annual number of publications on this topic has been increasing, in recent years 70 papers have been published each year. Cyclodextrenes are the cyclic oligomers of glucose, they are derived from starch and are used in the food and cosmetic industry. Separate publications mainly after 2011 can be observed for the remaining studied combinations of the keywords. Thus with the exception of cyclodextrins the use of the objects of supramolecular chemistry for the precise drug delivery is an insufficiently researched field. It is possible to be attributed to the complexity of the synthesis of such organic molecules.
To elicit the most favorable and rapidly developing approaches on the application of nanoparticles and nanostructures for precise drug delivery the comparison of the dynamics of scientific publications has been conducted by the two parameter – the mean time of doubling of publications and the total number of publications for the indicated period (see Table 1). The total number of publications (N) provides opportunity to assess the amount of accumulated scientific information on the researched problem, and the mean time of doubling (t2 years) characterizes the interest of scientist to the chosen research area. For example the mean time of doubling of the number of publications for the keyword drug delivery reaches 6,3 years, and for the research area drug nanocarriers (nanostructured carriers of drugs) – 1,9 years. The mean number of t2 for the chosen research areas makes 4,1 years. The mean number of publications N for all reviewed in the Table 1 areas of research makes 410. Based on these values the research areas can be allocated into 4 groups:
1. the slow growth, large number of publications (t2 > 4,1; N > 400);
2. the rapid growth, large number of publications,(t2 ≤ 4,1; N > 400);
3. the rapid growth, small number of publications (t2 ≤ 4,1; N < 400);
4. the slow growth, small number of publications (t2 > 4,1; N < 400).
The first group, which is characterized by the relatively slow growth and the large number of publications comprises nanostructures which were offered for precise drug delivery more than 30 years ago, such as liposomes, micelles, microemulsions, conjugates of drugs with polymers, including proteins.
CONCLUSIONS
According to the data presented in Table 1, most popular nowadays (i.e. characterized by the rapid growth of the number of publications and the large total number of applications) there are such areas of research as the application for targeted drug delivery of magnetic nanoparticles, silica nanoparticles, polymer nanoparticles, solid lipid nanoparticles, dendrimers, polymeric micelles and micelles of surfactants. It can be predicted that in the nearest 10 to 20 years these areas of research will develop further and probably with the lower speed growth of the number of publications which is indicative of the areas of research from the first group.
For the range of research areas from the third group (the rapid growth, small number of publications) in the nearest 10–20 years it is possible to expect the significant growth of the total number of publications, i.e. transfer to the second group. It will be preconditioned by obtaining new significant results, development of the breakthrough methods and technologies. The other areas of research from this group might no longer attract attention and the annual number of publications on them will rise slowly or decrease.
Majority of areas of study allocated into the fourth group are just the reseach ones, they are connected to the use of insufficiently studied nanostructures for precise drug delivery. In the nearest 10 to 20 years a part of them probably will cease to attract the attention of scientists and researches on them will be stopped. Another part of the research areas from the forth group will continue to develop, but relatively slowly, without the boost in growth, indicative of the third group. Some of the reseach studies that belong to the forth group will lead to the production of interesting and significant results, which attract the attention of the scientists. It will lead to the rapid growth of the number of publications in these areas of research and their transfer to the third group. ■
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