Clinical and demographical characteristics of the patients.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
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He joined University of Veterinary and Animal Sciences during 2003 as Assistant Professor where he was later selected and appointed as Associate Professor and Professor, in 2006 and 2011 respectively. His research focus is on selection and breeding of large and small ruminants. He also supervises and evaluates postgraduate research to ensure successful and timely completion of the projects focusing on genetic improvement, enhancing breeding efficiency and production enhancement of farm animals. In addition, he participates and conducts trainings, workshops, conferences and seminars, and writes scientific publications to disseminate knowledge and techniques to the researchers and livestock producers about various areas of animal husbandry for improving behaviour, health, growth, fertility and production of livestock. 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In comparison with adults, children and adolescents, however, infrequently develop these complications [1].
\nIt is now well accepted that PUD, the most common stomach disease, is an infectious disease, and all consensus conferences agree that the causative agent, H. pylori, must be treated whit antibiotics [2].
\nThe public health importance of H. pylori discovery, in 1982, and its role in stomach disease was recognized in 2005 with the attribution of the Nobel Prize in Medicine to Barry Marshall and Robin Warren. H. pylori was classified as a class I human carcinogen by World Health Organization in 1994.
\nNumerous diagnostic tests are available for detecting H. pylori infection: invasive techniques, which means endoscopy with biopsies for a rapid urease test (RUT), histology, culture and non-invasive techniques, such as serology, 13C-Urea breath test (13C-UBT), and the stool antigen test. There is no single method to detect H. pylori infection reliably and accurately. The choice of the diagnostic method depends on patients’ age and complaints, technical difficulty level, costs and extensive accessibility in hospitals.
\nThe same diagnostic methods used for adults can be used for children. However, H. pylori infection has certain particularities in children which have implications for diagnostic testing. H. pylori infection may slowly establish itself, so it is possible, in rare instances, to find the bacteria without traces of inflammation. At endoscopy, antral nodularity is common [2]. Histology provides an excellent diagnostic accuracy, allowing for the detection of the bacteria as well as for the grading of gastritis. The sensitivity and specificity of histology for the diagnosis depends on clinical settings, density of colonization and on pathologist’s experience [3].
\nThis was a prospective, single center study (in Maria Sklodowska Curie Children’s Emergency Hospital Bucharest, Romania) that evaluated consecutive children referred by their physicians for upper endoscopy because of dyspepsia. They were all screened for H. pylori and had a positive stool antigen test.
\nDemographic characteristics and family history of each patient were collected through a questionnaire, which was completed by parents or by patients depending on the age of the child. Demographic data included patients’ age, gender, and residency (urban or country area). Information on patient’s history of H. pylori infection as well as on previous therapies was obtained. History of siblings or parents infection was also assessed. Patients were asked about the time of onset and duration of gastrointestinal symptoms, use of proton pump inhibitors, H2 receptors antagonists, non steroidal anti-inflammatory drugs or steroidal drugs. Smoking status and alcohol consumption was determined as well.
\nExcluding criteria were: use of proton pump inhibitors or H2 receptors antagonists and antibiotics as well as non steroidal anti inflammatory drugs or steroidal therapy 2 weeks before the beginning of the study, history of intestinal surgery (except for polypectomy and appendectomy), concomitant severe disease (heart, lungs, kidneys and endocrine diseases), and smoking and alcohol consumption.
\nThe study was approved by Ethics Committee.
\nAll patients underwent endoscopy with biopsy specimens for histology (one for the antrum, one for the corpus). One sample from the antrum was used for rapid urease test. Two additional biopsies were taken from the antrum for bacterial culture. The samples were placed in separates vials, previously identified, containing the appropriate medium for each test.
\nThis procedure was performed in patients with a minimum of 10 hours of fasting, under general anesthesia or conscious sedation. Vital signs were continuously monitored for the entire procedure.
\nWritten informed consent was obtained from the parent or tutor of each child included in the study.
\nA biopsy of gastric body and antrum were fixed in a solution of formaldehyde 10%. Subsequently, the gastric mucosa samples were processed, following the usual steps of dehydration and paraffin embedding.
\nTwo stains were used for histological study: hematoxylin eosin and Giemsa. Hematoxylin eosin stain was used to evaluate inflammatory cells and H. pylori. Giemsa stain was needed when hematoxylin eosin stain failed to identify the bacterium. The Giemsa stain is the preferred stain for detecting H. pylori because of its technical simplicity, high sensitivity and low cost.
\nGastritis was graded according to the Sydney System [6] that assesses the severity of inflammation, the level of activity (the degree of polymorph neutrophil inflammation), and the presence of atrophy and of intestinal metaplasia on a scale from 0 to 3.
\nIn accordance with the Sydney System, the density of H. pylori infection was also semi quantitatively classified on a scale from 0 to 3 (mild, moderate, and marked).
\nH. pylori was recognized in the histological section appearing as a short curved or spiral bacillus resting on the epithelial surface or in the mucus layer.
\nThe biopsy specimens collected for bacterial culture were transported in commercial selective transport H. pylori medium, Portagerm pylori (BioMérieux SA, Marcy l’Etoile, France), and were inoculated after a few hours onto selective medium Pylori Agar (BioMérieux Italia). The plates were incubated under microaerobic condition at 37° for 72 h. Once incubated, the colonies resembling H. pylori were identified by Gram stain and by oxidase, catalase and urease tests. Suspensions from the primary plates were prepared in sterile solution to perform an E-test on Pylori Agar. An agar plate was streaked in three directions with a swab dipped into each bacterial suspension to produce a lawn of growth, an E-Test strip (E-Test; AB Bio disk, Solna, Sweden) was placed each onto separate plate, which was immediately incubated in a microaerobic atmosphere at 37°C for 72 h. Isolated strains were tested for amoxicillin, clarithromycin, metronidazole, and levofloxacin resistance following the recommendations of the European Committee on Antimicrobial Susceptibility Testing.
\nThe data was collected and analyzed with Microsoft Excel 2013 and PSPP version 1.0.1. Continuous variables with a normal distribution were expressed as a mean with standard derivation (SD) and continuous variables with a non-normal distribution as median with interquartile range (IQR). Differences between groups were analyzed using Student t-test and Mann-Whitney U test for continuous variables, and Fisher’s exact test for categorical variables. A p value <0.05 was considered statistically significant for all the analyzed parameters.
\nOf the 38 patients who underwent upper endoscopy with biopsies by protocol (Figure 1), nine were excluded because of negative results in both culture and histology.
\nFlow chart of the study.
In the study, the culture and histology examination findings were accepted as “gold standard”. The detection of H. pylori in at least one of the two tests was accepted as H. pylori positivity. Negative results in both culture and histology were accepted as H. pylori negativity.
\nTwenty-nine cases (76.31%) were included in the final analyses, 19 females (65.51%) and the 10 males (34.49%). The ages were between 3 years and 7 months and 17 years and 8 months (mean age 13.5 ± 4.53 years).
\nFour patients had a family history of peptic ulcer disease. In 15 children the duration of symptoms was more than 6 months and 12 patients were previously treated for H. pylori (Table 1).
\nMean age ± SD, years | \n13.5 ± 4.47 | \n
Male/female | \n10/29 | \n
Familial history for H. pylori infection | \n4/29 | \n
Peptic ulcer/non ulcer dyspepsia | \n1/28 | \n
Previous therapy | \n12/29 | \n
Clinical and demographical characteristics of the patients.
The mean duration of the period between the onset of symptoms and the effective diagnosis in patients with a family history of upper gastrointestinal diseases was 3.75 ± 3.69 and 8.66 ± 5.42 months in those with negative family history (p = 0.17). A family history of gastric or duodenal ulcer did not significantly alter the length of time between the onset of symptoms and the diagnosis according to our statistical results, which, however, may have been influenced by the restricted number of patients in our study population.
\nTwelve patients had previous therapies. The median age of patients who were previously treated was 14.5 ± 3.74 and 13 ± 4.71 years old of those without any anterior therapy (p = 0.2).
\nThe most common finding identified at endoscopy was macroscopic nodular antral gastritis, which was present in 22 patients (75.86%) (Figure 2). Among these, 10 had additional associated macroscopic lesions: 8 presented with nodular gastritis of gastric body, 1 with bulbitis, and one with esophagitis. Endoscopy showed antral hyperemia in 4 cases and a normal mucosal aspect in other 3 cases (Table 2).
\nEndoscopical aspect of Helicobacter pylori gastritis in children (macroscopic nodular antral gastritis).
Endoscopic features | \nn (%) | \n
---|---|
Macroscopic nodular antral gastritis | \n22 (75.86%) | \n
Nodular antral gastritis (only) | \n12 | \n
Nodular gastritis of corpus (with) | \n8 | \n
Erosive bulbitis (with) | \n1 | \n
Esophagitis (with) | \n1 | \n
Antral hyperemia without macroscopic nodularity | \n4 (13.79%) | \n
Normal | \n3 (10.34) | \n
Total | \n29 (100%) | \n
Endoscopic features associated to Helicobacter pylori infection.
We tried to find out if there was a significant difference in the severity of endoscopic findings between patients who received previous therapy and those who did not. Among the 12 previously treated patients, 7 (58.33%) presented with macroscopic nodular antral gastritis, 2 (16.67%) with antral hyperemia and 3 (25%) showed a normal mucosal aspect. In patients who were not previously treated, we observed macroscopic nodular antral gastritis in 15 cases (88.24%), antral hyperemia in 2 cases (11.76%) while a normal appearance of gastric mucosa was never detected (Table 3). There was not a statistically significant association between the severity of mucosal damage at endoscopy and the existence of a previous therapy against the infection (p = 0.06).
\nEndoscopic features | \nH. pylori infection without anterior therapies, n (%) | \nH. pylori infection with anterior therapies, n (%) | \n
---|---|---|
Macroscopic nodular antral gastritis | \n15 (88.24) | \n7 (58.33%) | \n
Nodular antral gastritis (only) | \n8 | \n4 | \n
Nodular gastritis of corpus (with) | \n6 | \n2 | \n
Erosive bulbitis (with) | \n0 | \n1 | \n
Esophagitis (with) | \n1 | \n2 (16.67%) | \n
Antral hyperemia without macroscopic nodularity | \n2 (11.76) | \n3 (25.0%) | \n
Normal | \n0 | \n12 (100%) | \n
Total | \n17 (100) | \n\n |
Endoscopic features associated to Helicobacter pylori infection: without anterior therapies versus with anterior therapies.
In our study, bleeding was the presenting symptom in 4 children; three of them had pan gastritis, and one had nodular gastritis and esophagitis.
\nThere is a clear association between H. pylori and gastritis, gastric ulcer, and duodenal ulcers. Studies have shown that this pathogen causes mucosa-associated lymphoid tissue (MALT) lymphoma in both children and adults. In fact, when the organism is eradicated, extra gastric metastases or sites of MALT lymphoma resolve [4].
\nThe finding of H. pylori-associated gastritis without duodenal or gastric mucosal lesions puts the pediatric gastroenterologist in a dilemma on recommending eradication treatment. H. pylori-associated gastritis without PUD rarely gives rise of symptoms or progresses to severe complications of the disease during childhood [5]. The risk of H. pylori- associated cancer or MALT-lymphoma during childhood is extremely low in Europe and North America. Ohno reported two cases in Japanese children, a 14-year-old boy and another 6-year-old boy with MALT and H. pylori infection [5]. The lower risk of complications in children may be in part explained by a different immune response against the infection. In comparison with adults, gastric biopsies obtained from children infected with H. pylori show a lower degree of inflammation. In addition, a higher number of immunosuppressive regulatory T cells and a more prominent IL-10 mediated anti-inflammatory response have been detected in pediatric patients [1].
\nDuring childhood, H. pylori is associated with antral predominant gastritis and duodenal ulcers [6].
\nIn our study, the most frequent lesion identified by endoscopy was macroscopic antral nodular gastritis, which was present in 22 patients (78.86%). This high frequency is in accordance with a retrospective study from Japan that also found out a marked prevalence of nodular antral gastritis associated with H. pylori infection (98.5%) [7]. A nodular antral gastritis frequency of 82.53% was also reported by a Turkish study conducted in adults and adolescents [8]. In a pediatric polish study, the sensitivity of antral nodularity associated with H. pylori was 91.6%, and the specificity was 91% [9]. A slightly lower value of specificity of antral nodularity, similar to our results (75.86%), was detected by several authors and ranged from 64 to 85.2%. Higher specificity was found by others [7, 8, 9].
\nAlthough the mechanisms underlying nodular gastritis in children is not clear yet, it is thought that lymphoid follicles with germinal center form nodules on gastric mucosa or that inflammatory reaction generated by H. pylori infection results in an exaggerated appearance of a normal gastric mucosa [10].
\nIn a 14-year-old boy we observed erosions at endoscopy. The frequency of these lesions in our study (3.45%) is similar to the one measured by another study conducted in Italy (3.40%) [11].
\nA prospective study, carried out during 1-month simultaneously in 19 centers among 14 European countries, showed a frequency of 8.1% of ulcers and/or erosions in children, occurring mainly in the second decade of life, but H. pylori infection and toxic gastric medications were less frequently implicated than expected in their development. On a total of 56 children with ulcers or erosions, H. pylori was present in 15 patients (27%), 8 used NSAIDs, 5 were treated with steroids, 5 with immune-suppressive drugs, 6 with antibiotics, 1 with antacids, 6 with H2 blockers and 8 with proton pump inhibitors (more than one risk factor was detected in 32 of 56 children) [12].
\nFor years, reports have noted an association between peptic ulcer disease and families with a strong history of upper gastrointestinal tract disease, in particular between gastric and duodenal ulcers. Family history of gastric cancer is an important component in the diagnosis and management of H. pylori infection in children. Children with a mother or a father with gastric cancer are considered to be at very high risk owing to shared genetic characteristics, environmental factors, and virulence features of the infecting strain of H. pylori [4].
\nIn countries with an elevated risk for gastric cancer, however, eradicating H. pylori in childhood could be more effective in preventing gastric atrophy, and ultimately, cancer development [13]. It still remains to be determined whether H. pylori-infected children with gastric atrophy are at increased risk for gastric cancer [14].
\nRecently, a decreasing proportion of H. pylori-positive peptic ulcers in adults has been observed, along with a decrease in the prevalence of infection, while, on the other hand, an increasing number of patients that use non-steroidal anti-inflammatory drugs (NSAIDs) has been noted [7, 15]. Regarding children, there are a few available data in the literature that investigate the trend of H. pylori prevalence in peptic ulcer [16].
\nIn our study, four patients had a family history of H. pylori infection, none of gastric cancer, two of peptic ulcer, and two of H. pylori chronic gastritis. In this situation, the period of the onset of symptoms and to presentation to the doctor was less than 3 months, so that the average duration of symptoms are 3.75 ± 3.69 months in comparison with 8.66 ± 5.42 months for those without family history for gastric or duodenal ulcers. Influence of family history for upper gastrointestinal tract diseases to the period of the onset of symptoms and diagnosis, can be explained by the consciousness of the disease and the risks than derive from it.
\nThe sex difference between the H. pylori-positive and H. pylori-negative group is also of great interest. We found female preponderance in the study group (65.51%), similarly with another report in our geographic area (78.49%) [17].
\nStudies have unanimously shown a male preponderance for peptic ulcer disease in children. It is still not known why primary peptic ulcers predominantly develop in infected male children. Epidemiological studies do not suggest any sex predilection in H. pylori infection [16].
\nMedian age for patients with previous therapies was 14.5 ± 3.74 years, comparative with 13 ± 4.71 years for patients without previous therapies, results or else expected. We do not have data to express if it is failure of antimicrobial therapy or reinfection. 1/12 patient with previous therapies had family history of peptic ulcer disease. We do not investigate all the family member of each child, and therefore we do not know the real status of H. pylori infection. Familial history for gastrointestinal disease was collected for interview. Magistà et al. [18] identified two variables by logistic regression analysis as predictors of H. pylori reinfection: age of primary infection and having an infected sibling. Multivariable analysis revealed that only age at primary infection correlates with an increased risk of reinfection [18].
\nIn patients with anterior therapies, the endoscopic features were less serious than in those without any previous treatment. All three patients with normal endoscopic mucosa were anteriorly treated. These results suggest that children might become “tolerant” to the bacterium or that the growing child is more resistant to H. pylori-induced lesions. The evidence that H. pylori infection in children coexist with normal gastric mucosa was reported in a percent comparable with our results (11%) [19]. This is the reason for which we strongly recommend to take biopsies at least for histological exam in children and adolescents, even if a normal appearance of mucosa is observed during endoscopy.
\nThe ability of H. pylori to manipulate the immune response (activation or inactivation of Toll-like receptors dependent response) may be responsible for bacterial survival and a mild course of infection in children [20].
\nThe main endoscopic feature found in our study was macroscopic nodular antral gastritis, in 75.86%. In 10.34% of cases the endoscopic aspect of mucosa was normal. All patients with normal endoscopic mucosa were previously treated. These results suggest that children might become “tolerant” to the bacterium or that the growing child is more resistant to H. pylori-induced lesions.
\nThe authors thank Dr. Augustina Enculescu for her histological support.
\nNone declared.
Nanomedicine is able to study the organism and especially the disease at the nanoscale level and offers a lot of structural and functional information for the development of new therapeutics and diagnosis strategies [1]. Nano-oncology refers to the applications of nanotechnology in the oncology medical field.
Oncological malignancies affect worldwide population with an incidence of 18.1 million new cancer cases and 9.6 million cancer deaths (GLOBOCAN 2018). Usually, the most used treatment scheme is surgery, radiotherapy and chemotherapy. These strategies are not very efficient because it does not only affect the disease site, but healthy tissues too, and in many cases, cancer can develop therapy resistance [2].
Nanotechnology tools have potential to overcome the side effects and the inefficiency of some therapies. Due to its small size, nanoparticles (NPs) can be used for molecular characterization of the disease, and based on this, it can contribute to discover new therapies. Moreover, various oncological chemotherapeutics are nanoformulated and now are involved in clinical trials [3].
Besides drug encapsulation, NPs can be used for the delivery of growth factors and other compounds applied in tissue engineering. On the other hand, NPs’ properties are advantageous for new sensing and molecular imaging tools development (Figure 1).
Nanotechnology applications in medicine.
For each of these applications, NPs’ formulations involve various encapsulation procedures, which need to meet specific characteristics. Firstly, the NPs should not interfere with the encapsulated compound pharmacological activity, and it has to prevent its premature degradation and to become biodegradable at the tumor site, thus decreasing its toxicity [4]. Secondly, for sensing applications, the nanosystem needs to have some unique chemical, electrical, and catalytical properties to provide accuracy of the measurements [5]. On the other hand, for molecular imaging applications, the NPs benefit from their optical properties like fluorescence in various spectra. Also, the features such as biocompatibility, stability and long circulation time are very important [6, 7, 8].
Theranostic side of the nano-oncology field focuses on developing new structures that able to perform efficient target therapy. Therefore, this type of NPs disposes of unique physical and chemical properties for active targeting of the desired cells providing imaging and therapeutic action against the disease [8].
The term “nanoparticles” is intensively used in the nanomedicine field in order to describe a particle with a size in the range of 1–100 nm. NPs are designed from a wide class of materials, including metals, silicates, metal oxides, polymers, organics, non-oxide ceramics, carbon and biomolecules. For biomedical applications, NPs are presented in different morphological states such as spheres, tubes, cylinders, platelets [9].
NPs have surface modifications that can facilitate the internalization/uptake of therapeutic agents and also their capability to travel through the bloodstream to the target sites. Generally, the structure of NPs is composed of three different layers, including the surface layer (can be functionalized with a wide range of small molecules, surfactants, metal ions and polymers), the shell layer (consists of different chemical material according to the core of the NPs) and the core (represents the central portion of the NP) [10]. Therefore, NPs have exceptional characteristics due to their structure and design and gained an enormous interest in multidisciplinary fields such as drug delivery [11], cancer therapy, tissue engineering, protein detection, multicolor optical coding for biological assays, manipulation of cells and biomolecules [12], imaging, biosensors, hyperthermia, photoablation therapy and gene delivery [13]. They exhibit special physical and chemical properties like a high surface area-to-volume ratio and also a unique quantum size effect superior to their corresponding bulk materials. Moreover, NPs’ controllable size and shape play an important role in medical applications [14]. Moreover, there are some nanomaterials that can exhibit intrinsic therapeutic properties such as gold nanoshells, which have the potential to deliver photothermal therapy [15].
Currently, the term “theranostics” starts to gain attention in the medical and research field, and it describes single biocompatible and biodegradable nanoparticle, which can contain both therapeutic and diagnostic compounds (Figure 2) [16]. Specifically, theranostic nanoparticles (TNPs) have been designed in order to be applied for multiple imaging approaches including optical imaging, ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), single-photon computed tomography (SPECT) and positron emission tomography (PET) [17]. Moreover, TNPs are able to improve the accumulation and delivery of the active compounds at the tumor site, enhancing therapeutic efficacy and reducing the intensity of side effects on healthy tissues [18], and they can be eliminated from the body in a short period of time and degrade into nontoxic bioproducts [19].
Theranostic nanoparticles used in the medical field in order to improve the diagnosis and therapeutic approaches.
Synthesis of NPs can be performed using various methods, which are divided into two main classes such as bottom-up (chemical synthesis) and top-down (mechanical attrition) approaches (Figure 3) [20]. Bottom-up method is based on larger nanostructures design beginning from smaller building blocks including atoms and molecules. Meanwhile, the top-down approach refers to larger molecules, which are decomposed into smaller building blocks and then converted into suitable NPs [10]. Traditional chemical and physical methods present some main drawback due to the presence of reducing and stabilizing agents, which carry a risk of toxicity to the environment and also to the cell [21].
Common methods used to synthesis NPs via top-down and bottom-up approaches.
Currently, green chemistry has been suggested as a valuable alternative for metal nanoparticles synthesis that employs biological entities including microorganisms and plant extracts [22]. The main role of microorganisms (bacteria and fungi) is involved in the remediation of toxic materials by reducing metal ions [23]. The most often used metal for green synthesis is silver, gold, iron, and copper [24]. Therefore, the size distribution of NPs is strongly depended on the presence of the biocompounds, which are found in the extract. These biocompounds (phenolic compounds, alkaloids, enzymes, terpenoids, proteins, co-enzymes, sugar and others) are mainly involved in reducing the oxidative state of the metal salts from positive to zero oxidative state [25]. Few bacteria have been shown the potential to synthesize silver nanoparticles intracellularly where intracellular components have the ability to act as reducing and stabilizing agents, respectively [26]. Thus, the green synthesis of nanoparticles could be a promising approach to replace many complex physiochemical syntheses due to their advantages such as no need to use toxic chemicals, free from hazardous by-products and also the use of natural capping agents [27].
In their study, Mirtaheri et al. had succeeded in synthesis of mesoporous tungsten oxide using a template-assisted sol-gel method, which relies on the photocatalytic degradation of Rhodamine B [28]. Mesoporous TiO2-SiO2 were synthesized by Haghighatzadeh et al. using an ultrasonic impregnation method. In addition, under 800°, they synthesized the anatase crystals with higher photocatalytic efficiency for degradation of methylene blue [29]. Deshmukh et al. synthesized various nanoparticles using plant extracts in order to evaluate their antibacterial and antioxidant activity for targeted applications [30]. Another study on this topic is showed by Baltazar-Encarnacion et al., which described the green synthesis of Ag nanoparticles using an E. coli for the production of NPs with antimicrobial properties against bacteria [31]. Green biosynthesis methods are more reliable and safer than chemical synthesis [32].
Structural DNA nanotechnology is a precise method, which is used to control the NPs shape. In particular, the DNA-origami method allows the controlled self-assembly of 2D and 3D nanostructures with nanometer precision [33]. Such nanoparticles can be used to detect short oligonucleotides in a microbead-based assay [34] and can be applied in the biological field, nanoelectronics and nanophotonics [35]. Therefore, these designs provide comprehensive understanding of cellular interactions regarding tumor detection strategies [36, 37].
Specifically, TNPs can be engineered in several ways. For example, TNPs can be obtained by conjugating therapeutic agents (chemotherapy and photosensitizers) to existing imaging NPs (quantum dots, gold nanocages and iron oxide NPs). On the other hand, NPs can encapsulate both imaging and therapeutic agents in biocompatible nanosystems such as ferritin nanocages, polymeric and porous silica NPs. Other unique NPs such as porphycenes, [64Cu] CuS, gold nanoshells or cages have inherent imaging and therapeutic characteristics [19].
Physicochemical properties of NPs (shape, size, composition, optics) can be analyzed through different techniques.
The morphology of NPs is characterized through microscopic techniques including polarized optical microscopy (POM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM), which are the most relevant techniques in this area. SEM technique provides relevant information regarding the nanoscale level of the NPs [38]. Moreover, TEM provides features about the bulk material used for NPs synthesis at very low to higher magnification [39]. The morphological features of the NPs exhibit a relevant interest since their morphology influences the NP’s properties [10].
Structural characterization is based on the study of the composition and nature of bonding materials. The common techniques used to study the bulk properties are X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), infrared spectroscopy (IR), Raman, Brunauer-Emmett-Teller (BET), energy dispersive X-ray (EDX) and Zeta size analyzer. Through XRD technique, the crystalline structure and the phase of the NPs are identified. The most sensitive technique used to characterize NPs is XPS, which determines the exact element ratio and bonding nature of the elements used for NPs synthesis [10].
Optical characterizations are widely used to obtain information about the absorption, reflectance, phosphorescence and luminescence of NPs. This method is based on the Beer-Lambert law and basic light principles. These properties are highlighted through several techniques, including diffuse reflectance spectroscopy (DRS), UV and UV-Vis, which reveal good knowledge about the mechanism of their photochemical processes [10].
For cancer research, NPs can be modified respecting the size, shape and surface to improve their ability to reach tumors. Smaller NPs have the ability to accumulate more easily in the leaky blood vessels of tumor sites compared to larger NPs, which can remain at the injection site [40].
Nowadays, ultrasmall nanoparticles (1–3 nm cores) are widely used for medical applications because of their advantages regarding biodistribution, targeting features, adsorption, easy surface modifications and pharmacokinetics [18, 41, 42, 43]. Gadolinium ultrasmall nanoparticles achieved theranostic potential without considerable toxicity in vivo in the case of brain cancers [44]. Another example is represented by ultrasmall silica nanoparticles functionalized with antibody fragments used to target HER2-overexpressed breast cancer as imaging agents [42].
Metallic nanoparticles can be designed as ultrasmall constructs too. In this regard, it is important to mention D-peptide p53 activator gold nanoparticle conjugates used for cancer target therapy [45], bimetallic nanoparticles for triggered ultrasound cancer therapy [46] and Cu ultrasmall nanoparticles’ valuable ability for photothermal cancer therapy [47].
On the other hand, NP shape influences the fluid dynamics and uptake into tumor sites. Non-spherical NPs present excellent optical properties due to surface plasmon resonances and are strongly recommended for cancer phototherapy applications [48, 49, 50]. Furthermore, rod-like shape nanoparticles are better accepted and tolerated by the organism [51, 52].
Specifically, spherical NPs started to be more common than non-spherical NPs due to challenges in synthesis approaches and testing [53]. Spherical silver nanoparticles ensure anti-inflammatory potential [54] and promote camptothecin apoptotic activity in cervical cancer [55]. Despite the advantages offered by silver nanoparticles, progress in spherical gold nanoparticles makes possible their use for combined therapies like drug delivery and photothermy [56].
There are other significant factors that contribute to a successful therapy development. Stability and distribution are affected by NPs charge. A positive charge is most effective according to tumor vessels targeting, but a switch to a neutral charge allows NPs to diffuse to the tumor sites [57]. In order to prolong blood circulation of NPs, their surface can also be modified with specific molecules (hydrophilic polymers/surfactants, biodegradable copolymers such as polyethylene glycol, poloxamine, polyethylene oxide and polysorbate 80), which facilitate cellular uptake into tumor tissue [58, 59].
Modern nanosystems can enhance drug diagnosis, delivery and also monitor therapeutic responses to the provided drugs [60]. In order to improve clinical outcomes, researchers tried to synthesize a theranostic platform consisting of multifunctional NPs, which exhibit valuable imaging properties. Therefore, TNPs can be composed of lipids, polymers, metals, carbon and ceramics [61].
Lipid nanoparticles are widely used in medical field due to their biodegradability, biocompatibility, low toxicity and high loading capacity for both hydrophobic and hydrophilic drug molecules [62, 63]. Moreover, they can improve the pharmacodynamics and the pharmacokinetics of therapeutic agents based on controlled release profile [64]. Another important characteristic of lipid NPs is their availability for functionalization with antibodies, peptides, small molecules or aptamers in order to perform target therapy [65, 66, 67].
Polymeric NPs are normally organic-based NPs with a diameter lower than 1 μm. They can be called nanospheres or nanocapsules depending on their composition [68, 69, 70]. These nanoparticles have the ability to improve both the solubility and the bioavailability of hydrophobic drugs [71] and are intensively used as delivery systems [72, 73].
Metallic NPs are designed from metal precursors, including noble metals (Cu, Ag, and Au). The most researched area in biomedical field is represented by gold NPs, which possess unique optical and electronic characteristics as well as chemical inertness. Also, their availability for surface functionalization [74, 75, 76] makes them very useful for a lot of medical applications such as biosensing [77], bioimaging [78] and photothermal therapy [79]. Silver nanoparticles exhibit unique properties such as thermal conductivity, high electrical conductivity, catalytic activity, chemical stability, antibacterial and improved optical properties [80]. These NPs are suitable for photonic [81], electronic [82], antimicrobial and disinfectant applications [83, 84], biosensors [85], drug delivery, photothermal therapy [26] and cellular imaging [86].
Another class of metallic nanoparticles is represented by semiconductor nanocrystals, which are well known as quantum dots. Many studies report their potential use in biomedical imaging [87], drug and gene delivery [88] and also in diagnosis [89] based on their unique chemical and optical properties.
Magnetic NPs represented by iron oxide NPs possess unique chemical, biological and magnetic characteristics including non-toxicity, chemical stability, biocompatibility, high magnetic susceptibility and high saturation magnetization [90, 91]. The main drawback of iron nanoparticle is that it has a tendency to oxidize [13]. To eliminate this unwanted process, coating with a biocompatible shell, such as a polymer [92], ceramics [93] or metals [13], is needed in order to prevent conglomeration. In addition, iron oxide NPs can be functionalized with proteins, antibodies, enzymes and anticancer drugs [13] and are investigated for different applications including magnetic hyperthermia [94], contrast agents in MRI (magnetic resonance imaging) [95], targeted drug delivery [96], multimodal imaging and gene therapy [61].
In the term of carbon-based NPs, fullerenes and carbon nanotubes exhibit promising biomedical applications. Fullerenes are suitable for multiple functionalization steps according to their particular globular network structure [97]. They are widely used as excellent antioxidants [98], antiviral agents [99, 100], drug and gene delivery systems [101, 102, 103] and photosensitizers for photodynamic therapy [104, 105]. On the other hand, elongated design of carbon nanotubes diagnostic imaging strategies [106, 107, 108, 109, 110], drug delivery [111, 112, 113] and also photothermal therapy [114, 115].
Ceramics NPs are inorganic non-metallic solids, which are synthesized by heating and successive cooling [116]. Therefore, these ceramics NPs are intensively used in the research field as photocatalysis, catalysis, agents for photodegradation of dyes and imaging agents [117].
There are significant challenges in engineering and designing new nanosystems. The “nanoparticle loaded nanoparticle” concept is described as an innovative strategy composed of at least two different nanoparticles. For example, porous nanoparticles made by silica can encapsulate DNA-conjugated small gold nanoparticles in their pores with great applicability in penetrating tumors [118].
Hybrid constructs gained increased interest in obtaining programmed nanoparticles. DNA nanorobots built of a DNA robot and a DNA aptamer that confers molecular recognition of nucleolin are used for target therapy in cancer [119].
Once the delivery system comes in the proximity of its target site, the drug must be internalized in order to fulfill its biological effect. While free drugs usually have the ability to pass through cellular membranes and accumulate inside the cell unless they are externalized by efflux pump mechanisms, NPs are internalized differently, mainly through various types of endocytosis [120], as presented in Figure 4.
Cellular internalization through endocytosis.
Phagocytosis is a mechanism by which specialized cells known as phagocytes recognize and engulf large particles (≥0.5 μm) into vesicles called phagosomes [121]. This process involves actin polymerization and the extension of pseudopods, which surround the opsonized target object [122] leading to its internalization (Figure 4(5)). Phagosomes fuse with early endosomes, followed by late endosomes and then lysosomes, becoming highly acidic and possessing hydrolytic enzymes leading to the degradation of the engulfed object [122].
Macropinocytosis is a process by which nonselective molecules suspended in extracellular fluid are internalized into the cell, giving rise to endocytic vesicles. Like phagocytosis, it involves cytoskeleton rearrangement beneath the plasma membrane. This leads to a plasma membrane circular ruffle formation that extends and entraps extracellular material, producing a so-called macropinosome [123]. The maturation of these vesicles involves shrinking while concentrating their contents, migration and digestion or recycling of their contents [124]. Depending on the cell line, macropinosomes can fuse with lysosomes or directly to the plasma membrane expelling their content to the extracellular space (Figure 4(4)) [124, 125].
Caveolae are small (60–80 nm) plasma membrane invaginations, important in processes such as endocytosis, transcytosis, potocytosis and certain signaling pathways [126]. Caveolin-dependent endocytosis is a triggered, energy-dependent event involved in the uptake of extracellular molecules and membrane components [127]. It is dependent on actin and dynamin, a GTPase, which is present at the neck of caveolae and is responsible for the release of the caveolar vesicle inside the cytoplasm [128]. These vesicles deliver the internalized molecules to caveosomes or to early endosomes (Figure 4(2)). Caveosomes bypass lysosomes, thus being an important approach for administering easily degradable therapeutic agents [129].
Clathrin-mediated endocytosis involves the uptake of extracellular molecules through invagination of the plasma membrane. The vesicles are formed when ligands interact with receptors on the plasma membrane, thus recruiting clathrin triskelions and adaptor proteins, which form a multifaceted cage structure [130] that is released inside the cell with the help of dynamin. These vesicles are known as clathrin-coated vesicles and can lose their clathrin coat and fuse with early endosomes (Figure 4(1)). They are directed towards degradation in lysosomes or recycled to the plasma membrane [131].
Extracellular cargo can also be internalized via clathrin- and caveolin-independent pathways (Figure 4(3)) [132].
Depending on the internalization mechanism, NPs have different fates. They can face lysosomal degradation when internalized through clathrin-mediated endocytosis while skipping this process when taken up through a caveolin-mediated mechanism [133].
Many nanomaterials are degraded in endocytic vesicles leading to new approaches of carrier designs that are able to escape the endosomal or lysosomal degradation. Three main strategies, presented in Table 1, are commonly used to bypass this cellular barrier for drug administration. They rely on molecules, which possess the ability to destabilize the endosomal membrane in a pH-dependent or independent way or to fuse with the endosomal membrane, leading to the release of previously internalized cargo. Another approach involves the photochemical membrane rupture via photothermal nanomaterials.
Strategy | Mechanism | Examples | Ref. | |
---|---|---|---|---|
Endosomal membrane destabilization | pH dependent | pH buffering (proton sponge effect) | Polyamines (PEI, PEAAc, Mglu-HPG) | [134] |
Pore-formation | Listeriolysin O (LLO) GALA peptide | [135] | ||
pH independent | Pore formation | Amphotericin B Melittin | [136, 137] | |
Fusion with endosomal membrane | Flip-flop mechanism | GALA peptide | [138, 139] | |
Via viral fusion proteins/peptides | HA2 fusion peptide/hemagglutinin | [140] | ||
Photochemical membrane rupture | Light-induced ROS and/or heat generation | TatU1A-photosensitizer conjugates M-PLL (melanin-poly-L-lysine) | [141, 142] |
Approaches for endosomal escape.
Molecular imaging is a medical discipline related to medical imaging and is representing the evolution of imaging techniques for diagnosis and therapy monitoring. It involves cell biology and molecular biology [143].
Current clinical applications of molecular imaging are CT, SPECT, PET, MRI, US and also hybrid imaging techniques SPECT/CT, PET/CT or PET/MRI. CT, MRI and US provide anatomical information, while PET/CT, and SPECT/CT offer functional and molecular information [144]. All these techniques are based on the accumulation of a contrast agent at the target site [145].
Even if they provide high-resolution images from anatomical [146] to molecular level for further clinical investigations [147, 148, 149, 150, 151, 152, 153], there are some disadvantages regarding the use of them. High doses of radiation and exposure can cause DNA damage in some tissues [154, 155]. Also, radiopharmaceutical biodistribution and effectiveness may cause image artifacts and also side effects for the patient [156, 157, 158, 159]. Moreover, the patient care quality is not granted in most of the cases [156].
Diagnostic imaging using NPs refers to the detection of specific disease sites through molecular recognition of tumor cell particularities like the overexpression of several genes and the presence of different cell surface molecules or media excreted compounds/molecules that are involved in various disease processes, microenvironment particularities and also cell development stages [160, 161].
Physical properties of nanoparticle systems are very important for molecular imaging applications. Nanoparticle accepted diameters for this application are between 30 and 150 nm. Usually, the nanoparticle surface is modified using a ligand in order to target specific tumor cell molecules. As more ligands are attached on the nanoparticle surface, there are more chances to bind the target cell. The amount of signaling groups influence the sensitivity of the detection method [145].
Some NPs have innate optical properties like QDs [162] and metallic NPs due to surface plasmon resonance [48, 163, 164, 165]. QDs nanoparticles labeled with 18F-Fluoropropionate and functionalized with RGD peptides demonstrate proper optical characteristics for PET imaging of prostate cancer [166].
Gold nanoparticles proved long circulation time and useful optical properties like high spatial resolution and high sensitivity for CT imaging. By functionalization with chitosan polymers, they were used for colorectal adenocarcinoma imaging [167]. Also, they were conjugated with antibodies for lymph nodes and metastases imaging in squamous cell carcinoma, head and neck cancer [168]. Moreover, gold nanoparticles radiolabeled with 111In and 125I can be used in SPECT imaging of epidermoid carcinoma [169].
Iron oxide nanoparticles are widely used in MRI imaging because they can improve and enhance the contrast [170]. In glioblastoma, iron oxide nanoparticles functionalized with peptides and polymers accumulate within tumor microenvironment by forming self-assembly structures [171].
Furthermore, polymeric materials such as mesoporous silica nanoparticles carry tumor targeting properties and are proposed for PET imaging in breast cancer. Besides this, they are able to perform drug delivery applications [172].
Regarding US imaging, perfluorocarbon nanoparticles can be used for a real-time and non-invasive analysis of thyroid carcinoma [173].
Considering the other nanoparticle formulations (nanoliposomes, micelles, polymersomes, dendrimers and aptamers), these ones need to be functionalized with specific contrast agents and fluorophores. The advantages to implement NPs such as molecular imaging tools are biocompatibility and biodegradability [174], encapsulation properties [175], water solubility in some cases [176] and targeting ligands accessibility [177].
Fluorophores are widely used in diagnosis applications and imaging of cellular processes. One drawback of conventional fluorophores is represented by the loss of fluorescence after a long exposure to light, known as photobleaching.
Various processes are known to induce the molecular relaxation without the emission of light, which depends on different chemical or physical factors like temperature, pressure, the presence of organic molecules or polymers and ionic strength, resulting in a decrease in the fluorescence intensity, referred to as quenching [178]. Quantifying this decrease in fluorescence emission can give information about the concentration of a specific compound in the proximity of the nano-objects. Lately, numerous diagnostic techniques based on this phenomenon have been introduced [179, 180].
On the other hand, another luminogen system based on a process called aggregation-induced emission (AIE), developed by Ben Zhong Tang’s group in 2001 [181], gathered increased interest for imaging and theranostic applications. Most luminescent systems have a lower efficiency in an aggregated state, thus limiting the concentration that can be used for imaging purposes and at the same time the achievable intensity of the emitted light. However, in the case of AIEgens, aggregation works constructively becoming highly luminescent in concentrated solutions or in an aggregated state. The utilization of AIEgens in theranostics has lately become a reliable approach, because of several advantages that include good biocompatibility, excellent optical properties and simple preparation and conjugation [182]. One example implies the conjugation of an AIEgen (TPS) with a short peptide (DEVD) that is susceptible to caspase-3 cleavage and that is bound to a prodrug that induces apoptosis [183].
Targeted therapy is a form of treatment, which implies the ability of a drug to accumulate at a target site in the body and thus decrease the side effects in healthy cells and tissues. Nanocarriers are often used to improve the bioavailability of the active compounds at the target site and allow the use of significantly reduced concentrations, therefore limiting the exposure of normal cells to the toxic effects of the drugs [184].
The most common strategies for drug delivery include local drug delivery, passive targeting, physical targeting, magnetic targeting and active targeting [185].
Local drug delivery is a promising strategy for the treatment of metabolic disorders (diabetes and obesity) [186], periodontitis [187] and bone disorders [188] due to its potential to keep drug availability in the target site for a prolonged period of time.
Passive targeting is based on enhanced permeability and retention effect (EPR effect) present in many tissues [189, 190]. Macromolecules and NPs from the bloodstream accumulate preferentially in tumors and inflamed sites, where the permeability of the vasculature is often enhanced. Moreover, the lymphatic drainage system is damaged in tumors, leading to a prolonged retention of the macromolecules and NPs in the tumor interstitium [191].
Physical targeting depends on the optical, thermal and electrical properties of the carriers [192], which can disintegrate at lower pH values or higher temperature and release the free drug. The tumor microenvironment is more acidic compared to the normal surrounding tissues, due to the accumulation of lactate, and therefore provides an opportunity for the use of pH-sensitive nanocarriers in cancer therapy [193].
Another approach for drug targeting refers to the accumulation of superparamagnetic carriers in target sites under the action of external magnetic field. Thus, a larger dose of the drug can be released at the tumor site for an increased period of time and side effects of chemotherapy can be diminished [194]. Once systemically administered, besides the type and intensity of the magnetic field and size of the NPs, many biological factors influence the infiltration of the superparamagnetic carriers to the target site, including the effect of Brownian motion, blood viscosity, interaction of the particles with the red blood cells and blood matrix [195].
While in the case of passive targeting the physicochemical properties of the nanocarrier system play the major role, active targeting relies on the interaction between the surface of the carrier and antigens expressed on target cells. NPs are functionalized by adsorption or chemical conjugation with a large variety of ligand types such as peptides, small molecules, proteins, and aptamers, which present a high specificity for epitopes or receptors that are uniquely expressed or overexpressed on the target sites [196]. Examples of commonly used ligands and their targets are presented in Table 2.
Class | Ligand | Targeted biomarker | Disease (clinical trials = *) | Ref. |
---|---|---|---|---|
Antibodies | Trastuzumab, cetuximab, Anti-CD20 mAbs (Rituximab) | HER2 receptor, EGFR, CD20 | Breast cancer*, esophageal carcinoma*, pancreatic adenocarcinoma*, head and neck cancer*, non-Hodgkin’s lymphoma*, rheumatoid arthritis* | [197, 198, 199, 200, 201, 202, 203] |
Peptides | Transferrin | Transferrin receptor | Cancer | [204, 205] |
Small molecules | Folic acid | Folate receptor | Rheumatoid arthritis*, ovarian cancer, lung cancer* | [206, 207] |
Aptamers | A10RNA, AS1411, Anti-MUC1 | Extracellular domain of the PSMA, nucleolin, MUC1 | Prostate cancer, breast cancer | [208, 209, 210] |
Commonly used molecules for active targeting.
*Refers to clinical studies.
Theranostics refers to the use of the nanoparticle for molecular imaging and therapy. Considering the biological barriers, the biocompatibility, easy surface modifications, controlled pharmacokinetics and biodistribution and accommodation in various microenvironment conditions are still necessary to be accomplished [211]. Polymers are widely used for NP formulations because of biocompatibility and biodegradability properties in vivo [212, 213, 214, 215]. Besides coating the nanoparticle surface with polymers, the fluorophores and other contrast probes are widely used to achieve high-sensitivity molecular imaging.
There are three main theranostic directions that involve the use of nanoparticles. The first strategy refers to treatment effect evaluation through molecular imaging with NPs as contrast agents. The aim of the second one is to assess a nanoparticle therapeutic strategy with molecular imaging probes. The third one describes nanoparticles as target therapy agents and molecular imaging tools at the same time. In this regard, for the first two procedures, the NP system is either the evaluator or the evaluated component, and for the last strategy, these roles are overlapping. Each one of these roles makes possible the development of future therapies (Figure 5).
Theranostic NPs action strategies.
The nanoparticles’ evaluator role (Figure 5(1)) can be emphasized in the next study. Zhang et al. developed Annexin A5-conjugated polymeric micelles with dual role: detection of apoptosis via SPECT and optical imaging and also therapy outcomes investigation. In this study, the apoptosis was induced by drugs like cyclophosphamide, etoposide, poly (L-glutamic acid)-paclitaxel and cetuximab (IMC-C225) anti-EGFR antibody. The NPs were used to observe the apoptosis-induced processes in lymphoma and breast cancer in vivo. Therefore, SPECT and fluorescence molecular tomography allowed cellular death visualization in tumors [216].
NP effect evaluation (Figure 5(2)) can be performed based on probes that are currently used in clinical molecular imaging. For example, 2-deoxy-2-[F-18]fluoro-D-glucose (18F-FDG) probe is used for metabolic activity measurements via PET/CT imaging. This radiolabeled probe can act as prognostic biomarker for nanoparticle-assisted photothermal therapy monitoring in neuroendocrine lung cancer in vivo [217].
Another strategy is to ensure both imaging and therapy at the same time (Figure 5(3)). In this situation, the nanosystem can be composed of two different components bonded together in order to perform a theranostic action.
The easiest way is to make use of the optical properties developed by some materials at nanoscale. Therefore, metallic nanoparticles can scatter and absorb the light in the NIR wavelength domain and are promising tools for cancer photothermal therapy [218].
In a different way, nanoparticles can be associated with molecular imaging techniques in order to enhance their efficiency. For example, doxorubicin-loaded polymeric micelles and perfluoropentane stabilized by the same block copolymer can perform US imaging and target therapy for breast and ovarian cancer [219, 220].
Some designs suggest the use of two different nanoparticles, which by conjugation with targeting ligands and drug molecules provide tumor visualization and target therapy. For example, quantum dot-mucin 1 aptamer-doxorubicin conjugates were used for ovarian cancer targeting and proved suitable optical properties for imaging and controlled release of the drug [221].
In addition to the molecular imaging techniques previously described, some nanoparticles can be used for photodynamic and photothermal therapy in order to perform targeting therapy.
Photodynamic therapy (PDT) implies the use of photosensitizer agents that under laser irradiation exert cytotoxic activity by generating reactive oxygen species [222, 223]. This therapy is very appreciated regarding multidrug resistance cancers and is suppose that it can replace the conventional chemotherapy [224]. PDT-specific nanoparticles are used as photosensitizer carriers [225, 226]. Moreover, these nanocarriers can be functionalized with targeting ligands for better tumor selectivity and also with drug molecules for therapeutic effectiveness [227, 228, 229]. Gold nanoparticles loaded with a fluorescent drug Pc4 targeting PSMA-1 membrane antigen in prostate cancer are promising tools for surgical guidance and further therapeutic intervention [228]. EGFR-targeted liposomal nanohybrid cerasomes are proposed for PDT and immunotherapy in colorectal cancer due to their sensitive detection properties and anti-tumor efficacy [229].
By a theranostic point of view, photothermal therapy (PTT), also known as hyperthermia or thermal ablation therapy, acts as a diagnosis and a treatment strategy. It uses electromagnetic radiation in infrared (IR) region and provides high specificity analysis and minimal invasiveness [230]. The nanocarriers used for PTT need to have the capacity to target the tumor site after heat generation under laser irradiation [231]. For this purpose, various drug molecules and targeting ligands are encapsulated into nanoparticles. Gold nanoshells targeting HER2 positive breast cancer proved optical contrast and high tissue penetration under NIR irradiation [218]. Polymer nanoparticles functionalized with IR820 and doxorubicin were used in ovarian cancer and showed prolonged circulation time and drug accumulation at the target site [232]. It is important to mention that the generated temperature is usually between 42 and 45°C and sometimes higher depending on tumor tissue [233, 234].
There are various types of theranostic NPs that can be designed and used for cancer diagnosis and therapy. Their applicability is highlighted by liposomes, which are intensively used in clinical trials due to their specific features. In Table 3, several theranostic nanoparticles used in clinical (clinical trials) and pre-clinical work for cancer diagnosis and therapy are shown.
Stage | Nanoparticle type | Therapeutic agent | Diagnostic agent | Pathology | Target | Ref. |
---|---|---|---|---|---|---|
Pre-clinical | Liposomes (100–200 nm) | Paclitaxel | pH-sensitive poly(ethylene oxide) (PEO)-modified poly(beta-amino ester) (PbAE) nanoparticles | Ovarian adenocarcinoma | EPR | [235] |
Silica (100–200 nm) | Paclitaxel and camptothecin | Superparamagnetic iron oxide nanocrystals | Pancreatic cancer | Folic acid | [236] | |
Iron oxide (10–25 nm) | Anti-EGFRIgG | Iron oxide nanoparticles | Glioblastoma | EGFR | [237] | |
Gold nanorod (10 x 40 nm) | Heat | Thermal/CT | Breast cancer | EPR | [238] | |
Quantum dots (30–50 nm) | Paclitaxel, doxorubicin, 5-fluorouracil | Quantum dots | Many cancers | CD44, folic acid | [239] | |
Clinical trials | Silica (6–7 nm) | cRGDY | Ultrasmall inorganic hybrid nanoparticles | Melanoma and malignant brain tumors | ανβ3 integrin | [240] |
Cyclodextrin (70 nm) | RNAi | Transferrin | Solid tumors | Transferrin receptor | [241] | |
Silica-gold nanoshell | Photothermal ablation | Nanoshell (MR and optical) | Head/neck cancer, primary and/or metastatic lung tumors | EPR | [242] | |
Gold (27 nm) | Tumor necrosis factor alpha | Gold nanoparticles | Solid tumors | EPR (passive mechanism) rhTNF (active mechanism) | [243] | |
Iron oxide | Endorem (superparamagnetic particles of iron oxide) | Iron oxide | Healthy volunteers | none | [244] |
Nanoparticles used in clinical (according to
Abbreviations: EPR, enhanced permeability and retention effect; EGFR, epidermal growth factor receptor; cRGDY, peptide cyclo-(Arg-Gly-Asp-Tyr); rhTNF, recombinant human tumor necrosis factor alpha; RNAi, ribonucleic acid interference; MR, magnetic resolution.
Theranostics has the potential to predict and evaluate therapy response, offering advantageous opportunities to modify the ongoing treatments and to develop new ones even in a personalized manner [245]. Nanoparticles have gained a lot of confidence in becoming important tools for a lot of medical applications due to their properties [17, 19].
The newest designs focus on hybrid nanostructures for better sensitivity and accuracy. These nanohybrids are currently studied and they proved effectiveness in cancer targeting by combining different imaging techniques with drug delivery strategies [246, 247, 248].
This research was funded by the research grants “Clinical and economic impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance”-CANTEMIR, POC-P-37-796/2016, “Innovative advanced approaches for predictive regenerative medicine”—REGMED, no. 65PCCDI/2018, PN-III-P1-1.2-PCCDI-2017-0782, “Increasing the performance of scientific research and technology transfer in translational medicine through the formation of a new generation of young researchers”—ECHITAS, no. 29PFE/18.10.2018, PNCDI III 2015-2020.
The authors declare no conflict of interest.
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