Nanobiotechnology in Diagnosis, Drug Delivery and Treatment. Группа авторов

et al. 2012; Xiao and Merlin 2012). These reports demonstrate promising results showing physiological changes in IBS, after application of such nanoconjugates with drugs and exploiting these differences to enhance specific delivery of drugs to affected tissue.

      GI tract disorders are statistically noticed in 5 to 50% of patients with primary immunodeficiencies (PIDs) which include rare, chronic, and serious disorders of the immune system. Patients suffering from PIDs cannot mount a sufficiently protective immune response, leading to an increased susceptibility to infections. The gut is the largest lymphoid organ in the body, containing the majority of lymphocytes and producing large amounts of immunoglobulin (Ig), therefore patients with PIDs might suffer from various GI disorders caused by microorganisms or parasites. Dysfunction of the regulatory mechanisms responsible for the balance between active immunity and tolerance in the gut may lead to mucosal inflammation and damage, and also lead to GI diseases (Agarwal and Mayer 2013).

Overall, nanoparticle and nanomolecule drug‐delivery mechanisms can be classified into active and passive targeting. Active targeting highly depends on the interaction between the target cell receptors and nanoparticles, whereas passive targeting relies on a number of factors such as longer biological half‐life, long‐circulating time at tumor locations, and the flow rate of nanoparticles to the impaired lymphatic system (Hong et al. 1999; Kaasgaard et al. 2001; Mishra et al. 2004; Gryparis et al. 2007; Romberg et al. 2008; Gholami and Engel 2018). Moreover, the effectiveness of the nanoplatform drug‐delivery system is determined by the enhanced permeability, retention effects, and nanoparticle clearance by the mononuclear phagocyte system (Maeda et al. 2000; Greish 2007). The reticuloendothelial system (RES) effect is one of the most common problems among all different types of nanoparticles used for diagnosis and therapy of various diseases. The RES effect refers to the quick absorption of nanoparticles by macrophages which usually results in clearing nanoparticles from the circulation in vivo (Owens and Peppas 2006; Torchilin 2007; Howard et al. 2008). Therefore, modification of nanomaterials, e.g. specific types of nanoparticle coating, may prevent and minimize the RES effect (Gholami and Engel 2018). Kovacevic et al. (2011) reported that nanoparticles with surfactants or covalent linkage of polyoxyethylene have shown to effectively minimize the RES effect. Similarly, the size of nanoparticles was found to affect the delivery of conventional therapeutics to solid tumors. Nanoparticles larger than 500 nm are shown to be rapidly removed from the circulation in vivo (Maeda et al. 2000; Cho et al. 2009).

      Although the application of diagnostics and therapeutics to the targeted sites along the GI tract and endoscopy are sometimes complicated, especially into the distal small intestine, it has been tried in many types of diseases, with varied success. The targeted delivery of therapeutic agents to the terminal ileum and colon was performed in the case of IBD and to the stomach in gastrin ulcers, while the theranostic probe was tried in the diagnostics of pancreatic, gastric and colonic cancers, or genes in gene therapy of gastric and colonic cancers (Jha et al. 2012). It suggests that application of nanomaterials in diagnosis and therapy of GI disorders is a very promising approach in nanomedicine.

3.6 Nanomaterials: Potential Treatment for Gastric Bacterial Infections

      Gastric diseases are defined as diseases that affect the stomach. Inflammation of the stomach resulting from infections caused by any infectious agent is called gastritis. Moreover, when this condition affects various other parts of the GI tract, it is called gastroenteritis. Long‐lasting (chronic) state of gastritis is associated with several diseases, including atrophic gastritis, pyloric stenosis, and gastric cancer. Another common disorder of the GI tract includes gastric ulceration or peptic ulcers. Ulceration damages the gastric mucosa, responsible for the protection of stomach tissues from the acids present inside this organ. The H. pylori infection is a common chronic infectious disease which is considered to be a main agent causing peptic ulcers (College et al. 2010). Besides peptic ulcer disease, it can lead to atrophic gastritis, gastric adenocarcinoma, and mucosa‐associated lymphoid tissue lymphoma (Angsantikul et al. 2018). The eradication rates of H. pylori are far from desirable for infectious diseases (Lopes‐De‐Campos et al. 2019) as the resistance of H. pylori to antibiotics has reached alarming levels worldwide (Angsantikul et al. 2018). Nowadays many researchers are focused on developing rapid detection and efficient drug delivery systems to meet the challenge of antibiotic resistance. Therefore, conjugation of antibiotics with micro‐ or nanodelivery materials is considered one of the most promising strategies to improve the efficacy of conventionally used drugs (Giau et al. 2019). Moreover, such carriers acting as encapsulating agents can protect antibiotics from enzyme deactivation, resulting in an increase of the therapeutic effectiveness of the drug (Lopes‐De‐Campos et al. 2019). Development of nanoparticles that encapsulate multiple antibiotics for concurrent delivery has been reported by Angsantikul et al. (2018). For example, amoxicillin (AMX) antibiotic has been encapsulated in several delivery systems such as polymeric nanoparticles, gastro‐retentive tablets, and liposomes (Lopes et al. 2014; Arif et al. 2018; Lopes‐De‐Campos et al. 2019).

      Overall, several types of nanomaterials such as micelles (Ahmad et al. 2014), carbon nanomaterials (Al‐Jumaili et al. 2017), magnetic nanoparticles (Tokajuk et al. 2017), mesoporous silica nanoparticles (Martinez‐Carmona et al. 2018), polymer‐based nanomaterials (Álvarez‐Paino et al. 2017), and dendrimers (Mintzer et al. 2012) have been used as vehicles to carry antimicrobial drugs in various type of diseases. Similarly, the micro‐ and nanosized materials such as liposomes, dendrimers, peptides, polymer, and inorganic materials were found to be compatible with and enhanced the sensitivities of conventional diagnostic tests by several orders of magnitude (College et al. 2010). It is also suggested that drug‐free nanomaterials that do not kill the pathogen but affect its virulent factors such as adhesins, toxins, or secretion systems can be used to decrease resistance of the pathogen and severity of the caused infection (Giau et al. 2019; Lopes‐De‐Campos et al. 2019).

Recently, H. pylori have been successfully eradicated using a variety of antibiotic‐loaded chitosan micro‐ and nanoparticles (Giau et al. 2019). The proposed mechanism of bacterial cell inactivation is presented in Figure 3.3. Westmeier and coauthors (2018) studied the behavior of a panel of model nanoparticles, varying in size, shape, surface functionalization, and material on H. pylori. They noticed that conjugation of nanoparticles with bacteria did not require specific functionalization or negative surface charge and that assembly in interfering medium was significantly influenced by low pH which effected on the bacterial surface. Moreover, it was also reported that silica nanoparticles (25% surface coverage) did not show significant bactericidal activity but it was observed that these nanoparticles have the ability to attenuate the pathogenesis of H. pylori by inhibition of the type IV secretion system (Giau et al. 2019). Beside all of these reports of nanotechnology in combating bacterial gastric infections, still there is a major challenge for the scientific community to develop such nanomaterials that should be effective in the changing pH of the GI tract (Lopes et al. 2015). One of the such promising materials is the ternary copolymer poly (ethylene glycol)‐block‐poly (ami‐nolated glycidyl methacrylate)‐block‐poly(2‐(diisopropyl amino) ethyl methacrylate) (PEG‐b‐PAGA‐b‐PDPA) which was recently used as a pH‐responsive micelle to target metastatic breast cancer (Giau et al. 2019).

Similarly, the efficacy of lipid nanoparticles (LNPs) against H. pylori was reported (Seabra et al. 2017). This type of nanomaterial is generally considered cost‐effective, easily scaled up, and also biocompatible and biodegradable, which enhances its interest for commercial purposes (Giau et al. 2019). Thamphiwatana et al. (2013) studied the novel pH‐responsive gold nanoparticle‐stabilized liposome system for gastric antimicrobial delivery. The anionic phospholipid liposomes were stabilized by positively charged small chitosan‐modified gold nanoparticles deposited on their surface. These liposome nanomaterials were stable in gastric acid while at neutral pH released gold stabilizers from their surfaces and gained the capability of fusing with bacterial membranes. The liposomes loaded with antibiotic (doxycycline) were used as a targeted delivery system to treat gastric pathogens such as H. pylori. Authors reported that the use of doxycycline‐loaded liposomes, which rapidly fused with bacterial membranes, showed