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 superior bactericidal efficacy compared to the use of free doxycycline. Based on obtained results the authors concluded that the liposome system has the potential for gastric drug delivery (Thamphiwatana et al. 2013).
Figure 3.3 Mechanism of Helicobacter pylori inactivation in epithelium cells by chitosan nanoparticles loaded with antibiotic.
The nanoparticles have been also conjugated with ligands such as mannose‐ or fucose‐specific lectins in order to target the carbohydrate receptors on H. pylori cells (Umamaheshwari and Jain 2003). H. pylori is able to change the rheological properties of the mucus layer due to urease secretion (Celli et al. 2009), resulting in an increase of the pH and subsequently in reduction of the viscosity of the surrounding environment. Therefore, mucoadhesiveness of the gastric mucosa is considered as a target in treatment of H. pylori infections. Changes in mucosa viscosity may improve the time of contact between the drug and bacterial cells, and consequently, the efficacy against these bacterial infections (Lopes et al. 2015).
3.7 Nanostructures for Colon Cancer Diagnostics and Therapeutics
Colorectal cancer (CRC) is a severe health problem and has the third highest incidence of tumors in both males and females. The global incidence of CRC is about 1.3 million cases per year (Viswanath et al. 2016). However, according to estimates from the International Agency for Research on Cancer in 2018, globally, CRC constituted approximately 1.8 million new cases and 900 000 deaths annually (Keum and Giovannucci 2019). Thus, CRC is a common health problem due to its high prevalence and high mortality rate. Adjuvant and neo‐adjuvant strategies, chemotherapy, and radiotherapy alone or in combination, have substantially improved survival and local recurrence rates. Their effectiveness remains limited due to the intrinsic build‐up of resistance of cancer cells to chemotherapy drugs, dose‐limiting toxicities and other major side effects (Gholami and Engel 2018). Colon cancer occurs due to certain routine factors and increasing age, with only some cases resulting from fundamental genetic disorders (Gulbake et al. 2016). Over the last few years, nanotechnology has improved available and developed novel methods for the detection and treatment of CRCs that cannot be achieved using the existing conventional technologies (Laroui et al. 2013; Viswanath et al. 2016). Moreover, targeted nanostructures offer potential solutions against the restrictions of standard chemo‐ and radiotherapy that may cause damages to normal tissues in proximity to and distant from tumors and clinical toxicities (Viswanath et al. 2016). Nanomaterials of different shapes, size, and compositions are considered as promising and important novel tools for CRC diagnosis, staging, and therapeutics (Dong et al. 2015).
There are some examples of the application of nanotechnology that directly address the in vitro diagnosis of CRC. Nanostructures, particularly nanoparticles, might be used as a label for direct visual detection. They offer multiplexing capabilities for detecting proteins or nucleic acids (Seydack 2004). Nanostructures may be also used for modifications of traditional contrast or imaging agents such as gadolinium or iron oxide, respectively, and thus enhance the diagnostic power of clinical imaging by using magnetic resonance (Laroui et al. 2013). Among the developing technologies that have potential in imaging GI diseases such as CRC, the use of near‐infrared fluorescence (NIRF) imaging can be highlighted, especially if the current clinical evaluation of CRC already uses fiber optic examination of luminal surfaces (Weissleder et al. 2005). Application of NIRF imaging agents such as tunable QDs during endoscopic visualization can enhance standard imaging techniques used for diagnostics of GI tumors, including CRC (Viswanath et al. 2016). Vigor et al. (2010) reported that SPIONs could be used to target and image cancer cells if functionalized with recombinant single‐chain Fv antibody fragments (scFv). Authors generated antibody‐functionalized (abf) SPIONs using a scFv specific for CEA, an oncofoetal cell surface protein present in human tumor cells. Obtained results demonstrated that abf‐SPIONs bound specifically to CEA‐expressing human tumor cells, generated selective image contrast on magnetic resonance imaging (MRI) (Vigor et al. 2010). Similarly, Tiernan and coauthors (2015) studied binding of antibody‐targeted fluorescent nanoparticles (CEA‐targeted nanoparticles) to colorectal cancer cells in vitro and in vivo after systemic delivery to murine xenografts. They found that CEA‐targeted, polyamidoamine dendrimer‐conjugated nanoparticles allowed strong tumor‐specific imaging and concluded that these nanoparticles have the potential to allow intra‐operative fluorescent visualization of tumor cells (Tiernan et al. 2015).
Beyond diagnostics, targeted nanostructures offer opportunities to develop novel treatment approaches of tumor diseases (e.g. colorectal tumor). Indeed, nanostructures have been assembled with antibodies, proteins, and small‐molecule ligands targeted to specific tumor‐associated receptors to deliver chemotherapeutic agents. The targeted use of chemotherapeutics in animal tumor‐xenograft models showed greater pharmacological and clinical efficacy and decreased adverse events as antibody‐targeted liposomes effectively accumulate in CRC cells (Fortina et al. 2007). Nanogels containing 5‐fluorouracil (5‐FU) were assembled to be used as new colon‐targeting drug carrier systems. This delivery system was characterized by its excellent pH sensitive release property and effectively reduced toxicity (Ashwanikumar et al. 2012). Moreover, potential application of activated nucleoside analogs for the treatment of drug‐resistant tumors by oral delivery of nanogel drug was shown in studies of Senanayake et al. (2013).
Targeted nanoparticles as a drug delivery system based on monoclonal antibodies are currently one of the main approaches for CRC therapy under preclinical development (Brennan et al. 2004; Weinberg et al. 2005).
An enhanced antitumor activity of the photosensitizer meso‐Tetra(N‐methyl‐4‐pyridyl) porphine tetra tosylate (TMP) through encapsulation in antibody‐targeted chitosan/alginate nanoparticles was reported by Abdelghany et al. (2013). TMP is a photosensitizer that can be used in photodynamic therapy to induce cell death through generation of reactive oxygen species in targeted tumor cells. However, TMP is highly hydrophilic, and therefore, its ability to accumulate intracellularly is limited. Thus, its encapsulation in chitosan/alginate nanoparticles improved TMP uptake into human colorectal carcinoma HCT116 cells, unlike TMP or nanoparticles used alone. Moreover, these nanoparticles were further conjugated with antibodies targeting death receptor 5 (DR5), the cell surface apoptosis‐inducing receptor, upregulated in various types of cancer and found on HCT116 cells. This conjugation of nanoparticles had antibody‐enhanced uptake and cytotoxic potency of the generated nanoparticles (Abdelghany et al. 2013). Similarly, Fay et al. (2011) demonstrated the induction of apoptosis in colorectal HCT116 cancer cells using Poly(lactic‐co‐glycolic acid)
