date, several nanoliposomes have been developed for therapy of colorectal cancer (CRC), namely Doxorubicin (Doxil®) or Marqibo® which are examples of Food and Drug Administration (FDA)‐approved nanoliposomes for chemotherapy of CRC (Barenholz 2012; Stang et al. 2012; Allen and Cullis 2013). Thermo‐sensitive liposome doxorubicin (Thermodox®) is another promising nanoliposomal drug for colorectal liver metastases in combination with radiofrequency ablation. This nanoliposome with doxorubicin formulation releases the drug upon a mild hyperthermic trigger and can deliver 25‐fold more doxorubicin into tumors than IV doxorubicin does (Stang et al. 2012).
3.3.2 Polymers
The polymers used as particulate vectors may be natural or synthetic, synthesized by standard polymerization chemical methods. The polymers used for diagnosis and treatment of diseases must be biocompatible, nontoxic, nonimmunogenic, and noncarcinogenic. They must also be (bio)degraded in the body, and their degradation products must be well tolerated and quickly eliminated (Laroui et al. 2011). Variable polymer chains can be used to form swollen nanosized structures called nano‐size hydrogels or nanogels. These polymer chains are usually formed by non‐covalent interactions or covalent crosslinking. Nanogels, in addition to typical nanomaterial properties, e.g. large surface area to volume ratio, are also characterized by size tunability, controlled drug release profile, excellent drug loading capacity, and responsiveness to environmental stimuli. In nanomedicine, they have attracted significant attention as imaging labels and targeted drug delivery, while reducing systemic side effects (Arunraj et al. 2014). Nanogels may be tailored to exhibit exceptional stability, low cytotoxicity, and higher blood compatibility (Chacko et al. 2012; Kong et al. 2015). They showed potential to be an oral drug delivery system (Senanayake et al. 2013). The polysaccharide chitosan nanoparticles have been also used as drug delivery systems (Figure 3.2). Polymers can be conjugated with proteins, and such nanoconstructs display reduced immunogenicity, enhanced stability, and prolong plasma half‐life (Ekladious et al. 2018). The conjugation of therapeutic agents to polymeric carriers offers improved drug solubilization, prolonged circulation, controlled release, and enhanced safety (Ekladious et al. 2019). The nano‐sized multi‐structural constructs of polymers with drugs displayed potential to improve pharmacological therapy of a variety of solid tumors. Polymer‐drug nanoconstructs promote tumor targeting throughout the increased permeability and retention effect, and in the cells, following endocytic capture, allow lysosomotropic drug delivery (Lee 2006; Gaur et al. 2008; Greco and Vicent 2009).
Figure 3.1 Nanoliposome as a carrier for drug delivery.
Figure 3.2 Chitosan nanoparticles loaded with drugs.
3.3.3 Core‐Shell Nanoparticles
The core‐shell nanoparticles are composed of two or more materials which can be synthesized with different combinations of inorganic and organic materials. Their functionality and stability can be increased by coating. Superparamagnetic iron oxide nanoparticles (SPIONs) are one of the most common core‐shell nanoparticles that are used in medical imaging and therapy (Damascelli et al. 2001; Gholami and Engel 2018). Their biocompatible polymer coating and core surface modification enable their use in nanomedicine and nuclear medicine applications. SPIONs exhibit magnetization only in an applied magnetic field and are able to load drugs and medical radioisotopes (due to their highly active surface) (Gholami and Engel 2018). There are key advantages of SPION drug delivery including longer circulation half‐lives, improved pharmacokinetics, capability of carrying a large amount of drugs, reduction in side effects, and targeting the drug to a specific location in the body (Laroui et al. 2011).
3.3.4 Quantum Dots (QDs)
QDs are fluorescent nanocrystals produced from semiconductor materials with unique optical and electrical properties (Matea et al. 2017). QDs have drawn a lot of attention for their simplicity of synthesis and abundance of the raw material in nature. They are rich in carboxyl groups on their surface, therefore QDs can absorb a lot of single‐strand carcinoembryonic antigen (CEA) aptamer through π‐π stacking interactions, leading to effective fluorescence quenching (Zhu and Gao 2019). The utility of fluorescent properties of QDs for cancer targeting and imaging applications has been suggested in many studies (Laroui et al. 2013; Gao et al. 2014). Semiconductor nanoparticles can accumulate at a target site due to their enhanced permeability and retention at a tumor site. For example, fluorescent QDs conjugated to various peptides specifically target either the vasculature of normal tissues or, alternatively, cancer cells (Fortina et al. 2007). QDs were found to be useful in diagnosis of leishmaniasis, a parasitic disease caused by parasites of the Leishmania type (Andreadou et al. 2016). Authors developed a Leishmania‐specific surface antigen and DNA detection methods based on a combination of magnetic beads and CdSe QDs with a test specificity of 100% and a low limit of detection of 3125 ng μl−1 for Leishmania DNA and 103 cells ml–1 for Leishmania protein. Based on obtained results the authors concluded that this method showed considerable potential for clinical application in human and veterinary medicine.
3.4 Nanoparticle Uptake in the Gastrointestinal Tract
The GI tract is one of the portals for nanoparticles to get across the human body. However, inhaled nanoparticles can also be ingested by the GI tract once they are cleared through the respiratory tract (Hoet et al. 2004; Gaur et al. 2008). The kinetics of particle uptake in the GI tract depends on diffusion through the mucus layer, initial contact with enterocytes, cellular trafficking, and post‐translocation events (Medina et al. 2007). Once ingested, nanoparticles readily penetrate the mucus layer and come into contact with enterocytes of the intestinal lining. The smaller the particle diameter is, the faster they can diffuse through the mucus layer and reach the colonic enterocytes. However, nanoparticles may escape from active uptake by enterocytes as they are scavenged by M‐cells overlying the intestinal mucosa. Due to cellular transposition they can reach the bloodstream and distribute all over the body (Szentkuti 1997; Gaur et al. 2008).
It is suggested that similar to the lungs, the GI tract is also easily exposed to stimuli that can induce an inflammatory response. IBD, which is a group of inflammatory chronic disorders of the gut, can result from a combination of genetic predisposition and environmental factors (Podolsky 2002; Gaur et al. 2008). However, none of the published studies have reported direct toxicological effects of nanoparticles in the GI tract (Gaur et al. 2008).
On the one hand, the successful action of nanomaterials used for diagnosis or therapy of GI diseases depends heavily on their size, size distribution, morphology, hydrophilic–hydrophobic balance, and surface functionalization (Laroui et al. 2011). However, this action of nanomaterials also depends on conditions in each part of the digestive tract. These distinct conditions introduce many challenges to the application of therapeutics to GI tract. It should be highlighted that physicochemical properties and aggregation of nanomaterials will be also affected by co‐ingested material present in the gut, namely food matrices, proteins, mucus, and bile acids secreted within the gut (Walczak et al. 2015; Bouwmeester et al. 2018). Studies by Peters et al. (2012) and Walczak et al. (2013) reported that properties of 60 nm silver nanomaterials and nanometer‐sized silica were affected by the food matrix during transit before they were available for uptake in the small intestine.
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