location by loading in mesoporous silica NMs (Qi et al., 2013). The prerequisite for effective target therapy is to target macrophages with NMs, make macrophages active, and then release the drug (Xiong et al., 2012).4 Controllability: As mentioned above, the controlled release of any drug is crucial for its action mechanism. Conventional delivery methods failed to maintain controlled and sustained release of many drugs. This resulted in either high drug levels for short time periods or very low drug levels. Thus, repeated dosage is given, which has its own side effects. NMs' ability to slowly release the drugs at therapeutic concentration results in reduced frequency of dosing and pain. The prolonged drug release from NM‐based delivery systems provides better inhibitory effects on microbial growth (Liu, Zhang, Li, Yang, Pan, Kong, & Zhang, 2016).Further, the drug release from NMs can also be controlled by making them responsive to various stimulatory factors like temperature, pH, light, chemicals, or magnetic field (Lim, Chung, & Chung, 2018; Wu et al., 2016). Similar systems are already being explored for better controlled drug release. For example, drugs like levofloxacin are delivered using solid–lipid NMs, which prolong the retention for ocular applications (Baig et al., 2016).
5 Combination: Another important advantage of NM‐based drug delivery is its ability to deliver multiple drugs at the same time through the same channel. In many cases, the targeted site of infection has multiple microbes present, requiring the delivery of specific drugs for each type. In such cases, multiple drugs can be packed and delivered using same NMs. Also, for single‐cell type, it is difficult to develop resistance to multiple antibiotics that are delivered through same NM at the same time. Multiple action mechanisms make this kind of system more efficient.
On the other hand, two or more types of NMs can also be combined to overcome the disadvantages of a single type of NM. The much explored liposome‐based drug delivery system has a short shelf life, less stability, and low encapsulation efficacy. This system can be combined with other delivery systems like solid lipid NMs to obtain hybrid NM with improved properties. Another example of a hybrid NM delivery system are lipid–polymer NMs with better efficacy (Hadinoto, Sundaresan, & Cheow, 2013).
1.7 Antibacterial Application of NMs
Generally, NMs have been used as an antimicrobial coating material for implantable medical devices such as heart valves, dental implants, and catheters (intravenous catheters or neurosurgical catheters). One of the best examples is the coating of drug‐loaded mesoporous TiO2 on the implants, which inhibits the growth and even the adhesion of E. coli (Della Valle et al., 2012; Xia et al., 2012). The skin is part of the primary immune defense system in our body where trauma or burns or chronic ulcers damage skin and compromise its functions. Common microbial infections associated with skin wounds are Staphylococcus, Streptococcus, E. coli, and Klebsiella species. Here, the infections involve multiple bacteria including antibiotic‐resistant bacteria where the antimicrobial agent needs to have a broad spectrum of antimicrobial property. In this regard, NMs have been exploited in the preparation of wound dressing materials. Silver NPs along with polyvinyl alcohol and chitosan have been used in the synthesis of fiber mat for wound healing. Nanosilver with high antimicrobial property significantly inhibited the growth of bacteria and along with mat fiber enhanced the wound healing rate (Li et al., 2013). In addition, NMs with antimicrobial properties have been also used in bone and dental implants. Bone cement containing polymethyl methacrylate (PMMA) with silver‐doped silica glass powder significantly inhibited the formation of biofilm over the implants (Miola et al., 2015). TiO2 mixed with prosthesis retarded bacterial growth and prevented biofilm formation over light exposure (Aboelzahab et al., 2012). Among various NMs, the most commonly exploited antibacterial NMs include nanometals, metal oxides, carbonaceous materials, and cationic polymers.
1.7.1 Nanometals
Metals over a threshold concentration exhibit toxicity on the biological system. Among them, heavy metals such as arsenic, cadmium, chromium, lead, and mercury are highly toxic to the living system (Tchounwou et al., 2012). The property of metal toxicity has been exploited to prepare antibacterial nanometals that are toxic to bacterial cells. An additional advantage of nanometals is the possibility of tuning the properties of the system during the synthesis phase.
Metal NMs include silver NPs, copper NPs, and iron NPs. Silver NPs are one of the well‐known antimicrobial materials that have been used in various healthcare, industrial, and medicinal sectors, their mechanism of action being the toxic effect of Ag+ ions exerted by interacting with sulfhydryl groups in proteins. Further, silver ions also inhibit DNA replication and also affect the cell membrane integrity, thus compromising the permeability (Feng et al., 2000). Wigginton et al. (2010) showed that the Ag NPs have high affinity for tryptophanase protein of E. coli. It is evident from the literature that the enzyme tryptophanase is crucial for the production of indole from tryptophan amino acid where indole plays a crucial role behind the multidrug exporters and also acts as a signaling molecule in biofilm formation. It was clearly evident from the study that the binding of Ag NPs deactivated the enzyme which could make the bacteria prone to effect of drugs and other antimicrobial materials (Wigginton et al., 2010). Ag NPs exhibited bactericidal activity by inactivating the enzyme phosphomannose isomerase in bacteria, which converts mannose 6 phosphate to fructose 6 phosphate. This conversion is one of the crucial steps in glycolysis of bacterial sugar metabolism (Dakal et al., 2016; Sundar & Kumar Prajapati, 2012). In another study, Elechiguerra et al. (2005) showed that the interaction of Ag NPs with HIV‐1 was not random but based on the structure of virus envelope. The envelope consists of a protruding gp120 glycoprotein connected to intracellular matrix protein p17 through a transmembrane glycoprotein gp41. Importantly, HIV‐1 binds to CD4 receptor sites on the host cell using gp120 protein knobs. It was observed in this study that Ag NPs attach to the HIV‐1 surface by sulfur‐containing residues of the gp120 protein (Elechiguerra et al., 2005). Next to silver NPs, copper NPs have gained attention in the past few years as cost‐effective alternatives to the former. Copper NPs also exert a mechanism similar to that of silver. They act by damaging the bacterial cell wall and disrupting the DNA structure (Raffi et al., 2010).
1.7.2 Metal Oxides
Similar to metal NMs, oxides of metal also exhibit antimicrobial activity through the metal ions released from the system. The mechanism of action is the ROS production induced by metal ions or by the accumulation of NPs inside the cells. Most metal oxides are semiconductors in nature with larger bandgap energy. Among the metal oxides, ZnO (3.2 eV) has the highest bandgap energy similar to TiO2, which gets activated at a wavelength of about 390 nm to induce ROS production. CdO has a bandgap energy of about 2.1 eV with activation wavelength at 590 nm (Table 1.2).
Among the metal oxides, the most widely used are TiO2, ZnO, CuO, and MgO for antibacterial activity. A vastly studied metal oxide is TiO2, which is used in various industrial and environmental applications such as in sunscreen preparation, implant coatings, and removal of water and air contaminants. The antimicrobial efficiency of a system depends on the wavelength of light used for activation, the intensity of light, concentration, interaction time, temperature, and target microbes (Markowska‐Szczupak, Ulfig, & Morawski, 2011). Efficacy of the TiO2 system depends on the photoinduced generation of ROS, which happens effectively at the oxide anatase phase. When light of energy equal to or higher than the bandgap energy (3.22 eV, anatase phase) is exposed, photocatalytic activation produces an energy‐rich electron–hole pair. The electron produced is transferred to reducible species such oxygen to generate free radicals like superoxides O2−. In a similar way, it induces the production of hydroxyl radicals and hydrogen peroxide in acidic conditions (Kühn et al., 2003). A schematic representation of photoactivated ROS generation and antimicrobial property of NMs is given in Figure 1.2 as described by Gardini et al. (2018)
