**5. Challenges in treating infectious diseases using nanotechnology**

Use of antibiotics began with commercial production of penicillin in the late 1940s and claimed to be a great success until the 1970–1980s when newer and even stronger antibiotics were additionally improved [29]. Resistance to antimicrobial drugs becomes a threatening problem not only in hospitals but also in communities, resulting in fewer effective drugs available to control infections by "old" well-known bacteria [30]. Carrier systems allow antibiotics to be delivered selectively to phagocytic cells and to increase their cellular penetration in order to treat intracellular infections, particularly in the case of antibiotics active against microorgan‐ isms that produce this type of infection but that have a low intracellular penetration capacity [31]. Nevertheless, significant challenges remain for implementation of clinically viable therapies in this field. New challenges in the development of nanotechnology-based drug delivery systems include: the possibility of scale-up processes that bring innovative therapeu‐ tic techniques to the market rapidly, and the possibility of obtaining multifunctional systems to carry out several biological and therapeutic requirements [32]. Thus, a drug delivery system should be multifunctional and possess the ability to switch on and switch off specified functions when urgent. Another important requirement is that different properties of the multifunctional drug delivery systems are harmonized in an optimal fashion [33]. Therefore, design, discovery, and delivery of antimicrobial drugs with improved efficacy and avoidance of resistance are extremely requested [34].

#### **5.1. Advantages of nanoantibiotics**

mucosal barriers, nonspecific uptake of the particle and non-specific delivery of the drug (as a result of uncontrolled release) [20]. Passive nanoparticulate targeting of chemotherapeutics to the cells and organs of the reticuloendothelial system (RES) has been a significant area of research for the treatment of chronic infectious diseases. The RES comprises monocyte-lineage immune cells such as macrophages and dendritic cells, as well as the spleen, liver, and kidneys. These components of the RES are consistently implicated as sites of nanoparticle clearance and localization [21]. The few studies that have compared targeted and nontargeted systems have demonstrated that the role of targeting ligands in localization at the target site is application dependent. Targeted delivery to atherosclerotic lesions is greatly enhanced by targeting ligands which impart an improved ability to accumulate at the target site [22]. Many active targeting strategies use the enhanced permeability and retention (EPR) effect, so that active and passive targeting mechanisms act synergistically that lead to higher concentration of nanostructures in the infected region than that in healthy tissues [23]. Targeted antimicrobial drug delivery to the site of infection, particularly intracellular infections, using NPs is a sensational prevision in treating infectious diseases [24, 25]. Intracellular microorganisms are taken up by alveolar macrophages (AMs), intracellulary survive or reproduce, and are persistent to the antimicrobial agents. Antibiotics loaded NPs can enter host cells through endocytosis, followed by releasing the payloads to delete intracellular microbes [26, 27]. The need to target drugs to specific sites is increasing day by day as a result of therapeutic and economic factors. Nanoparticulate systems have shown enormous potential in targeted drug

**5. Challenges in treating infectious diseases using nanotechnology**

Use of antibiotics began with commercial production of penicillin in the late 1940s and claimed to be a great success until the 1970–1980s when newer and even stronger antibiotics were additionally improved [29]. Resistance to antimicrobial drugs becomes a threatening problem not only in hospitals but also in communities, resulting in fewer effective drugs available to control infections by "old" well-known bacteria [30]. Carrier systems allow antibiotics to be delivered selectively to phagocytic cells and to increase their cellular penetration in order to treat intracellular infections, particularly in the case of antibiotics active against microorgan‐ isms that produce this type of infection but that have a low intracellular penetration capacity [31]. Nevertheless, significant challenges remain for implementation of clinically viable therapies in this field. New challenges in the development of nanotechnology-based drug delivery systems include: the possibility of scale-up processes that bring innovative therapeu‐ tic techniques to the market rapidly, and the possibility of obtaining multifunctional systems to carry out several biological and therapeutic requirements [32]. Thus, a drug delivery system should be multifunctional and possess the ability to switch on and switch off specified functions when urgent. Another important requirement is that different properties of the multifunctional drug delivery systems are harmonized in an optimal fashion [33]. Therefore, design, discovery, and delivery of antimicrobial drugs with improved efficacy and avoidance

delivery, specially to the brain [28].

158 Application of Nanotechnology in Drug Delivery

of resistance are extremely requested [34].

The use of NPs as delivery vehicles for antimicrobial agents suggests a new and promising model in the design of effective therapeutics against many pathogenic bacteria [35]. Antimi‐ crobial NPs propose several clinical advantages. First, the surface properties of nanoparticles can be changed for targeted drug delivery for *e.g.* small molecules, proteins, peptides, and nucleic acids loaded nanoparticles are not known by immune system and efficiently targeted to special tissue types [36]. Second, nanocarriers may overcome solubility or stability issues of the drug and minimize drug-induced side effects [37]. Third, using nanotechnology, it may be possible to achieve co-delivery of two or more drugs or therapeutic modality for combination therapy [33]. Fourth, NP-based antimicrobial drug delivery is promising in overcoming resistance to common antibiotics developed by many pathogenic bacteria [38]. Five, adminis‐ tration of antimicrobial agents using NPs can progress therapeutic index, extend drug circulation (i.e., extended half-life), and achieve controlled drug release, increasing the overall pharmacokinetics [30]. Six, the system can be used for several routes of administration including oral, nasal, parenteral, intra-ocular etc [39]. Thus, antimicrobial NPs are of great interest as they provide a number of benefits over free antimicrobial agents [35].

#### **5.2. Disadvantages of nanoantibiotics including nanotoxicology**

Although nanoantibiotics promises significant benefits and advances in addressing the key obstacles in treating infectious diseases, there are foreseeable challenges in translating this exciting technology for clinical application [40]. Profound knowledge about the potential toxicity of nanoantibiotics is also needed to guarantee successful clinical translation [41]. The toxic effects of antimicrobial NPs on central nervous system (CNS) are still unknown, and the interactions of NPs with the cells and tissues in CNS are poorly understood [42]. Furthermore, NPs represent size-specific properties that limit the use of currently available *in vitro* experi‐ ments in a general way, and there is no standardized definition for NP dose in mass, number, surface area, and biological samples (e.g., blood, urine, and inside organs) [43, 44]. This means that there is a high request to develop new characterization techniques that are not affected by NP properties as well as biological media [45]. NPs usually have short circulation half-life due to natural defense mechanism of human body for eliminating them after opsonization by the mononuclear phagocytic system. Therefore, the particles surfaces need to be changed to be hidden to opsonization [46]. A hydrophilic polymer such as polyethylene glycol is prevalently utilize for this purpose because it has worthwhile characteristics such as low degree of immunogenicity and antigenicity, chemical inertness of the polymer backbone, and availabil‐ ity of the terminal primary hydroxyl groups for derivatization [47].
