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Nanoparticles and nanomedicine

I. Definition of nanoparticles (NPs):
NPs can be defined as particles ranging in in size from 1- 100 nm (Prasad and Shrivastav, 2014; Khan et al., 2017). The prefix nano has its origin in the Greek and Roman terms nannos/ nanus, which describes dwarfs or dwarf-like structures (Mehlhorn, 2015).

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Nanometer as defined by nanotechnology refers to one thousand millionth of a meter (i.e. 1 nm = 10-9 m). Thus, nanotechnology is the science that particularly deals with the processes that occur at molecular level and of nano length scale size (Bahtia et al, 2016).

Nanomedicine is an emerging field that combines nanotechnology using various NPs with pharmaceutical and biomedical sciences, with the goal of developing drugs and imaging agents with higher efficacy and improved safety and toxicological profiles (Bobo et al., 2016).

II. Historical overview

NPs have been known since ancient times. The history of nanoparticles dates back to 9th century in Mesapotamia, in West Asia (Deepika, 2015). Silver NPs were used by ancient Romans and Phoenicians in the manufacture of water storage containers to produce glittering effect on the surface of pots (Hill and Pillsbury, 1940; Alexander, 2009).

Development of NPs in the medical field had been started by one the giant scientists Paul Ehrlich in the late 1960s and early 1970s who believed that NPs could be used for targeted delivery to greatly improve drug therapy. He called this delivery system “magic bullets” (Kreuter, 2007).

This was followed by the work done by Ursula Scheffel and colleagues then the extensive work by the group of Professor Peter Speiser who first focussed on the development of NPs for vaccination purposes. Further developments were then introduced for the use of nanoparticles for many purposes in biomedical and industrial fields (Kreuter, 2007).

III. Properties

Owing to their small size and very large surface area to volume, NPs have unique physical and chemical properties different from the bulk material, which enable their potential applications in many biological and medical fields (Hasan, 2015).

Large surface area of NPs in relation to volume facilitates the attachment of multiple molecules (antibiotics, nucleotides, proteins, antibodies) to nano-structured surfaces by chemical and electrostatic means (Huh and Kwon, 2011). In addition, the small size of NPs offers them the ability to overcome various biological barriers to transport and deliver therapeutic agents to the target tissue (Jiao et al., 2014).

Interactions of NPs with their biological surroundings depend on the interaction between the controllable properties of the NPs and the largely uncontrollable properties of the surrounding media (Nel, et al., 2009). Particle shape, size, and surface chemistry are key factors that determine performance criteria, including the degree of protein adsorption, cellular uptake, biodistribution patterns, and clearance mechanisms (Bobo et al., 2016).

Particle size has a main role in clearance of nanomaterials from the body. Small particles (10 nm) are cleared through the liver and the mononuclear-phagocyte system (Elci et al., 2016).

The desired clearance mechanism can be a factor in the design of the NP; e.g. selecting small sized particles that are rapidly cleared if they are not taken up into the target organ might be an important factor to design molecular imaging agents. In contrast, it is favorable for drug-delivery vehicles to circulate for longer times, allowing greater accumulation of the drug in the disease site (Yadav et al., 2011).

IV. Classification of nanoparticles:

NPs are broadly classified into various categories depending on either their morphology, size, chemical properties or preparation process.

A. Classification of NPs according to preparation process:
NPs may be divided into nanocarriers and nanodrugs. Nanocarriers refer to materials prepared by the dissolution or dispersion of drugs with a variety of nanoparticles, which may be classified as either nanospheres or nanocapsules according to the preparation process. Nanodrugs involve the direct application of micronization and technologies to process the drugs into the nanoscale (Li et al., 2017).
Nanospheres have a matrix in which drugs are dispersed or adsorbed onto their surfaces. Nanocapsules are systems surrounded by a unique membrane and drugs are entrapped in the core or adsorbed onto their exterior (Bagul et al., 2012).

Figure ( ): Nanocapsules and nanospheres (Kashef et al., 2017).

There are many types of NPs with different size, shape, composition, and functionalities. Furthermore, each type of NPs can potentially be synthsesized using different techniques (Wang and Wang, 2014).

B. Chemical classification of NPs:

Based on their chemical characteristics, some of the well-known NPs can be classified into liposomal NPs, polymeric NPs, protein based NPs, magnetic NPs and metallic NPs. About 51 FDA-approved nanomedicines were identified and 77 products still in clinical trials (Bobo et al., 2016; Khan et al., 2017).

1. Liposomal NPs:

Liposoms are spherical vesicles with a membrane composed of phospholipids bilayer. Liposomes can be composed of naturally-derived phospholipids with mixed lipid chains (like egg, phosphatidylethanolamine), or of synsthetic components (Bagul et al., 2012).
Unique advantages of liposomes are their diverse range of compositions, abilities to carry and protect many types of biomolecules, so they can allow the entrapment of hydrophilic compounds within the core and hydrophobic drugs in the lipid bilayer itself (Xing et al., 2016).
Since the lipid bilayer can fuse with other bilayers (e.g., the cell membrane), thus liposomal NPs are one of the first NPs to be applied for gene delivery and the delivery of drugs which are normally unable to diffuse through the cell membrane (Wang and Wang, 2014).

Figure ( ): Liposomal NPs with liplid bilayer enclosing an aqueous core (Uchechi et al., 2014).

2. Solid Lipid Nanoparticles:

The solid lipid nanoparticles are new generation of submicron-sized lipid emulsions where the liquid lipid (oil) has been substituted by a solid lipid dispersed in water or in an aqueous surfactant solution (Mukherjee et al., 2009).
Solid lipid nanoparticles offer unique properties that make them effeicient carrier systems; small size, large surface area and high drug loading. So they are attractive carriers to improve performance of pharmaceuticals and other materials (Bahtia et al., 2016).

Figure ( ): SLN NPs with liplid monolayer and solid lipid core (Uchechi et al., 2014).

3. Protein based NPs:

Natural biomolecules such as proteins are commonly used in drug formulations because of their safety (Lohcharoenkal et al., 2014).
In fact, protein-based NPs show many advantages over other types of NPs. In addition to their biocompatibility and biodegradability, their simple preparation under mild conditions and without use of toxic chemicals or organic solvents allows them to be widely used in various applications (Tarhini et al., 2017).
Protein based NPs may contain Albumin, gelatin, elastin, soy proteins and other peotein members (Lohcharoenkal, et al., 2014).

4. Polymeric NPs:

Polymeric NPs are formed of different hydrophobic polymers including poly L -glutamic acid, poly ethylene oxide, poly L-lactic acid, melamine and chitin (Bagul et al., 2012; Bahtia et al., 2016).
Polymeric NPs have been formulated to encapsulate hydrophilic and/or hydrophobic small drug molecules, as well proteins and nucleic acid macromolecules (Wang et al., 2008).
Polymeric NPs are defined by their morphology and the composition of their core and periphery. The therapeutic agent is either conjugated to the surface of the NP, or encapsulated and protected inside the polymeric core (Prabhu et al., 2015).
Due to feasibility to develop with defined molecular weight, good entrapment efficiency and offering surface for functionalization which allows the binding of different ligands to their surface; variety of polymers (single or in combinations) are used for designing drug delivery system (Bahtia et al., 2016).

Figure ( ): Different types of polymer based nanoparticles (Kumar et al., 2012(a)).

Acting as drug carriers, polymeric NPs can effectively allow slow and controlled drug release at target sites and thus increase therapeutic benefit, with minimizing side effects and improving the safety of the carried drug (Wang and Wang, 2014).
Several polymer-based therapeutic NPs have been approved for clinical use (Prabhu et al., 2015). Either synthetic polymers are used to prepare nanoparticles such as; poly (d,l-lactide-co-glycolide) (PLG) , poly (d,l-lactic-coglycolic acid) (PLGA) , poly (g-glutamic acid) (g-PGA) and poly (ethylene glycol) (PEG), or natural polymers based on polysaccharide have also been used to prepare nanoparticles including; pullulan , alginate , inulin, and chitosan (Zhao et al., 2014).
Chitosan (Cs), a polymer from the chitin family has diverse pharmaceutical and bio-medical utility. Recent pharmaceutical research has examined the use of Cs-based systems for drug delivery applications in various diseases (Rajitha et al., 2016).

5. Inorganic NPs:

Many inorganic nanoparticles have been studied for their use in medicine. Owing to their rigid structure and controllable synthesis, they are widely used in many applications although these nanoparticles are mostly nonbiodegradable (Zhao et al., 2014).
Inorganic drug delivery systems, such as gold NPs, silica NPs (SiNPs), iron oxide NPs, and other inorganic NPs with hollow or porous structure, have emerged as promising alternatives to organic systems for a wide range of biomedical applications (Tang and Cheng, 2013).

6. Magnetic NPs:

Iron oxide NPs have an iron oxide core with a hydrophilic coat of dextran or other biocompatible compound to increase their stability (Wang and Wang, 2014). Because of their magnetic properties which enable them to be magnetized with the application of an external magnetic field); iron oxide NPs are widely studied as targeting imaging agents (Xiang et al., 2013).
Magnetic NPs have been successfully used as magnetic contrast agents in magnetic reasonance imaging. They have several advantages over conventional contrast agents including decreased toxicity and increased imaging sensitivity and specificity. They can also be degraded to iron and iron oxide molecules that are metabolized, stored in cells as ferritin, and incorporated into hemoglobin (Hasan, 2015).
They can be also used in targeted cancer treatment (magnetic hyperthermia), stem cell sorting and guided drug delivery (Wu et al., 2015).

7. Metallic NPs

Various metals have been studied though silver and gold nanoparticles are of chief importance for biomedical use (Bahtia et al., 2016).
Metallic nanoparticles have been used for active delivery of drugs, bioassays, imaging and many other applications (Zhang et al., 2016).
In addition, silver nanoparticles are proved to have a good antimicrobial efficacy against bacteria, viruses and parasites. They are used as antimicrobial agents, in textile industries, for water treatment, wound dressings, and biomedical devices (Hasan, 2015). Silver NPs are also used as anticancer agents, and have ultimately enhanced the tumor-killing effects of anticancer drugs (Chernousova, et al., 2013).
Gold NPs can transform absorbed light into heat and therefore, have been used in phototherapy (Hasan, 2015).

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