Current advances in nanocarriers for biomedical research and their applications

Abstract

Nanodrug delivery systems sometimes referred to as nanocarriers (NCs) are nanoengineered biocompatible materials or devices, which in conjugation with desired bioactive compounds plays an indispensable functional role in the field of pharmaceutical and allied sciences. The diversified ability of this bioengineered colloidal or noncolloidal molecule to breach the biological barriers to reach the targeted location in the biological system uplifts its other versatile natures of mono- or polydispersity in biodistribution. Furthermore, its nontoxicity and biodegradability result in making it a unique candidate for its purpose as drug delivery system. A number of different conjugations of chemical and biological substances are currently implemented for the synthesis of this biofunctional hybrid nanomaterial by simple methods. The use of these bioconjugated as a nanoparticulated system is currently being used for the treatment of various deadly incurable infectious diseases such as tuberculosis and disorders such as diabetes and cancers of various forms. Henceforth, the objective of the present review article is to provide overviews of the diversified and types of nanoparticulated systems, their beneficial as well as deleterious impacts along with the future prospect of nanodrug delivery system based on present status.

Keywords:

• Nanocarriers
• nanoparticles
• biodistribution
• biocompatible
• drug delivery

Introduction

Innumerable effort and ideas from various corners of the world put forth the scientific elucidation of nanoparticles (NPs) and their use in a diversified technology called nanotechnology. The concept of nanoparticles and their development were greatly derived from the works of Michael Faraday and Richard Feynman during the early eighties. Simultaneously, production of nanoscale objects and their nanoscale manipulations were put forward by the work by Jatzkewitz and Bangham, where they developed polymer–drug conjugates and liposomes in the nanoscale range respectively [1,2]. However, the concept of molecular manipulations of NPs put forward by Eric Drexler has revolutionized the whole field and increases the dimension of its applications.

The science of nanotechnology mostly deals with production, manipulation and use of materials ranging in nanometers (metal NPs and their oxides). With advancement in modern science, research on nanomaterials (NMs), the implementation has gained momentum and has become more rapid among researchers all over the world. Nanotechnology provides a platform to modify and develop the important properties of metal in the form of NPs having encouraging uses diagnostics and therapeutics fields (nanomedicine). This achievement of nanoparticles can be credited to their unique physical, chemical and biological properties such as surface Plasmon resonance, polydispersity, stability and biocompatibility, which are exploited clinically in cell labelling, contrasting agent for biological imaging, antimicrobial agent and biomarkers in diagnostics and drug delivery systems [3]. Of the different applications of NPs, its potential as a drug delivery system (DDS) to a targeted site via bio-conjugated nanoparticulated systems remains an indisputable and fascinating application among pharmaceutical scientists. Earlier, naturally occurring nanosized vesicles secreted by monocytes and macrophages (exosomes) were being used as an exosomal-based delivery system for a potent antioxidant to treat Parkinson’s disease, but with development of bioconjugated nanoparticulated systems like nanoencapsulated quercetin in zinc NPs, it has now become conceivable to progress the bioavailability of natural phytocompounds such as flavonoid, as a potential treatment for Alzheimer’s disease when administered orally [4,5]. Although nanotechnology-based DDS has great beneficiary efficiency in almost every aspect of life, still there are certain limitations that are need to be concerned exploration and implementation of this technology for the betterment of mankind [6].

With the current developments in technology and the diversified ability of the bioengineered molecule to breach the biological barriers and reach the targeted location in the biological system is another stepping stone towards success. These nanotechnology-based drug delivery systems can be readily fabricated either from soft (organic and polymeric) or hard (inorganic) materials with their controlled sizes and compositions being engineered to carry range of drugs in a variety of configurations [7]. Currently, targeted drug delivery system and the adapted control release tactics are used in dealing different types of diseases and disorders such as cancer, neurodegenerative disorders, chronic lung infection, hypertension, pulmonary tuberculosis, malaria, HIV-AIDS, metabolic disorders and many more [4,8,9]. It is not late when the advancement of this nanoengineered therapeutic agent may pave the path for a new era where nanotechnology-based drug would be available for almost any kind of disease and health aliments. At present, some of the NPs with multiple therapeutic activities are under clinical trials, while some have already been permitted by Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for their usages as potential drugs [10]. Henceforth, the review article highlights the advances in the development of diverse types of nanoparticulated systems (Figure 1), based on their origin, morphology and certain internal composition and their beneficial (Figure 1) as well as deleterious impacts, along with the future prospect of DDSs.

Figure 1. Main nanoparticulated systems aiming applications in biomedical research.

Types of drug delivery systems and their applications

Metallic nanoparticles (MNPs)

The growing interest in the use of MNPs in medicine is due to their unique size and shape-dependent optoelectronic properties achieved from the source and techniques through which they have been synthesized. Commonly synthesized MNPs are gold (Au), silver (Ag), Ag–Au, copper (Cu), zinc (Zn)/(ZnO), iron (Fe), iron oxide (Fe₃O₄), titanium (Ti), aluminium (Al), lead (Pb), palladium (Pd), carbon (C), cobalt (Co), cadmium (Cd), nanoshells and nanocages. MNPs have been synthesized both from chemical as well as biological sources. Despite their efficiency in conjugated drug delivery, the use of MNPs is limited to certain NDSs due to the concern on toxic yield from chemical and physical synthesis processes, generation of reactive oxygen species (ROS), etc. However, there is still a minuscule gap between the current and the efficient application of NPs in biomedical research that is needed to be ameliorated by using MNPs of biological origin [11].

Enormous researches in the nanotechnology field have provided a list of various routes for synthesizing MNPs at present such as photochemical synthesis, electrochemical synthesis, template-directed growth and solution phase synthesis, but in addition to this all synthesis techniques, Green synthesis has stood more remarkable one due to its environment friendly, less expensive properties. In this technique, many biological systems such as plants, fungi, diatoms, bacteria, yeast and human cells are used to form MNPs by reducing the proteins and metabolites of organisms. MNPs can be synthesized from those plants, which have high capacity for the reduction and accumulation of strong metal ion, and the accumulated metals can be recovered after harvesting via smelting and sintering methods. The capacity of various plants Medicago sativa (alfalfa) and Brassica juncea (Mustard greens) to synthesize MNPs has been studied, and it has also been seen that metals gathered in the plants are in their nano form. For example, M. sativa and Iris pseudacorus (Yellow iris) accumulate icosahedra gold of 4 nm and semispherical copper of 2 nm were found respectively when grown on their respective metals [12]. Furthermore, their modification with heterogeneous functional groups opens a wide area to be conjugated to various biological ligands, antibodies and desired therapeutic drugs for their potential applications pharmacology, biotechnology and other related applied sciences, more specifically, tasks such as magnetic separation, preconcentration of the targeted analytes, targeted drug/gene delivery and biosensors for disease diagnosis and finally for various imaging modalities as an aid to image various disease states [13].

Iron oxide nanoparticles

Inorganic compounds such as iron (III) oxide (Fe₂O₃) are paramagnetic in nature and occur naturally as magnetite mineral. Because of their ultrafine size, magnetic properties and biocompatibility, these superparamagnetic iron oxide NPs have emerged as a novel entity for a number of pharmaceutical or biomedical applications; for instance, it can be used as an resolution contrast enhancing agent in MRI, targeted drug delivery and imaging, hypothermia, gene therapy, stem cell tracking, molecular/cellular tracking, magnetic separation technologies and diagnosis of infectious diseases such as tuberculosis, early detection of inflammatory, cancer, diabetes and atherosclerosis.

Though this ultra-small iron oxide nanoparticle is currently being explored numerous applications, it is still far from the threshold limit of utilization. The major limiting factor of this oxide NP is its surface disorder, which simply means atoms at the surface have fewer neighbours than atoms at bulk. The particle’s physicochemical properties are directly hampered due to this lower coordination and unsatisfied bonds. And lastly, the in vitro and in vivo nanotoxicity arising due to nanoparticles accumulation and the production of excess reactive oxygen species such as free radicals (superoxide anion, hydroxyl radicals and nonradical hydrogen peroxide) is the most sever limiting factor, which suppresses the vigorous utility in the field of biomedical or in pharmaceutical sciences.

Silver nanoparticles

The corresponding small size attributed by respective MNPs such as silver nanoparticles (AgNPs) are still charming the current scientists in every phase of scientific advancement to explore new dimension for their utilization specifically biomedical research [14]. Current utilization of these MNPs is growing day by day starting from paints to very sophisticated in vitro and in vivo DDS. Among all the biomedical applications, the antimicrobial (antibacterial, antifungal and antiviral) activity of AgNPs is been widely explored in pharmaceutical industries, food storage, textile coatings and bioremediation and sustainable environment management [14–17]. Though the Green synthesis of these NPs is proven to be ecofriendly and nonpathogenic but still than the controversy, linking its in vitro and in vivo toxicities is unclear.

Gold (Au) nanoparticles

AuNPs are also extensively exploited in different domains of science diversified domains; biomedical is one of those fields where the particles have shown its effectiveness. It bears some specific physical, optical and chemical properties such as large surface area, small dimension, shape, amphiphilicity, noncytotoxicity, excellent biocompatibility, tunable stability, optical properties and the ability to form heterogeneous biointeraction; these NPs could serve as one of the most suitable candidates for controlled drug delivery, treatment of various diseases and disorders, early detection and diagnosis and detection and biomedical imaging [18]. Currently, AuNPs are successfully used in the destruction of tumours by inducing localized hyperthermia, radiotherapy for cancer, safe targeting, computed tomography imaging and photodynamic therapy. By encapsulating the AuNP with active functional groups such as zwitterions and polyethylene glycol, it can be used as nanocarrier to increase the adsorption of plasma protein [19]. Colloidal AuNP, which has become the current attraction of today’s date, is very small in size equal to the size of DNA and proteins making it easy to enter into the tissues and cells. They have high affinity towards the thiols, carboxylic acid and proteins; in conjugation with, AuNPs are used as therapeutic agents for cancer therapy. These nanoparticles are used as indicating probes due to the unique optical property of being inert during the reaction with the alkynes. DNA-NP probe is formed when the AuNP is labeled with the n-alkylthiolated DNA. These probes, immobilizing on the substrate, change their optical properties after reacting with the analytes and function as a biosensor. In conjugation with protein, AuNPs are used as immunosensors, giving rise to radiolabelled bioconjugates for cancer diagnosis.

Silica nanoparticles

It is pre-defined that one of the conspicuous advancements in the relative application of NPs is the recognition of the steric stabilization, which can increase the particle stability in a biological environment [20]. This ability of NPs is further exploited in the field of DDS through heterogeneous conjugation with other forms of natural polymer, resulting in a simultaneous need or designing of appropriate surface ligands for these nanoparticulated systems, for the enhancement in their ability to interact with the target molecules within the host. Silica-based nanoparticulated systems are one of the such primarily used for this propose, avoiding drug resistance due to high surface tolerability and also assisting in linking different organic groups as cell-specific ligands on its surface for targeting specific drug delivery [21]. The efficient use of porous, nonporous and mesoporous silica NPs, in the field of biomedical application, has paradigmatically shifted the concept of medicine to a different level.

There are several methods for fabricating silic-based nanoparticulated systems, which includes different etching techniques such as electrochemical, stain, photochemical, gas, vapor, spark, induced etching and a recent emerging technique of thermal and nonthermal plasma-induced syntheses. They are generally achieved through variation in current density, electrolyte concentration, concentration of dopant (p-type or n-type) and crystalline orientation of silica wafer [22] Silica NPs consists of micropores (<2 nm), mesopores (2–50 nm) and macropores (>50 nm). Characteristic features of silica NPs such as specific size, volume, distribution and high surface tolerability to silanol functionalization are some of the other modifiable features that immensely contribute to their current efficiency and applicability [20]. Apart from their application in diagnostics and treatment of different diseases, the ability of silica-based DDSs to carry different drugs/therapeutic agents of biological origin as phytochemicals could be another application area where researches are lacking behind and need subsequent attention in near future.

Carbon-based NPs

Carbon nanotubes, fullerenes, nanodiamonds (NDs), carbon nanohorns, carbon nanodots, graphenes and its derivatives are some of the common carbon-based NMs whose application in the field of nanomedicine or as drug delivery vehicles along with their ability to coronate with different biomolecules and bioimaging has been largely exploit in recent times. The reason for the exemplary application of carbon-based NMs is their unique physiochemical properties such as high mechanical strength, thermal as well as electrical conductivity, superparamagnetism, strong near infrared spectral absorption, high surface adsorption potential, photo-acoustic properties and phenomenal biochemical coronations along with their ameliorate level of cytotoxicity [23,24]. These dynamic properties of carbon-based NMs are coupled strongly to the structural conformation of carbon atoms that reflected in their hybridization state.

Carbon nanotubes (CNTs)

Sumio Iijima from Japan is generally credited for the discovery of CNTs, though its morphology was presented by Oberlin almost a decade earlier. In general CNTs are hexagonal networks of carbon atoms or a monolayer of graphene sheets rolled up in a cylindrical fashion with an axial diameter of about 1 nm and length varying in between 1 and 100 µm. The small size, mass, high strength and high thermal and electrical conductivities are some of the multipotential properties of CNTs, which have contributed for their wide applications in fields of medical science and biomedical research. Based on the composition or arrangement/layers of grapheme, carbon nanotubes are classified as single-walled carbon nanotubes (SWCNTs) with diameter 0.4–2 nm and multi-walled carbon nanotubes (MWCNTs) within 2–100 nm. As most of the NMs, CNTs have both lethal and beneficial effects but investigate on its lethal/toxic effects are the primary concern of nanobiotechnologists. Mitigation of their lethality may result in possible broad spectrum application of CNTs in the field of medical science for the management and/or diagnosis and treatment of multiple diseases and disorders. Henceforth, currently there has been rigorous search for altering the toxic effects of CNTs to avail its efficient serviceability in the field of biomedical research.

Fullerenes

The first fullerene molecule named buckminsterfullerene (C₆₀) was developed by Richard in the late eighties. Chemically, it is composed of carbon in hollow spherical form comprising of 12 pentagonal carbon rings encircled by 20 hexagonal carbon rings and having a diameter of about 0.7 nm. As CNTs, fullerene carbon molecules are sp2 and sp3 hybridized out of which, only sp2 carbon atom represents considerable angle strain within the molecule. Because of the expendable physical and chemical properties, diversified experimental methodologies have been derived for the bizarre chemical and structural transformations of the sphere that results in the production of several varieties of C60 derivatives, possessing different cutting-edge physical and chemical properties.

More specific chemical and structural natures of fullerene include higher photo-thermal effect due to broad range of light absorption in the UV–Vis region, ions or ion clusters within inner sphere and durable triplet state to scavenge electron with a bilateral nature of electrophilic and nucleophilic characteristics [25]. These features have contributed greatly towards their application in various amalgamated fields of science such as nanobiotechnology, nanopharmacology for various diseases and disorders due to their biocompatibility, antitumor immune response, anticancer activity, etc., and many others form have resulted in production of some of the astonishing utilities for detection and diagnostics as biosensors and bioprobe [26–28].

Nanodiamonds (NDs)

Nanodiamonds represent a new distinct class of nanomaterials, which unlike CNTs and fullerenes NDs contains sp3 carbon atoms in the core, with sp2 carbons on the surface, in a form of dispersed individual particles of nano size. The overall size of NDs ranges between 5 and 100 nm [29]. Currently, nanodiamonds are being extensively applications in medical science mainly due to its chemical immutability, biocompatibility, nontoxicity and its exceptional ability to conjugate with biomolecules. One of the common uses of NDs in biomedical is the immobilization of enzyme for efficient proteolytic activity. Wei et al. [30] demonstrated it by immobilizing trypsin on the surface of NDs (trypsin-NDs), which could successfully digest myoglobin in the time period of 5 min. Prosthetics are another booming field, where NDs are widely being exploited. Development of ultrananocrystalline diamond (N-UNCD) electrode comprising an array of 256 stimulating with a pitch of 150 μm to be used in the microfabrication process of stimulating retinal ganglion cells for the enhancement in the quality of vision experienced by patients using retinal prostheses is one of the major achievements [31]. The surface modification or coating of rat blood with NDs studied by Tsai shows that no immune invoking, toxicity or complications appeared in the blood’s physiological conditions by comparing both the results obtained by in vitro and in vivo [29]. With their biocompatibility properties, NDs could play an important role of a vital DDS that could be enhanced through further development.

Organic nanoparticles

Organic NPs are solid particles composed of organic compounds such as lipids and polymers ranging in a diameter from 10 nm to 1 µm. These NPs in the form of biopolymer renders a diversified array of advantages starting from the easy mode of preparation to well-defined functionalizable stability and biodegradability till profound biocompatibility within the host. Some of these biopolymers include polymeric nanoparticles (PN), lipid-based nanoparticles, dendrimers (DEN), liquid crystal (LC) systems, niosomes (NIO), microemulsions (MEs) and nanomicelles (NAs) [17].

Polymer-based NPs

Polymers are the concatenation of a large number of repeating units’ having an appearance of matrix or scaffold, but when dispersion, the polymeric matrix is used for encapsulating a therapeutic agent, resulting in the formation of colloidal polymeric particles polymeric nanoparticles (PNPs) with a diameter ranging between 1 and 1000 nm. On the basis of structure and composition, these NCs can be of two types, that is, nanospheres and nanocapsules [32]. In polymeric nanospheres, the therapeutic agents are dissolved, entrapped or attached to the surface of it but in the case of polymeric nanocapsules, polymeric matrix membrane encompasses the therapeutic agents within its core. Currently, various types of PNCs are being used for multiple biomedical applications. Out of those PNCs, especially poly (lactide-co-glycolide) (PLGA)-based NPs has been given much emphasis due to its numerous serviceable properties such as biological degradability, compatibility and their ability to carry and withstand the therapeutic drug or gene for longer period of time and target specific control release [33]. Currently, the efficiency of these versatile nanoparticulated systems can be enhanced by their conjugation with functionalizing/linking them with molecules/proteins/NPs with respect to desired application [34]. Today, PNP-based materials offered a better prospect for designing new framework of materials with heterogeneous structure and a distinctive property to form stable associations. The required properties of PNPs could be accomplished by manipulating their source/origin or the methods of synthesis. Though at present, there are multiple PNPs with diverse functions and applications, but still there is a wide gap between their efficient utilization in the field of medical science [33]. Polymer-based NPs are mostly designed and estimated for their ability to carry synthetic drugs that may have complications, instead of which NPS should be fabricated to load natural therapeutic agents such as phytoconstituents and evaluate their efficiency in biomedical applications.

Lipid-based NPs

Lipid-based material with the ability to carry solute particle commonly referred to as liposomes were first demonstrated by Bangham. With further advancement in the field of science and technology, solid–lipid NPs (SLN) and nanostructured lipid carriers (NLC) were developed, which consisted of a mixture of one or more lipids, solids, surfactants and water. Lipid-based DDSs are highly multifaceted drug delivery platform due to its heterogeneous selection and union of solid–lipid, lipid–lipid and hybridization with disparate form of polymers. These highly modifiable DDSs are currently being used as the building blocks for manufacturing various nanostructures applicable as potential nanodrug carriers. Extensive research on lipid NPs has being carried out owing to their unique properties such as biological compatibility, biodegradation, convenient and easy industrial scale-up process and multiple routes of administration. Further evaluations are essential regarding the efficiency of these highly versatile molecules to encapsulate and deliver natural bioactive phytocompounds for the diagnosis and treatment of various diseases and disorders.

Dendrimers

Dendrimers are nanosized highly symmetrical/ordered, branched macromolecules with well-defined, homogenous and monodispersed structure. The architectural regions of the nanosized structure can be divided into core or focal moiety, layers of branched repeat units and functional end groups on the outer layer [35]. These hyperbranched macromolecules with cautiously customized architecture and the tunable end-groups further provide an additional opportunity for their user-dependent modulation of physicochemical or biological activities. The advantage of these well-defined macromolecules is their ability to linearly increase the diameter, which attains a more globular shape that further favours their self-generation. Their biorelevent properties such as polymer size, charge, composition, lipid bilayer interactions, cytotoxicity, internalization, blood plasma retention time, filtration and biodistribution are some of the essential requirements of therapeutics [36,37]. Therefore, this nanoparticulated system is presently exploited for various pharmaceutical or biomedical researches specifically for the purpose of DDS, diagnostics and imaging.

Niosomes

Niosomes are thermodynamically stable polyhedral multilamellar or unilamellar nanostructures formed by self-assembly of nonionic amphiphiles surfactants with hydrating mixture of cholesterol in an aqueous medium. Initially, niosomes were used as a feature of the cosmetic industry, but with further studies and advancement in nanotechnology and pharmacology, they have found wide applications as a drug targeting agents. They acts as carriers for several forms of drugs including amphiphilic, hydrophilic and lipophilic moieties or drugs for long-term activity, reduced drug intake by improving bioavailability of medication and less side effects [38]. Niosome-based DDSs are used to delay drug elimination, complete metabolized drug and give sustained activity with solving the instability, insolubility and rapid degradation problems. These nanoparticulated systems also have superior characteristics over other forms of liposomes owing to their better chemical stability, greater osmotic activeness, easier pilot plant scale-up feasibility and cheaper cost of production along with longer storage, eliminating the drawbacks associated with sterilization and the stability [39].

Advantages of nanobased drug delivery system

Application or implementation of nanoparticles as potential drug carriers is a result of years of research and development in field of nanotechnology, biotechnology, biomedicines and pharmaceutical sciences. Nanoparticles as DDSs are considered as wonder drug or often regarded as ‘Magic bullets’ due to their unique ability to deliver drugs with the safety of the drug from dilapidation/metabolization, its control release at the target site and biodistribution as well as reduced side effects or toxicity towards nontarget cells. Nanomaterials of different origin can be used as adjuvant in vaccine or drug carrier in which the active ingredient (drugs) is dissolved, entrapped, encapsulated, adsorbed or chemically attached and may be released through desorption, diffusion or nanoparticle erosion in target tissue. Characteristic nanostructured biomaterials display exclusive physicochemical and biological properties including controllable size, large surface area to mass ratio, high reactivity and tunable structure that enhanced the reactive area as well as an ability to cross cell and tissue barriers makes them a favourable material for biomedical applications [40].

Various nanostructures had been developed such as liposomes, polymers, dendrimers, silicon or carbon materials, inorganic and polymeric nanoparticles and magnetic nanoparticles, nano rods and quantum dots to function as potential drug carriers, and many are in pipeline to be tested as carriers in drug delivery systems. Different nanomaterials have their own unique characteristic features and mode of action that enable them to transport drugs to different sites. Liposomes are known for enhancing permeability and retention effect for preferential extravasations, and fullerenes can act as excellent lubricants for drugs and help to reach target site. SLN have wide possible application spectrum as dermal, oral and intravenous drugs’ carrier with improved bioavailability, controlled and/or targeted drug release and fortification of sensitive drug molecules from external climatic conditions. NLC are highly unordered lipid structures helping to accommodate large number of drugs and administer as traditional drug delivery routes (oral/parenteral) or even through subcutaneous, intramuscular and intravenous routes. Nanoshells have highly encouraging optical and chemical characteristics that impart them as excellent sources for biomedical imaging and therapeutic uses. Dendrimeric vectors have been generally regarded as parenteral or intravenous sources of drug delivery to various tumour tissues [6,41].

NPs provide massive advantages over conventional drug delivery system by faster drug absorption, controlled dosage delivery and release, and with their ability to combine diagnosis and therapy, it is seen as a major boost in nanomedicine. Other addition merits are control release (induced by pH, temperature, light, etc.) of the encapsulated drug after administration, partial immunogenicity, deterrence in clearance by the reticuloendothelial system (RES) and increased plasma half-life thereby resulting in less frequency of doses and improved patient compliance [42]. Moreover, the limitation of synthetic materials and large-scale uses of green synthesized biomolecules in the formation of nanoparticle allows sustained drug release to target site and offers better biocompatibility and sustainability over a period of days or even weeks [43].

Limitations of nanobased drug delivery system

Although nanoparticles have several advantages over conventional methods of drug delivery eliminating high doses, susceptibility across the intestinal epithelium, limited accessibility, first pass effect, high reactivity, instability and fluctuations in plasma drug levels, they do have limitations. The increased applications of NPs have a high risk of nanotoxicity. Increased intracellular ROS level is closely linked to elevated bioaccumulation of different NPs leading to oxidative stress resulting in adverse impacts on respiratory system, skin, liver, kidney, reproductive system along with embryo development, central nervous system and immune system, as shown in Table 1 [44]. Such adverse effects are mainly due to the size of NPs, which shows altered properties from that of their larger counterparts of the same composition.

Table 1. Adverse effect of NPs and their possible positive influencers.

Nanoparticles	Effected cells/organ/organism	Adverse effect	Possible positive influencers	References
Inorganic NPs
Metal-based nanoparticles (MNPs)	Goldfish	Nanotoxicity	Elevated atmospheric CO2 levels leading to bioaccumulation and increased ROS intensity	[50]
Copper oxide, lead oxide and zinc oxide NPs	Outbred white male rats	Acute pulmonary subchronic systemic toxicity	Triple metal-NPs’ combination resulted in increased oxidative stress	[51]
MNPs	Isochrysis galbana	Ecotoxicity	Decreased photosynthetic efficiency	[52]
Zinc oxide NPs	Medaka embryos	Embryotoxicity	Higher mortality, increased heart rate, late hatching time and increased abnormality percentage	[53]
Gold NPs	Tubifex tubifex	Ecotoxicity	Bioaccumulation	[54]
Nitric oxide ameliorates zinc oxide NPs	Triticumaestivum L. seeds	Phototoxicity	Enhanced levels of hydrogen peroxide and lipid peroxidation	[55]
Iron (II,III) oxide (Fe3O4) NPs	hPDLF	Cytotoxicity	Increased ROS concentration	[56]
Silica NPs
Amorphous silica-engineered NPs with lipopolysaccharide (LPS)	A549	Genotoxicity and cytotoxicity	Increased oxidative stress	[57]
Silica NPs, associated with ultrafine particles (UFPs), lead acetate (Pb), a typical air pollutant
Silica NPs	Zebra fish embryos	Cardiac toxicity	Neutrophil-mediated cardiac inflammation and cardiac contraction	[58]
Silica NPs, methylmercury (MeHg)	Zebrafish embryos	Bradycardia	Induced oxidative stress and inflammatory response	[59]
CNTs
Carbon nanohorns (CNH)	A549, NCI-H322, HNEpC	Respiratory cytotoxicity	Size-dependent reactivity and toxicity	[60]
Buckminsterfullerene	B6C3F1/N mice	Respiratory toxicity and immunotoxicity	Size-dependent reactivity and toxicity	[61]
MWCNTs, SWCNTs and TiO2 NPs	Mice	Respiratory toxicity, immunotoxicity, cardiovascular toxicity, transplacental genotoxicity, central nervous system toxicity, pre- and postnatal deaths and delay in growth	Increased ROS concentration	[62]
Lipid-based NPs
Cationic NPs-liposome	HepG2	Cytotoxicity	ROS production	[63]

Areas of nanomaterials, which could be further improved, include stability in the biological environment, distribution of bioactive compounds, improved drug intake capacity, site-specific targets, transportation to desired sites, controlled release in drugs and interaction with biological membranes/barriers. Undesirable effects of nanoparticles strongly depend on their hydrodynamic size, shape, amount, surface chemistry, the route of administration, reaction of the immune system (especially a route of the uptake by macrophages and granulocytes) and residence time in the bloodstream and need major improvement [40,45]. The design of multifunctional nanoparticles is certainly another exciting future challenge in the field. There are still an ample of works and research need to be done, before considering the nanoparticles as a generic platform for administration of drug and drug targeting. The cytotoxicity of several nanoparticles and their by-products still remains a major setback. Improvements in the biocompatibility and feasibility of nanodrugs are also areas of concern and are challenges that are needed to be dealt before the commercialization of nanoparticles or nanotechnology-based medication. Henceforth, advanced safety measures for identification, characterization and exposure of the toxicity is the current basic need. Scientists have spent more than a decade evaluating and monitoring the impact of NPs on biological system. A large number of researches have been done in this preferred area and are still being carried out, suggesting that the toxic effect of the NPs is a variable and can be reduced.

Commercial nanobased drug delivery systems

Despite several drawbacks as mentioned earlier, the versatility of the NPs, their formulation and design has attracted researchers worldwide for developing nanobased materials. Some of these inorganic and organic NPs are therefore could be successfully used for therapeutic and diagnostic purposes. The current application of NPs in biomedical research includes nanomedicines for cancer, iron-replacement NP therapies, NP imaging agents, vaccines, anesthetics, fungal treatments and macular degeneration [10,46]. Some of the current NP-based diagnostic/therapeutic efficiencies and their status in the clinic are reported in Table 2. The relatively smaller sized, customized large surface area to react, improved solubility and stability, and multidisciplinary functionality of nanoparticles had been put in use for several applications and will continue to open doors for further potential uses in the field of biomedical, nanomedicines, etc.

Table 2. Commercialized NPs, their therapeutics efficacy and status of application.

NPs (name and type)	Therapeutics and diagnostics efficacy	Status (approved)	References
Feraheme (AMAG)/Rienso (Takeda)/Ferumoxytol, iron polyglucose sorbitol Carboxymethylether colloid	Iron deficiency in patients with chronic Kidney disease	FDA (2009)	[46]
Injectafter/Ferinject (Vifor), iron carboxymaltose colloid	Iron-deficient anemia	FDA (2013)
Diprivan, liposomal propofol	Induction and maintenance of sedation or anesthesia	FDA (1989)	[64]
AmBisome (Gilead Sciences), liposomal amphotericin B	Cryptococcal Meningitis in HIV-infected patients Aspergillus, Candida and/or Cryptococcus species infections (secondary) and Visceral leishmaniasis parasite in immunocompromised patients	FDA (1997)	[10]
Visudyne (Bausch and Lomb), liposomal verteporfin	Treatment of subfovealchoroidal neovascularization from age-related macular degeneration, pathologic or ocular histoplasmosis	FDA (2000) and EMA (2000)	[65]
Clinical trials
Nanocort (Enceladus in collaboration with Sun Pharma Global), liposomal Prednisolone (PEGylated)	Rheumatoid arthritis and hemodialysis fistula maturation	NCT02495662 (Ph II) NCT02534896 (Ph III)	[10]

Future prospect of NPs/NCs

The annals of the future are directed by scientific frictions of the present. In other words, present guides the future scientific inventions. Therefore, future prospect of NPs also depends on the present advancement of nanotechnology and other applied subjects. In the field of biomedical research, however, the progress made is in itself an outstanding achievement of the present decade. Researchers have shown that a control release of drugs from a nanoparticulated system can be achieved through changes in physiological environment such as temperature, pH, osmolality and via an enzymatic activity [47]. Quantum dots, Raman probe and fluorescence- or chemiluminescence-based real-time detection on one side could be the reason behind tremendous success in biomedical research for disease diagnosis. Therapeutic advancements such as prolonged circulation time and tunable targeted drug releasing capacity with decreased toxicity have conclusively shifted the present expectations to the next achievable level [48]. More extensive studies of NP drugs should be conducted using different higher animal models enabling scientists to develop drug loading, targeting, transporting, releasing, interaction with the barriers, low toxicity and safe conditions. The efficiency of NPs in detecting malignant cell delivering different drugs at same time, visualizing the location by imaging agents, killing cancer cells with minimum side effects and monitoring and treating at the same time could be further improved [47]. The future waits for mankind to conquer the uprising threat bestowed on the current health deteriorating diseases and disorders through next-generation nanomedicines. The probability of eliminating almost all the drawbacks put forth by conventional therapeutics and diagnostics seems obvious in the future era of nanomedicines. Because of variegated competency of the nanoengineered molecule with gated retention and release of therapeutic agents such as DNA, siRNA and proteins for the treatment and diagnosis of pathogenic diseases, metabolic/hormonal disorders have managed to put forth a direction for its future use [49]. Moreover, the capacity to breach almost any biological barriers such as BBB and BCSFB to reach the targeted location in the biological system that too without any toxicity or compromised side effects has promote its application in the treatment of cancer, neurodegenerative diseases and many others.

Conclusion

Despite the advancement and application of nanotechnology in the field of biomedical research, the expected fruitfulness achieved is questionable. However, the fact remains clear about the potential of nanotechnology for disease diagnosis and their treatment. Therefore, current consideration of pharmacologist and nanobiotechnologists should focus towards evaluating biomedical uses of both inorganic and organic NPs either in the conjugated form or in the nonconjugated form. The surface Plasmon resonance of inorganic NPs and biocompatibility and nontoxicity of organic NPs are considered as the greatest valued properties of NPs. The indescribable size, in contrast, is both boon and curse. In the case of inorganic NPs, the toxicity increases with decrease in size, while in the case of organic NPs, there is no question of toxicity despite the diversity of size. Moreover, organic NPs are further exploited for their exceptional ability to convalesce the toxicity of the therapeutic agent they are withholding. One advanced way of improving the serviceability of such magnificent smart particles is by replacing their encapsulated therapeutic agent of toxic chemical or physical origin by therapeutic natural phytoconstituents. Hence, with continuous advance and growing technology, biocompatible DDS can be achieved that will be best suited in the treatment of various health aliments and disorders.

Acknowledgements

The authors are grateful to the authority of Dongguk University, Republic of Korea for support. This work was supported by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through the Agricultural Research Center Project and Agricultural-Bio Technology Development Program funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA)(710003-07-7-SB120, 116075-3).

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No potential conflict of interest was reported by the authors.