Abstract
Drugs can be delivered using oral nanocarriers in controlled, site-specific releases. Target receptors are physically, chemically, and biologically conjugated while administering a specific medicine. Since micro carriers have a 200 nm width, nanomedicine typically refers to objects with that size. Drugs can be delivered by nanocarriers to parts of the body that are inaccessible. Nanocarriers cannot deliver large pharmaceutical dosages due to their small size. Emulsion-based nanocarriers often have poor drug loading and encapsulation, which restricts their potential for therapeutic use. Various therapeutic nanocarriers exist. Ultrabright nanocarriers, polymeric nanocarriers, smart nanocarriers, nanocomposites, protein nanocarriers, nucleic acid-based nanocarriers, carbon nanotubes, and nanobubbles are examples of novel nanocarriers. All of them have successfully treated cancer. This review looks at targeted drug delivery methods and nanocarriers.
Key words: ultrabright, polymeric, nanocomposites, carbon nanotubes, nanobubbles
INTRODUCTION
Application of nanotechnology in medicine or nanomedicine is revolutionising the medical practice both in the areas of diagnostics and therapy. Over the last several decades, numerous nanocarriers have been developed that include liposomes, polymeric particles, drug conjugates, dendrimers, solid lipid nanoparticle, protein and carbohydrate as well as inorganic system like iron, carbon, silica and so on.[1] The biocompatible and biodegradable carriers hold great potential to be used in drug delivery applications. Nanocarriers has found its interest in biomedical application due to its nano size nature, its increased surface area for higher functionalization with target specific molecules, thus leading to lower dosage and minimal side effects and an improved in vivo biodistribution.[2] Various nano- formulation techniques have been developed and employed for improving drug delivery, e.g., nano-micelles, liposomes, solid lipid nanoparticles, nanoparticles/crystals, polymeric nanoparticles, dendrimers, nano-hydrogels, self-assembly techniques etc. Each has their limitations and advantages based on drug encapsulation efficiencies, biodegradability, biodistribution, colloidally stable minimum particle size, and surface functionalization capabilities. Most of the administration of such formulations is through systemic circulation and few through pulmonary or sub-dermal route. On the other hand, advancements in enhanced imaging technologies in biomedical field have been made using various nanomaterials, e.g., fluorophores, quantum dots, gold nanoparticles and iron oxide nanoparticles.[2]
Recent advances in many fields like biotechnology also allow the selection and the preparation of novel macromolecular compounds such as peptides, proteins and DNA analogs to be used as drugs (e.g., hormones, monoclonal antibodies, vaccines) for therapeutic purposes. Such compounds show powerful and selective therapeutic activity, but unfortunately they must often be dropped at some development stage, because of their high enzymatic susceptibility, short shelf life or unsuitable efficacy after the administration to the patient, owing to immunogenic reactions or poor bioavailability.[3] In some cases, from a physicochemical point of view, they cannot reach or enter target cells. Moreover, the drug must cross several biological barriers to reach the site of action, and along its path it can be inactivated or produce undesired side effects. Several approaches have been evaluated to overcome these issues. The drug targeting is a promising tool to solve most of the aforementioned problems. This approach consists of designing a system able to selectively deliver the drug to the area of interest.[3] Transport systems can be designed to control the dispatch of the loaded drug to target areas, increasing its local concentration and bioavailability, while prolonging its retention, half-life and effectiveness. This strategy can avoid diffusion of the drug into normal organs, thus avoiding negative side effects.[4]
The targeting method should ensure that the pharmacological impact only occurs in the target area. Today’s systems are built of three major blocks: the pharmacologically active chemical, a carrier to enhance the amount of active molecules per system (often a nanosized carrier), and a targeting moiety to bring the whole system to the desired location of action. Ehrlich recognised antibodies as the best targeting moieties due to their affinity and specificity for antigen. Since then, numerous different targeting strategies and carriers have been created based on novel facts on toxicity, tolerance, biocompatibility, and acceptability by living creatures.[5] Nanotheranostic techniques combine medication delivery and imaging enhancement in a single nanocapsules/system. Most nanoparticles can be coupled with polyethylene glycol (PEG) tails to promote colloidal stability and circulation with minimal blood protein adsorption in systemic circulation. Targeted distribution of nano-carrier to certain cell types can be done by conjugating specific antibodies, aptamers, or other peptides.[6]
TYPE OF NANOCARRIERS IN THE MANAGEMENT OF DISEASES AND DISORDERS
Ultrabright nanocarriers
Bioimaging contrast agents are fluorescent nanoparticles. Today, researchers are investigating ultrabright nanocarriers. Molecular-based Fluorescent nanoparticles (NPs) with brightness similar to semiconductor quantum dots are an example. These ultra-bright NPs incorporate emitting dyes as individual moieties or aggregates in a silica or polymeric matrix and are more biocompatible than semiconductor quantum dots. Ultrabright materials created by heavily doping the structural matrix, requiring tight dye contact. Interactions between molecular emitters’ ground and excited states produce proximity- and ag gregation- caused quenching (ACQ). PCQ and ACQ combined with FRET amplify nanoprobe quenching. The Table 1 shows some of the reported researches and reviews on ultrabright nanocarriers.[5,6,7,8,9,10]
| No. | Author | Year | Encapsulated Material | Formulation | Description/Applications |
| 1 | Peng et al.[5] | 2018 | Cellulose acetate | Ultrabright fluorescent nanoparticles | For imaging tumors through systemic and topical applications |
| 2 | Melnychuk et al.[6] | 2018 | Dyes in a polymer matrix | Ultrabright fluorescent nanoparticles | Amplified detection of nucleic acids |
| 3 | Goetz et al.[7] | 2016 | Lanthanide | Ultrabright nanoparticles | Photosensitizing behaviour was used of targeting delivery |
| 4 | Shulov et al.[8] | 2015 | Rhodamine | Ultrabright nanoparticles | For bioimaging and light-harvesting delivery |
| 5 | Sun et al.[9] | 2013 | Polyethyleneimine | Ultrabright/Multicolorful Fluorescence | Combined imaging and therapy applied |
| 6 | Bok et al.[10] | 2012 | Organosilicate | Ultrabright suprananoparticles | Fluorescence imaging for the theranostic application |
Polymeric carriers
Polymeric nanocarriers offer clinical potential. The polymeric nanocarrier is expected to have diagnostic and therapeutic uses. Biocompatibility, biodistribution, side effects, and biological obstacles are all issues for carrier systems in living beings. Nanocarriers have multifunctional properties to address this difficulty. Polymeric nanocarriers are useful for active or passive breast cancer targeting. Micelles are nanoscopic amphiphilic colloidal aggregates polymer dispersed in aqueous medium. Their inner cores are formed of hydrophobic polymer blocks that hold drug reservoirs. The hydrophilic polymer shells give micelles water solubility and lengthy blood circulation time in vivo. Physical or chemical crosslinking of polymers creates polymeric nanogels, which are 3D nanosized hydrogels. Nanogels’ customizable chemical and physical structures and in vivo stability govern medication delivery. Polymeric nanofibers have fibrous diameters less than 1 m. Polymeric nanofibres distribute drugs in situ. Many studies demonstrate nanofibers can boost anticancer medication effects. Antibacterial, intelligent textiles, smart clothes, electromagnetic shielding, and flexible sensors are some applications of conductive fabrics. The Table 2 displays polymeric nanocarrier research and reviews.[11,12,13,14,15]
| No. | Author | Year | Encapsulated Material | Formulation | Description/Applications |
| 1 | Pieper et al.[11] | 2019 | Doxorubicin | Polymeric nanoparticle | Assessed of anticancer efficiency |
| 2 | Shelake et al.[12] | 2018 | Fenofibrate | Polymeric nanoparticle | Bioavailability enhancement of the poorly soluble drugs |
| 3 | Patel et al.[13] | 2017 | Hydrophobic or hydrophilic drug | Polymeric nanoparticle | Tumor targeting for the bioavailability enhancement |
| 4 | Bohrey et al.[14] | 2016 | Diazepam | Polymeric nanoparticle | biocompatibility and controlled drug release |
| 5 | Solar et al.[15] | 2015 | Superparamagnetic iron oxide | Polymeric nanoparticle | Multifunctional platform for the diagnosis and treatment of cancer |
Ultrasound mediated nanocarriers
With ultrasound, nanoparticles transport liquid emulsions and solid genes in vitro and in vivo. Small packaging lets nanoparticles enter tumours. Ultrasonic medication and gene delivery utilising nanocarriers has good potential because many pharmaceuticals and genes can be delivered to specified areas noninvasively.[16,17,18] Due to their tiny size and lengthy circulation period, polymeric nanocarriers are valuable in diagnostic and therapeutic applications. These nanocarriers transport medications across capillary and cell membrane barriers. It’s also employed as gene/drug-loaded nanocarriers. Polymeric nanocarriers can improve intracellular medication uptake and should be tiny enough to circulate freely in blood circulation. On the other hand, it should be large enough to avoid renal excretion yet stable enough to prevent biodegradation until ultrasonic triggered.[19,20]
Ultrasound and DNA-bound bubbles improve in vitro and in vivo DNA transfection compared to bare DNA alone. Coating nanoparticles with polymer chains prevents blood protein adsorption and RES cell recognition. Ultrasound-mediated drug/gene delivery uses nanocarriers. Nanobubbles operate as medication carriers in ultrasonography. By utilising this carrier, time and space-controlled medication deliver y may be achieved.[21,22] Techniques for loading bubbles with drugs include associating them with the superficial shell and encapsulating drugs in the bubble’s oil reservoir. In addition, drugs can be encapsulated in a nanoparticle and linked to the microbubble surface. Unknown medication delivery mechanisms. Low- and high- intensity ultrasound cause bubbles to behave differently. Low-intensity ultrasound stabilises cavitation. Another proposed method for ultrasound-mediated drug/gene delivery is localised tissue temperature rise, which increases phospholipid bilayer fluidity and membrane permeability. Endocytosis and active membrane transport also create effects. Contact aided distribution mixes nanodroplet phospholipid membranes into target cell membranes, releasing their payload directly into the cytoplasm.[23,24,25,26] The Table 3 shows some of the reported researches and reviews on ultrasound mediated nanocarriers.[16,17,18,19,20]
| No. | Author | Year | Encapsulated Material | Formulation | Description/Applications |
| 1 | Tharkar et al.[16] | 2019 | Cancer treatment | Ultrasound mediated nanocarriers | Nano-enhanced drug delivery system for the cancer treatment |
| 2 | Baghirov et al.[16] | 2018 | Antitumor drug | Ultrasound mediated nanocarriers | Delivery in brain parenchyma targeted |
| 3 | Paris et al.[17] | 2018 | Mesoporous silica | Ultrasound-mediated cavitation | Controlled-release drug delivery using silica nanocarriers |
| 4 | McClure et al.[18] | 2016 | Antitumor drug | High-intensity focused ultrasound | Targeted drug delivery for the tumor targeting |
| 5 | Zhou et al.[20] | 2014 | Gene and other curative drug | Ultrasound mediated nanocarriers | Ultrasound molecular imaging for the gene based delivery |
Smart nanocarriers
In smart nanocarriers, the 8 most important nanocarriers are reported: liposomes, micelles, dendrimers, meso-porous silica nanoparticles (MSNs), gold nanoparticles (GNPs), super paramagnetic iron oxide nanoparticles (SPIONs), carbon nanotubes (CNTs), and quantum dots (QDs). Smart drug delivery systems (SDDS) assist identify physiochemical distinctions between cancer and healthy cells. Passive and active targeting are used to identify cancer cell sites. Passive targeting indirectly increases tumour permeability. Overexpressed cancer cell surface receptors are used for active targeting. Nanocarriers release dugs by external or internal stimuli, depending on their nature and smar tness.[27,28,29] Nanopar ticles are 1–100 nm smart nanocarriers. Nanoparticles are classified as VSSA. Nanocarriers transport modules on nanoparticles. Conventional nanocarriers can’t carry and release medications at the proper concentration at the targeted spot. Smart nanocarriers have these properties.[30,31] Co-deliver genetic materials, imaging agents, and chemotherapeutics. The RES removes the nanocarrier from circulation and it assembles in the liver, spleen, or bone marrow. PEGylation solution is used to avoid this cleaning. PEGylation decreases cell drug absorption.[32,33,34,35]
Nanocarriers can be help to identify the cancer cells exactly out of healthy ones. Physiochemical differences between cancer cells and healthy ones are only the identification marks to separate the two types of cells. The modification of nanocarriers are done with the help of ligands matching the overexpressed proteins. These ligands help to identify the cells with the receptor proteins. Third, the drug conveying to the target site is not the termination of the process. In smart carrier the releasing of the drug under stimulation is the next big challenge. Fourth, changes are also done for the anti- cancer drugs codelivery together with other substances, including genetic materials, imaging agents or even additional anti-cancer drugs. The potential codelivery observed by Liposomes, micelles, dendrimers, GNPs, quantum dots and MSNs.[36,37,38] The Table 4 shows some of the reported researches and reviews on smart nanocarriers.[21,22,23,24,25]
| No. | Author | Year | Encapsulated Material | Formulation | Description/Applications |
| 1 | Li et al.[21] | 2019 | Mesoporous silica | Smart nanocarriers | Targeted fluorescence-photoacoustic bimodal imaging |
| 2 | Moradi et al.[22] | 2019 | Dopamine | Smart nanocarriers | Brain targeting approach by the nanocarriers |
| 3 | Hossen et al.[23] | 2018 | Drug material | Smart nanocarrier | Smart drug delivery systems |
| 4 | Cui et al.[24] | 2015 | Anticancer drugs | Smart nanocarrier | Self‐assembled smart nanocarriers |
| 5 | Choi et al.[25] | 2011 | Doxorubicin and camptothecin | Smart nanocarrier | Controlled release drug delivery |
Nanocomposites
It’s nanoparticles that mix components to improve specific qualities (composite). Nanoparticles (clay, metal, carbon nanotubes) dilute a matrix, usually polymer, in nanocomposites. Nanocomposite mechanical, electrical, thermal, optical, electrochemical, catalytic characteristics will differ from component materials.[39] Inorganic components include zeolites, two-dimensional layered materials like clays, metal oxides, metal phosphates, chalcogenides, etc. Experiments have shown that almost all nanocomposite materials have better characteristics than their macro composite counterparts. Nanocomposites promise novel applications in mechanically reinforced lightweight components, non-linear optics, batter y cathodes and ionics, nano-wires, sensors, and other systems.[40] In situ growth and polymerization of biopolymer and inorganic matrix are ideal for bioceramics and biomineralization. Lamellar nanocomposites increase interphase interactions. Intercalated and exfoliated nano- composites are two types. In the first, polymer chains alternate with inorganic layers in a set compositional ratio and number of polymer layers in intralamellar space. In exfoliated nano-composites, the number of polymer chains between layers is almost continually changeable. Intercalated nano-composites have good charge and electronic transfer. Mechanically, exfoliated nanocomposites are better. Polyamides, polypropylene, polyethylene, styrenics, vinyls, polycarbonates, epoxies, acrylics, polybutylene terephthalate, and polyurethanes are prominent nanocomposites polymers.[41] The most popular filler is montmorillonite clay, which has a platy structure and a 1000∶1 aspect ratio. Property improvement requires modest loading. Nanocomposites improve modulus, flexural strength, thermal distortion temperature, barrier characteristics, and other benefits, unlike standard mineral-reinforced systems, which sacrifice impact and clarity.[42,43] The application of Nanocomposites commercially increasing at higher rate. Less than two years it observed that, the worldwide production is estimated to exceed 600,000 tonnes and is set to cover the following key areas in the next five to ten years.[44]
Superior strength fibres and Improvements of films in mechanical property have resulted in major interest in nanocomposite materials in numerous automotive and general/industrial applications. These include potential for utilization as mirror housings on various vehicle types, door handles, engine covers and intake manifolds and timing belt covers.[45]
In general more applications currently being considered include usage as impellers and blades for vacuum cleaners, power tool housings, mower hoods and covers for portable electronic equipment such as mobile phones, pagers etc. Nowadays nanocomposite research is conducted and is widespread by companies and universities across the globe.[46] The production of Nanocomposites is modified by incorporating the clay into polymers this method also more cost-effective. It shows a marked increase in oxygen, carbon dioxide, moisture and odour barrier proper ties, increased stiffness, strength and heat resistance, and maintains clarity to film and impact strength. Nanocomposites also show more important applications in numerous industrial fields, a number of key technical and economic barriers exist to widespread commercialization. This technique includes improve performance, the complex formulation relationships and routes to achieving and measuring nanofiller dispersion and exfoliation in the polymer matrix.[47,48,49,50] The Table 5 shows some of the reported researches and reviews on nanocomposites.[26,27,28,29]
| No. | Author | Year | Encapsulated material | Formulation | Description/Applications |
| 1 | Shabatina et al.[26] | 2020 | Antibacterial substances dioxidine or gentamicin sulphate | Nanocomposites | Cu/dioxidine nanocomposites |
| 2 | Sharma et al.[27] | 2018 | Ondansetron | Nanocomposites | Controlled drug delivery |
| 3 | Ghaderi-Ghahfarrokhi et al.[28] | 2018 | Diphenhydramine hydrochloride and diclofenac sodium | Nanocomposites | Modified halloysite nanotubes of targeted delivery |
| 4 | Jafarbeglou et al.[29] | 2016 | Clay | Nanocomposites | Combination in composites and hybrids |
Protein nanocarriers
Proteins are natural molecules with specific biological and manufacturing features. Nanomaterials from protein, albumin, and gelatin. These nanoparticles are biodegradable, nonantigenic, metabolizable, surface modifiable, stable during in vivo release and storage, and easy to create and monitor. Covalently attaching drugs and ligands to these particles. Protein nanoparticles reduce toxicity, increase medication release, improve bioavailability, and improve for mulation. Protein nanoparticles work at lower doses and reduce medication resistance.[51,52,53] The nanoparticles boost medication solubility and surface area. Oral, vascular, and inhalation delivery can identify nanoparticles. The Table 6 shows some of the reported researches and reviews on protein nanocarriers.[31,32,33,34,35]
| No. | Author | Year | Encapsulated material | Formulation | Description/Applications |
| 1 | Wu et al.[31] | 2014 | Poly (lactic-co-glycolic acid) | Protein nanocarrier | Encapsulation and delivery of proteins and peptides |
| 2 | Mattu et al.[32] | 2013 | Tripolyphosphate-crosslinked chitoson nanoparticles | Protein nanocarrier | Encapsulation and delivery of biomacromolecule |
| 3 | Lee et al.[33] | 2009 | Polyionic complex micelles | Protein nanocarriers | Protein delivery into cytoplasm |
| 4 | Hanafy et al.[34] | 2017 | Folic Acid | Hybride Polymeric Protein nanocarriers | Targeted delivery of TGFβ inhibitors to hepatocellular carcinoma cells |
| 5 | Kang et al.[35] | 2015 | Biological fluid like blood, carbo- hydrates and protein | Protein nanocarriers | Exhibiting specific cell targeting |
Nucleic acid based nanocarriers
Cancer therapy uses nucleic acid nanocarriers. Due to its endless cell growth, infiltration of healthy tissues, and metastasis, cancer is a leading cause of death worldwide. Radiation and chemotherapy have more adverse effects and damage cancer and healthy cells. Targeted drug delivery reduces conventional drug delivery’s negative effects. Nucleic acid-based nanoparticles are a cancer- fighting medication delivery method. Fast-advancing nucleic acid-based nanomedicine will result in excellent tumor-targeted medication delivery. Nucleic acids may be an excellent nanocarrier and cancer treatment tool due to their focused medication delivery, biocompatibility, and self-programmability.[54,55,56] The Table 7 shows some of the reported researches and reviews on nucleic acid based nanocarriers.[36,37,38,39,40]
| No. | Author | Year | Encapsulated Material | Formulation | Description/Applications |
| 1 | Chen et al.[36] | 2017 | Polyacrylamide | Nucleic acid‐based hydrogel nanoparticles | Controlled drug release of the formulation |
| 2 | Almalik et al.[37] | 2013 | Hyaluronic acid coated chitosan triphosphate | Nucleic acid nanoparticles | CD44‐mediated nucleic acid delivery |
| 3 | Gill et al.[38] | 2006 | Nucleic Acid | Nucleic acid nanoparticle | Catalytic labels for the chemiluminescent Detection of DNA and proteins |
| 4 | Li et al.[39] | 2007 | Lipid and Nucleic acid | Lipid based nanoparticles | Nucleic acid and gene delivery carrier |
| 5 | Lee et al.[40] | 2012 | Peptides and Folate | Nucleic acid nanoparticles | For targeted in vivo siRNA delivery |
Carbon nanotubes
CNTs are cylinder-shaped molecules with single-layer carbon atom sheets. Single-walled CNTs have a diameter of less than 1 nm, while multi-walled CNTs have sizes more than 100 nm. Micrometers or millimetres measure their length. CNTs have particular electrical, thermal, and mechanical properties inherited from graphene, making them attractive for novel material creation.[57] Mainly there are 2 types of carbon nanotubes one is single walled and another one is multi walled carbon nanotubes the difference of types is only their purity, length and functionality.[58,59,60] The Table 8 shows some of the reported researches and reviews on carbon nanotubes.[41,42,43,44,45]
| No. | Author | Year | Encapsulated Material | Formulation | Description/Applications |
| 1 | Mohseni-Dargah et al.[41] | 2019 | Pyridine multi-walled carbon nanotubes | Carbon nanotubes | Delivery of iC9 suicide gene for killing breast cancer cells |
| 2 | Pardo et al.[42] | 2018 | Doxorubicin and gemcitabine | Carbon-based quantum dots and nanotubes | Cancer targeting and drug delivery of the pre- pared formulation |
| 3 | Abbaspour et al.[43] | 2007 | Piroxicam | Carbon nanotubes | Electrochemical monitoring of piroxicam |
| 4 | Dumortier et al.[44] | 2006 | 1,3-dipolar cycloaddition reaction and the oxidation/amidation treatment | Carbon nanotubes | Non-cytotoxic and preserve the functionality of primary immune cells |
| 5 | Guo et al.[45] | 2007 | Radioactive 99mTc atoms | Carbon nanotubes | Biodistribution of functionalized multiwall carbon nanotubes in mice |
Self-Nanoemulsifying drug delivery dystem (SNEDDS)
Nanoemulsion or nanoemulsions are SNEDDS. When put into aqueous phase under mild agitation, anhydrous isotropic mixes of oil, surfactant(s), and medicine create O/W nanoemulsions (typically with globule size less than 200 nm). GI motility provides agitation for nanoemulsion production. This system can additionally comprise co-emulsifiers, co-surfactants, and/or solubilizers to increase drug integration or enable nanoemulsification in SNEDDS.[61,62] The Table 9 shows some of the reported researches and reviews on Self-nanoemulsifying drug delivery system.[46,47,48,49,50]
| No. | Author | Year | Encapsulated Material | Formulation | Description |
| 1 | Shanmugam et al.[46] | 2011 | Phosphatidylcholine | Solid self-nanoemulsifying drug delivery system | Enhanced bioavailability of highly lipophilic bioactive carotenoid lutein |
| 2 | Friedl et al.[47] | 2013 | Cremophor RH 40 and triacetin | Solid self-nanoemulsifying drug delivery system | Develop a novel mucus diffusion model |
| 3 | Fahmy et al.[48] | 2015 | Avanafil | Solid self-nanoemulsifying drug delivery system | Improve aqueous solubility and Enhanced Bioavailability |
| 4 | Shakeel et al.[49] | 2016 | Ibrutinib | Solid self-nanoemulsifying drug delivery system | Enhance dissolution and bioavailability/pharmacokinetic profile of anticancer drug Ibrutinib |
| 5 | Shakeel et al.[50] | 2014 | Glibenclamide | Polymeric solid self-nanoemulsifying drug delivery system | Delivery of glibenclamide using coffee husk |
Nanobubbles
Nanoscaled ultrasonic contrast agent (UCA) can be utilised as a theranostic agent due to its imaging capacity. Poly (lactic-co-glycolic acid) (PLGA) nanobubbles are stable, have high-efficiency coating, stable loading, tiny size, and controlled release. At 10 microL/mL, UCA had a 450 nm diameter and delivered 25.5 dB in vitro improvements. The UCA provided great in vivo power doppler and pulse inversion harmonic pictures at low sound power levels. Nanobubbles were small enough to pass through tumour cell membranes. Differential centrifugation separates particles by size. Perfluoropropane gas protects bubbles for more than two weeks.[63] The acoustic behaviour of the nanosized contrast agent was examined using Power Doppler imaging in a nor mal rabbit model. Experiments showed that a 3 minutes, 20 g sample was the best for tumour imaging and US-mediated targeted therapy. EPR helps nanobubbles accumulate in malignant t issue s. Experiments showed that coumarin put into nanobubbles can transport drugs to cells. The 1% Tween 80, 3 mg/mL lipid nanobubbles demonstrated the best in vivo liver imaging. Other experiments produced small, positively charged chitosan nanobubbles. Nanobubbles can protect DNA. Ultrasound stimulated DNA transfection in vitro. No DNA-loaded nanobubble concentrations transfected without ultrasound. After 30 seconds of ultrasound, transfection was moderate. Shorter sonication times did not transfect DNA cargo into cells, while longer sonication times impacted cell viability. None of the transfection dosages exhibited for mulation-induced cytotoxicity. This chitosan nanobubble could be used in ultrasound-responsive DNA delivery formulations.[64,65] The Table 10 shows some of the reported researches and reviews on nanobubbles.[51,52,53,54,55]
| No. | Author | Year | Encapsulated Material | Formulation | Description |
| 1 | Wang et al.[51] | 2009 | Coumarin-6 | Nanobubbles | For ultrasound imaging and intracelluar drug delivery |
| 2 | Song et al.[52] | 2017 | Ultrasmall superparamagnetic iron oxide/paclitaxel | Magnetic nanobubbles | Tumor-targeted therapy for breast cance |
| 3 | Marano et al.[53] | 2016 | Doxorubicin | Nanobubbles | Delivery of doxorubicin in anaplastic thyroid cancer |
| 4 | Deng et al.[54] | 2014 | Doxorubicin | Poly (lactic-co-glycolic acid) nanobubbles |
Doxorubicin drug delivery into HeLa cells |
| 5 | Zhou et al.[55] | 2019 | Doxorubicin hydrochloride | Chitoson nanobubbles | Targeted drug delivery of doxorubicin |
TOXICITY AND BIOCOMPATIBILITY OF NANOCARRIERS
It is vit al to invest ig ate the biocompatibility of nanoparticles because they will be entering the body for use in biomedical applications and coming into direct touch with tissues and cells.
Hemocompatibility
Applications in medication administration, gene delivery, and biosensing, all of which involve direct contact with blood, utilize nanocarriers as vectors. In this article, we look at the blood-compatibility behaviours of a few nanocarriers. Haemolysis is considered to be a simple and reliable measure for estimating blood compatibility of material, and studies on blood cell ag gregation and haemolysis, as well as experiments on coagulation behaviours, have recently been carried out to evaluate the blood compatibility of nanocarriers in vitro.[66]
Histocompatibility
One of the areas of study that is being investigated to the greatest extent is that of targeted medication delivery, and the application of nanocarriers for diagnostic purposes has already reached the realm of biomedicine. The biocompatibility of numerous different types of nanomaterials, including superparamagnetic iron oxides, dendrimers, mesoporous silica particles, gold nanocarriers, and carbon nanotubes, is the primary emphasis of the present review.[67]
Cytotoxicity
The intensity of the toxicity may vary, depending both on the route of administration and the areas where it is deposited. For this reason, information on toxicity is presented using a system-based approach, with a focus on lung, cutaneous, liver, and nervous system targets. This helps to ensure that the information remains clinically relevant. The benefits and drawbacks of each of the possible routes are compared. Each compartment within a eukaryotic cell has its own unique function and is enclosed by its own membrane. The nucleus and the organelles, which comprise the mitochondria, endoplasmic reticulum, Golgi apparatus, peroxisomes, and lysosomes, are the primary types. Other types include endosomes and lysosomes.[68]
Neurotoxicity
The brain and spinal cord make up the central nervous system. Both of these organs are extremely sensitive and need special protection against xenobiotics. Multiple nanocarriers, including Polysorbate 80-coated PBCA nanocarriers and PEGylated PLA immunonanoparticles, have been shown in recent studies to cross the BBB after being administered intravenously and subsequently accumulate in the brain. However, once within the brain, the nanocarriers’ unique physicochemical properties such as their enor mous surface area may produce neurotoxicity. Consequently, it is necessary to assess the possible neurotoxic consequences of these nanocarriers on CNS function, as the precise mechanisms and pathways through which nanocarriers may exert their toxicity are as yet completely understood.[69]
SHORTCOMING, LIMITATIONS AND FUTURE PROSPECTS OF NANOCARRIERS
The use of nanoparticles has many advantages, including the elimination of side effects due to large doses, intestinal permeability, poor accessibility, the first pass effect, strong reactivity, instability, and fluctuations in plasma drug levels, among others. Using a nanocarrier raises the possibility of nanotoxicity. Bioaccumulation of nanocarriers is associated with elevated levels of reactive oxygen species within cells, which leads to oxidative stress and damages multiple body systems (respiratory, skin, liver, kidney, reproductive, central nervous, and immune). These adverse results are mainly attributable to the fact that nanocarriers are smaller than their bigger counterparts of the same composition, which means their characteristics are different.[70]
The malleability of nanocarriers in terms of both their composition and their design have attracted scientists from all over the world. The medicinal and diagnostic potential of nanocarriers is not limited to inorganic nanocarriers. Cancer therapy, iron replacement therapy, imaging agents, immunizations, anaesthetics, fungus therapies, and macular degeneration eye drops all involve nanocarriers. Today’s scientific discoveries will undoubtedly influence the course of future events. Future scientific advances will be influenced by the present. The development of nanocarriers will be driven by nanotechnology and related industries. In the last ten years, biomedical research has made tremendous progress. Drug release from a nanoparticulate system can be controlled by environmental factors like as temperature, pH, osmolality, and enzyme activity. Potentially important in biomedical research advances in disease diagnostics are quantum dots, Raman probes, and real-time fluorescence or chemiluminescence detection. Expectations have shifted to the next attainable level as a result of therapeutic advancements including increased circulation duration and the capacity to focus drug release. Drug loading, targeting, conveying, releasing, barrier interaction, low toxicity, and safe environments for nanocarriers medications should be researched using higher animal models. Nanoparticles have the potential to improve cancer treatment by facilitating the detection of cancer cells, the delivery of multiple drugs at once, the visualization of the treatment site with imaging agents, the destruction of cancer cells with minimal side effects, and the simultaneous monitoring and treatment of the patient.[71,72,73]
CONCLUSION
The use of nanoparticles to deliver medications, such as anticancer and chemotherapeutic drugs, is a significant step forward made possible by nanotherapy. There are many novel nanocarriers that have extraordinary benefits for drug delivery. Some examples of these nanocarriers include ultrabright nanocarriers, polymeric nanocarriers, ultrasound-mediated nanocarriers, smart nanocarriers, nanocomposites, protein nanocarriers, nucleic acid-based nanocarriers, carbon nanotubes, and nanobubbles. Other examples include self-nanoemulsifying drug delivery systems and nanobubbles. Many of the latest nanocarriers being developed as medication delivery systems have been detailed in this study. The research is still under process and many new nanocarriers are under study for the betterment of drug delivery. In addition to the other nanocarriers, the ones about which this paper is concerned play a significant part in the treatment of a wide range of diseases and disorders. This highlights the undeniable significance of nanocarriers in community health care and illness management.
DECLARATIONS
Acknowledgments
We, thank you to the Suresh Gyan Vihar University, for their constant support and providing all facilities to complete this work.
Author contributions
Preeti Khulbe and Deepa Mohan Singh: Wrote and revised the first draft. Anshu Aman: English editing. Eknath D. Ahire and Raj K. Keservani: Proofreading and editing of final draft. All authors are agreed the final version and submitted the article.
Ethics approval
Not applicable.
Conflicts of interest
Eknath D. Ahire and Raj K. Keservani are Editorial Board Members. The article was subject to the journal’s standard procedures, with peer review handled independently of these Members and their research groups.
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