A REVIEW: NANOCARRIERS Shrikrushna Subhash Unhale *, Prof . Rahul Sarode , Quazi Bilal Ansar , Vaishnavi Gajghane , Vaishnavi Sathe , Prof . Dr. K . R. Biyani

Anuradha college of pharmacy , chikhli , Dist –Buldana ( MS ) India 443201

Author1 : shrikrushnaunhale11@gmail.com

ABSTRACTS :

In this review article , we discussed about Nanocarrias and its type . These are the various drug delivery systems used to target the drug. The aim of pharmaceutical nanotechnology is primary to deliver the drug in the form of nanoparticles by enhancing their therapeutic potential.

The development of therapeutics and theranostic nanodrug delivery systems have posed a challenging task for the current researchers due to the requirement of having various nanocarriers and active agents for better therapy, imaging, and controlled release of drugs efficiently in one platform.

Nanocarriers are useful transport agents due to their small size and the ability to modify physical characteristics such as the charge and shape to carry therapeutic agents to tissues . Nanocarriers are important components in novel drug formulation. They increase bioavailability, protect and stabilize more sensitive agents (e.g. proteins), minimize side effects and provide means for active targeting

Key words : Nanocarriers , Nanotechnology , drug delivery systems , drug , components .

INTRODUCTION :

Nanocarrias are the materials or device for nanoscale made up of different biodegradable material like natural or synthetic polymers , lipid phospholipid and even organometallic compounds. Nanocarrier being of submicron size have a very high surface to volume ratio , leading to increased dissolution rate. 1 Nanotechnology applied to health sciences contains new devices used in surgery, new chips for better diagnostics, new materials for substituting body structures and some structures capable to carry drugs through the body for treatment of a number of diseases. These structures can be made of a number of different materials and they are very different in structure and chemical nature. All these nanostructures are called nanocarriers and they can be administrated into the organisms by topical and transdermal routes. Nanocarriers are a powerful weapon against a lot of illnesses since they are so small to be detected by immune system and they can deliver the drug in the target organ. For that reason, drug doses using nanocarriers and side effects decrease a lot. 2

In recent years , the interest in sub- micron systems in pharmacy has surged . This is in part due to the advantages these systems may provide over existing systems . The high protein binding property of certain drugs hinders their passage into the brain and other organs . Suitable drug delivery systems are crucial and this is supported by a recent report stating that pharmacutical account for approximately 65 billion in drug revenue every year . Poor bioavailability far too often results in not only higher patient costs and inefficient treatment , but also , more importantly increased risks of toxicity or death. 3

Fig. Nanocarrias Systems

TYPES OF NANOCARRIAS :

NANO PARTICLES

Nanoparticles are defined as particulate dispersion or solid particles with a size in the range of 10 – 1000 nm . The drug is dissolved , entrapped , encapsulated or attached to the nanoparticles matrix . Depending upon the method of preparation , nanoparticles , Nano spheres or Nano capsule can be obtained.

Nano capsules are systems in which the drug is confined to a cavity surrounded by a unique polymer membrane.

Nano spheres are matrix systems in which the drug is physically and uniformly dispersed.

The major goals in designing nanoparticles as a delivery system are to control particles size , surface properties and release of pharmacologically active agent in order to achieve the site specific actions of the drug at the therapeutically optimal rate and dose regimens. Though liposome have been used as potential carrier with unique advantage including protecting drug from degradation , targeting to site of action and reduction toxicity or side effects.

Their application are limited due to enherent problems such as low encapsulation efficiency rapid leakage of water soluble drug in the presence of blood components and poor storage stability .

Nanoparticles main objectives is to convey the therapeutic molecule they are drugs , protein , Nucleic acid , directally into target organ or tissue. Many polymers are used for the synthesis of nanoparticles and among the currently most employed material several biocompatible synthesis polymer namely Polylactic Acid ( PLA ) , poly lactic co- glycolic Acid ( PLGA ). , And polyethylene glycol ( PEG ) .

Advantages :

1. Particle size and surface characteristics of nanoparticles can be easily manipulate to achieve both passive and active drug targeting after parenteral Adam.

2. They control and sustain release of the drug during transportation and at the site of localisation .

3. Controlled release and particle degredation characteristics can be modulated by the choice of matrix constituents .

4. Drug loading in relatively high and drug can be evaporated into the system’s without any chemical reaction.

5. The system’s can be used for various routes of administration including oral , nasal , parenteral and intra ocular etc.

Limitations :

1. Their small size and large surface area can lead to particle – particle aggregation physical handling of nanoparticles difficult in liquid and dry forms.

2. In addition small particles size and large surface area readily results in limited drug loading and burst release.

INORGANIC NANOPARTICLE

Inorganic nanoparticles are non-toxic, hydrophilic, biocompatible and highly stable compared to organic materials. Drug delivery systems designed for enhanced drug efficacy and reduced adverse effects have evolved accompanied

by the development of novel materials.14 Biomedical applications of nanotechnology are mainly suited for diagnostic techniques, nano drugs and delivery systems, and biomedical implants. Nano-enabled drug delivery has been projected as the single largest market opportunity. Recent advancement in nanotechnology has led to the introduction of various inorganic nanoparticles other than calcium phosphates as excellent drug delivery matrices.15,16

Inorganic nanoparticles they have certain physical properties that mainly include size dependent optical , magnetic , electronic and catalytic properties.

Silver

Silver nanoparticles have proved to be most effective because of its antimicrobial efficiency against bacteria , Viruses and other eukaryotic microorganisms. They are most widely used nanomaterial among all there by being used an antimicrobial agents .

eg. Biosynthesis of silver nanoparticles by plants such as Ajadirachta indica , capsicum annum .

Gold

Gold nanoparticles are used in immunochemical studies for identification of protein interaction . They are used as lab tracer in DNA fingerprinting to detect presence of DNA in sample . They are also used for detection of aminoglycoside antibiotics like streptomycin , gentamicin , and neomycin. Gold nanorods are also used to detect cancer stem cells .

Alloy

Silver has the highest electrical conductivity among metal fillers and unlike other metal , oxides have better conductivity .

Magnetic

Magnetic nanoparticles like Fe3O4 (magnetite ) and Fe2O3 ( maghemite ) are called as biocompatible . They have been actively investigated for targeted cancer treatment .

eg. Drug delivery , gene therapy , DNA analysis and magnetic resonance imaging (MRI )

POLYMERIC CELL

In last few decades, polymers have gained a great deal of response in area of drug delivery.they offer number of agreeable features in drug delivery. they are solid in nature having nanosized ( 10-1000 ) these are colloidal particles made up of biodegradable polymers . They are structural nonosphere (matrix type)& nanotype (reservoir type ) Nanospheres type of PNPs disperse/entrap the drug in

theirpolymer matrix, while in case of nanocapsules type of PNPs, the drug is dissolved/dispersed in liquid core of oil or water encapsulated by a solid polymeric membrane. the adsorption or chemical conjugation of drug on to the surface (of the matrix or capsule) is also possible in both types. depending upon the composition and the desired properties of PNPs, A number of methods have been developed to prepare PNPs. There are are two methods namely dispersion of preformed polymers and direct polymerization of monomers. In the dispersion of preformed polymers include solvent evaporation, salting out, nanoprecipitation, dialysis and supercritical fluid technology. 4

Fig. Structure of polymeric cell

The methods involving direct polymerization of monomers include emulsification polymerization, miniemulsion polymerization, microemulsion polymerization, interfacial polymerization and controlled/living radical polymerization. PNPs are prepared by number of natural and synthetic polymers which are biodegradable and biocompatible . Inside the body biodegradable polymers are degraded into individual monomers and these are removed from the body by various metabolic pathways. Synthetic polymers are polylactic acid (PLA), polyglycolic acid (PGA), PLGA, PEG, polycaprolactone (PCL), N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, polyaspartic acid (PAA) and polyglutamic acid. However albumin, alginate, chitosan, collagen, dextran, gelatin and heparin are natural polymers 5,6.

POLYMERIC MICELLES

PMss are colloidal particles which are formed by the self-assembly of synthetic amphiphilic di- or triblock copolymers in an aqueous milieu . PMs having

nanosized (10 -100 nm). di- or tri-block copolymers contain both hydrophobic and hydrophilic segments because it is amphophilic in nature 7. These block copolymers form micelle when they are exposed to an environment above certain concentration .This concentration is called critical micelle concentration (CMC) . The hydrophobic segment of block copolymer constitutes the core of micelle, while hydrophilic segment forms the shell of micelles 8,9 .

Fig. Structure of polymeric Micelles

Therefore, PMs have a core/shell structure with a hydrophobic core and a hydrophilic shell. the entrapment of hydrophobic drugs and controlling of the drug release properties of PMs are facilated by hydrophobic core of PMs . However, the hydrophilic shell of PMs serves to stabilize the core, ensures the PMs’ solubility in the aqueous milieu and controls in vivo pharmacokinetics . The drugs can either be incorporated into the PMs with the help of physical entrapment or via chemical attachment . Various methods such as dialysis method, oil-in-water emulsion method, solvent evaporation method, cosolvent evaporation method and freeze-drying method have been utilised for preparation of PMs . PMs give various nanocarrier for delivery of anticancer drugs .10,11 SOLID LIPID NANOPARTICLES

Solid lipid nanoparticles are at the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery, clinical medicine and research, as well as in other varied sciences. Due to their unique size-dependent properties, lipid nanoparticles offer the possibility to develop new therapeutics. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could be used for secondary and tertiary levels of drug targeting.48,49

Fig. Structure of Solid liquid nanoparticles

Hence, solid lipid nanoparticles hold great promise for reaching the goal of controlled and site specific drug delivery and hence have attracted wide attention of researchers. This review presents a broad treatment of solid lipid nanoparticles discussing their advantages, limitations and their possible remedies. The different types of nanocarriers which were based on solid lipid like solid lipid nanoparticles, nanostructured lipid carriers, lipid drug conjugates are discussed with their structural differences. Different production methods which are suitable for large scale production and applications of solid lipid nanoparticles are described. Appropriate analytical techniques for characterization of solid lipid nanoparticles like photon correlation spectroscopy, scanning electron microscopy, differential scanning calorimetry are highlighted. Aspects of solid lipid nanoparticles route of administration and their biodistribution are also incorporated. If appropriately investigated, solid lipid nanoparticles may open new vistas in therapy of complex disease.50,51

NANOCRYSTAL AND NANOSUSPENSION

A Nanocrystal is a typical based upon material particle having bat least one dimension smaller than 100 nanometers and mainly built of atoms in either single or poly- crystalline arrangements 3. The production techniques of nanocrystal is known as ' nanonisation '. The nanocrystal are aggregate of hundreds or thousands of molecules that combine in a crystalline form, made up of pure drug with only a thin coating comprised of surfactant or combination of surfactant.2

LIPOSOME

Liposomes are colloidal , vesicular structure built from one or more lipid bilayers surrounding an same numbers of aqueous compartments . A sphere like shell encapsulated a liquid interior which contain elements such as protein , hormones , peptides , enzymes, antifungal , antibiotics as well as anticancer agents . The important part of liposome is made by phospholipids , which is amphiphilic molecules .2 The hydrophilic part is essential it is mainly phosphoric acid bound to a water soluble molecules , where the hydrophobic part consists of two fatty acid chains with 10-24 carbon atoms and 0-6 double bounds in each chain.

Fig. Structure of Liposomes

Types of liposomes

Classified on the basis of

A . Base on structural parameters Unilamellar vesicles Types Size range (nm) Small unilamellar vesicles 20-40 nm Medium unilamellar vesicles 40-80 nm Large unilamellar vesicles 100-1000 nm

B. Based on method of Liposome preparation

1. REV : Single vesicles made by Reverse phase evaporation method

2. MLV – REV : Multilamellar vesicles made by Reverse phase evaporation method

3.SPLV : Stable plurilamellar vesicles

4. FATMLV : Frozen and Thawed MLV

5. VET : Vesicles prepared by extrusion technique

6. DRV : Dehydration – rehydration method

C. Based upon composition and application

1. Conventional Liposomes ( CL )

2. Fusogenic Liposomes

3. pH sensitive liposomes

4. Cationic Liposomes

5. Long Circulatory Liposomes ( LCL )

NANOCRYSTAL AND NANOSUSPENSION

A Nanocrystal is a typical based upon material particle having bat least one dimension smaller than 100 nanometers and mainly built of atoms in either single or poly- crystalline arrangements. 3 The production techniques of nanocrystal is known as ' nanonisation '. The nanocrystal are aggregate of hundreds or thousands of molecules that combine in a crystalline form, made up of pure drug with only a thin coating comprised of surfactant or combination of surfactant. 1

NANOTUBES

A nanotube is a nanometer scale tube like structure. Nanotubes are members of the fullerene structural family. Their name is obtained from their long , hallow structure with the walls formed by one – atom – thick sheets of carbon called graphene. 3

Nano tube categories by :

Single walled nanotube ( SWCNTs )

Multi walled nanotube ( MWCNTs)

Double walled nanotube ( DWCNTs )

Triple walled nanotube (TWCNTs )

Fig. Structure of types of nanotubes

DENDRIMERS

The different branches of polymers are called dendrimers . Dendrimer-based drug delivery systems for antitumor therapy have a great advantage. dendrimer are unique Nano carrier for drug delivery application because of The physicochemical properties, suchas structure and size, aqueous solubility, monodispersity and the high drug delivery ability . 12

Fig. Structure of Dentrimers

Moreover, dendrimer also has efficient renal filtration properties. dendrimer has three distinguishable parts: a core, branching Dendrons and surface-active groups. the physiochemical properties of the Dendrimer are determined by The active groups on the dendrimers surface , Based on the surface groups, it may be either hydrophobic or hydrophilic .13 Due to its nanoscale size, monodisperse nature. Wojnarowicz et al,(2018) synthesized a dendrimer based multifunctional NCs coated with polydopamine (PDA) and magnetite nanoparticles(Fe3O4). The synthesized nanocarriers were reported as nontoxic and it can load the drug photothermal and chemotherapeutic agents effectively to treat liver cancer cells at the solution of low nanoparticles . 8Sharma et al, (2017) that the surface of dendrimers has water soluble functional groups that are responsible for the excellent water solubility . . Fu et al, (2014) had have developed a multifunctional dendrimer-based nanocarrier conjugated with polyethylene glycol modified with lactobionic acid and encapsulated with doxorubicin for liver cancer therapy.14,15,16

Mesoporous silica nanoparticles (MSNs)

Silica (SiO2) materials have got increased applications in the field of biomedicine owing to their simple synthesis procedures and availability for mass production . Among silica materials, mesoporous silicas are of particular importance in drug delivery as they are able to host large amounts of drugs by virtue of their honeycomb-like architecture with hundreds of pores .24

Fig. Structure of Mesoporous silica nanoparticles (MSNs)

There are several attractive features such as good biocompatibility, large specific surface area and pore volume, high loading capacity, controllable pore diameters ranging from 2 to 50 nm with narrow pore size distribution, good thermal and chemical stability and versatility of loading drugs with hydrophilic and lipophilic characteristics, which make them promising nanoscale drug carriers.22 MSNs to enhance therapeutic efficacy and reduce the toxicity of drugs it is enabled by ease of surface functionalization for controlled and targeted drug delivery . This class of nanocarriers at an ideal position for the delivery of anticancer drugs because of Unique architecture and attractive properties of MSNs. 25,26

Quantum Dots as a Diagnostic Agent for Liver Cancer

Quantum dots (QDs) are one of the most efficient diagnostics agents used in theranostic applications for diagnosis and therapy of liver cancer due to their unique physico-chemical characteristics. 35,36

Fig. Structure of Quantum Dots

especially photoluminescence characteristics . Olerile et al, (2017) showed that HepG2 cells of liver tumors were detected by the NLC nanostructured lipid carrier-loaded QDs. QDs are suitable for targeted imaging of liver cancer cells,where QDs are incorporated as a platform of bioimaging systems for liver cancer detection and imaging , these was found by 6 Das & Mohapatra (2017 ) .QDs-based liposomes carrier for liver cancer imaging of suicide gene therapy applied by Shao et al (2015) . Al-Jamal et al (2009) demonstrated that the nearinfrared fluorescence imaging accumulated efficiently in liver cancer cells of mice via QD fluorescence . QDs can be encapsulated within the lipid bilayers of liposomes to form nanoscale vesicles and perform as a contrast agent to identify liver cancer imaging . 40,41

CERAMIC NANOPARTICLES

Ceramic nanoparticle is a type of nanoparticles that is composed of ceramics, which are generally classified as inorganic, heat-resistant, nonmetallic solids that can be made of both metallic and nonmetallic compounds. The material offers unique properties. macroscale ceramics are brittle and rigid and break upon impact. However, Ceramic nanoparticles take on a larger variety of functions, including dielectric, ferroelectric, piezoelectric, pyroelectric, ferromagn etic, magnetoresistive, superconductive and electro - optical . 52

Ceramic nanoparticle were discovered in the early 1980s. They were formed using a process solgel . which mixes nanoparticles within a solution and gel to form the nanoparticle. Later methods involved sintering (pressure and heat). The material is so small that it has basically no flaws. Larger scale materials have flaws that render them brittle. 53

USES :

1. It is used in drug delivery systems , especially in chemotherapy. 2. Nanocarriers used to target the small pores, lower pH and higher

temperatures of tumors . 3. The used of micelles to stabilise and effectively mask the hydrophobic

nature of hydrophobic drugs provides new possibilities for hydrophobic anti cancer drug. 45

4. Detection of protein 5. Probing of DNA structure 6. In MRI studies.47 7. In pharmacokinetics study

CONCLUSION :

In this review , we present a detailed overview about Nanocarriers , and build a dada base of nanoparticles .our study concludes that Nanocarriers has a tremendous growth in recent years . A wide range of opportunities are available some of the nanoparticles get synthesized are cost effectiveness.

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