Biomedical Applications of Nanobiotechnology for Drug Design, Delivery and Diagnostics

 

Soumya Khare¹, Amit Alexander², Ajazuddin², Nisha Amit¹*

¹Kalyan PG College, Sector-7, Bhilai, Chhattisgarh

²Rungta College of Pharmaceutical Sciences and Research, Bhilai, Chhattisgarh

 

ABSTRACT:

Nanotechnology deals with features as small as a 1 billionth of a meter, began to enter into mainstream physical sciences and engineering some 20 years ago. Recent applications of nanoscience, now a days include the use of nanoscale materials in electronics, catalysis, and biomedical research. The scientists around the world have revealed the facts associated with the nanotechnology by accepting the technology. The applications of this technology have paved a great emphasis on the biomedical applications. Many drugs falling into different categories like, anti-cancer, antibiotics, anti-inflammatory, anti-allergic, etc. have been successfully loaded to the nano-sized delivery systems. In the present article we have emphasize the importance of some of the applied nanoparticles for the delivery of the drug and at the same time for the diagnosis too.

 

 

INTRODUCTION:

Nanotechnology is an emerging field and dealing with the fabrication and engineering of materials, structure and the system with nanoscale size (Fig. 1)¹. Nanomaterial is being used these days for commercial purposes such as drug carrier, semi-conductor devices, cosmetic, catalyst and microelectronic etc². Richard Feynman introduced the concept of nanotechnology in his pioneering lecture “ these’s plenty of room at the bottom” at the 1959 meeting of the American Physical  Society. However, only recently has our ability to harness the properties of atoms, molecules and macromolecules advanced to a level that can be used to build material, devices and system at the nanoscale³.  The emergence of another field in which the physical, chemical and biological science are converging. That field is nanotechnology. The US Govt. National Nanotechnology Initiative define Nanotechnology as “Anything involving structure less than 100 nm in size”. Nanobiotechnologyis defined as a field that applies nanoscale principles and techniques to understand and transform biosystem (living or nonliving) or uses biological principles and material to create new devices and system integrated from the nanoscale^{2, 4-6}.

 

The basic processes of life-molecular sub cellular mechanisms and formation of the tissues primary structures occur at the nanoscale. For this reasons, understanding the design of biological system can shape the development of life sciences and medicine as well as of highly efficient and versatile new devices and system^7-10.

 

Nanomaterials and devices provide unique opportunities to advance medicine. The application of nanotechonolgy to medicine is referred to an “Nanomedicine or Nanobiomedicine” and could impact diagnosis, monitoring and treatment of diseases as well as control and understanding of biological system. In this review, we discuss the use of nanobiotechnology for medical application with focus on its use for drug design, delivery and diagnostic ^11-14.

 

Nanoparticles – processes in the living cell.

Nanoparticles have unusual properties that can be exploited to improve drug delivery because of their fine size, they are often taken up by cells where larger particles would be excluded or cleared from the body. Small molecules, peptides, protein and nucleic acid can be loaded into nanoparticles that are not recognized by the immune system and that can be targeted to particular tissue types. Recent strategies include the use of poly(ethylene glycol) PEG to increase circulation times as well as the use of PEG in competition  with binding groups to reduce nonspecific attachments or uptake ^15-26.

 

 

Figure 1: Relative size of nanoparticles.

 

Nanoparticles are stable, solid, colloidal particles consisting of macromolecular material and vary in size. Nanoparticles represent on interesting carrier system for the specific enrichment in macrophage containing organs like liver and spleen. Injectable nanoparticle carrier have important potential application as in site specific drug delivery. Nanoparticle are generally similar in size to proteins in the body. They are considerably smaller than many cells in the body. By combining cellular organelles with advanced techniques in nanomaterials and nanofabrication, it will be possible to develop new therapeutic, advanced materials and improved imaging techniques ^27-34.

 

Cell growing in tissue culture will pick up most nanoparticles ^35-37. The ability to be taken up by cells is being used to develop nanosized drug delivery system. Once in the body, some types of nanoparticles may have the ability to translocate and be distributed to other organs, including the central nervous system. The ability of nanomaterial to more about the body may depend on their chemical reactivity, surface characteristic and ability to bind to body protein.

 

Nanoparticles can travel through blood stream without blockage of the micro vasculature. Small nanoparticles can circulate in the body and penetrate tissues such as tumors. In addition, nanoparticles can be taken up by the cells through natural means such as endocytosis. Nanoparticles have already been used to delivery drugs to target sites for cancer therapeutics ^38-41.

 

Advantage of using nanoparticle as a drug delivery

·        Small size ranging from (10nm to 100nm)

·        Target specific

·        Easily synthesized

·        Cost effective

·        Less dose of drug required to encapsulated

·        Flexibility of modifying size, shape and surface potential.

·        Nanoparticles can be made Biofunctional i.e. by attaching functional group, ligands, peptides, antibiodies and imaging agent .

·        Biodegradable – effective excreted through kidney.

·        Extremely stable and bind antigen with nanomolaraffinity .

·        Nanoparticle can be humanized

·        Ability to cross the human blood brain barrier to reach targets in the brain.

 

Nanobiotechnology for combination of drug design and drug delivery.

Nanobiotechnologyis also used to facilitate drug delivery. Nanoscale materials can be used as drug delivery vehicles to develop highly selective and effective therapeutic and diagnostic modalities. The single cell is an ideal sensor for detecting various chemical and biochemical processes. The ability to work with an individual cell using nanotechnology  is very promising. Numerous Nanodevices and nanosystem for sequencing single molecular of DNA are feasible. Nanobiotechnology will play an important role in the study of system biology also referred to as pathways network or integrative biology in which nanomedicine plays important role.

 

Drug delivery and therapeuties

Drug delivery system have already had an enormous impact on medical technology, greatly improving the performances of many existing drug and enabling, the use of entirely new therapies (Fig. 2) ⁴².

 

Application of nanoparticles includes tissue targeting, sensing and imaging, localized therapy and use of much lower doses. Nanotechnology benefits are especially relevant to cancer. Since the potential sensitivity of these  platform could allow the early detection of tumors before the cancer metastasizes. Technologies under development could allow DNA and protein markers to be detected in the same sample simultaneously. Nanostructure lend themselves to loading with either drug or tags including tumor can be targeted identified and treated using much lower levels of the therapeutic agent ^{38, 39, 43-46}.

 

Figure 2: Overview of Nanomedicine

 

Nanopartices as drug carriers

Nanopartices are with their characteristic that make them special and unique in a particular environmental based on surface potential, size, pH, temperature and side group attached on the surface of the molecules. Surface chemistry of nanoparticles can be modified to display high condition of a therapeutic drug/molecule for tissue specific recognition. Some of the applied nanoparticles for the delivery of drugs are dendrimers, liposomes, fullerenes, micelles, chitosan, etc.

 

Dendrimers

Dendrimers polymeric macromolecule structured as concentric shells are one type of nanoparticle that can be functionalized with chemical groups to allow attached of drugs or molecules of interest ^{47, 48}. Chemical properties of core and surface layer can be modified i.e. it is possible to reach nucleophilic surface group with other electrophilic group to form joint dendrimer complexes. However, they are very flexible in nature, they have the ability to change their conformation to form layers or lipid like structure based on the secondary interaction i.e. the end groups to a particular surface to which they are interacting. By the addition of branched molecule to central core ^49-52. The core having sticky end to which various chemical units are attached cavities present in the core structure and folding of branches create cages and channels that confer high loading capacity by encapsulation and absorption and thus protect from enzymatic degradation (Fig. 3 and 4). Polyvalent dendrimers interact with multiple drug target^53-56. They can be developed into novel, targeted cancer therapeutic whereas traditional drug delivery in monovalent i.e. a single drug molecule bind to a single cellular receptor, dendrimer can be engineered to carry a large number of drug molecules. On their spherical exteriors, in such a fashion that interaction with the receptor studded cellular membrane mimics the natural binding of a large viral entity to the target cell ^57-60.

 

Figure 3: Components of Dendrimer (A typical polyamidoamine (PAMAM) dendrimer. Z = 64 NH2 groups for PAMAM G4-NH2 dendrimers or Z = 64 OH groups for PAMAM G4-OH dendrimers.)

 

Figure 4:  A typical structure of Polypropyleniminetetrahexacontaamine Dendrimer, Generation 5.0.

 

Liposomes

Liposomes have been under development as delivery vehicles, since the early 1990. liposomes are spherical vesicles with a phospholipid bilayer membrane, ranging from size nm to m, are used to deliver drugs or genetic material into a cell  (Fig. 5) ^61-63. They have low toxicity are versatile in size, composition and bilayer fluidity and are capable of displaying drugs on their surface or encapsulating them within. They can entrap pharmacological compound like antimalarial, antiviral, anti-inflammatory, anti-fungal agent, antibiotic, prostaglandins, steroids and bronchodilators ^64-66. They enhance the biocompatibility of the liposomes and also reduce the toxicity. These systems are more popular with successful drug delivery to epithelial cells. However, they also have suffered from low delivery efficiencies and high drug leakage.

 

Figure.5: Structure of liposome

 

Fullerenes

Fullerenes molecule is that they have numerous points of attachment allowing for grafting of active chemical group in 3D orientation ^67-69. Fullerenceare made up 60-80 carbon atoms arranged is hexagon or pentagon in shape (Fig. 6). Fullerence have many potential medical application in industrial coating and fuel cells, so a number of toxicology studies have been done with them ^{70, 71}. Because can be easily excreted through kidney. Functionalizing can make them more soluble and stable ⁷². They are extremely strong and can resist pressure and sticky to each other with vanderwaals force that make them a good lubricant ^{73, 74}. This attribute, the rational drug design, allow positional control in matching fullerences compound to biological targets. Body show higher tolerance towards then is because they are made up of carbon (C60) thereby exhibiting wide scope in medical application from delivery of radioisotopes to cancer cells and to MRI by encapsulating noble gases inside the cage ^75-78. Also to enhance their electronic and photonic properties, hybrids made out of ferrocenes and fullerences has enabled the formation of vesicles for enhanced drug delivery.

 

Fullerenes also effective in scavenging the free radical hence they have a potential application in the treatment of diseases where oxidative stress play a role in pathogenesis (eg neurodegenerative diseases) C60. Fullerenes has  30 conjugated C-C double bonds, all of them can react with a radical species.

 

Another application of fullerenes in nuclear medicine as an alternative to chelating compound that prevent the direct binding of toxic metal ions to serum components. This could increase the therapeutic potency of radiation treatment and decreases their adverse effects because fullerenes are resistant to biochemical degradation within the body ^79-81.

 

Micelles

Micelles are self-assembled amphiphilic block copolymers. They are hydrophilic in nature and form hydrogen bonds outside. The core is hydrophobic to products the gene or drug from enzymatic degradation (Fig. 7) ^82-84.

 

Figure 6: Structure of Fullerene

 

Micells are clear, thermodynamically stable solutions that generally contain water, a surfactant and an oil. The oil in this case is the supercritical fluid phase ⁸⁵. The water microdomains have characteristics structural dimensions between 5-100nm ^86-88. They can solubilize  the hydrophobic drugs so as to increase the blood circulation time i.e. distribution and lower the interactions with reticuloendothelial system. Ligand conjugated with copolymer micelles can be used for therapeutic use ^{89, 90}. Their size is generally below 50nm. Drug can either be encapsulated inside a hybrophobic core or can be covalently attached to component molecules of micelles ^91-94.

 

Chitosan

Chitosan is a linear polysaccharide composed of randomly distributed B(1-4) linked D- Glucosamine (deacetylated unit) and N-acetyl- D-Glucosamine (Acetylated unit) are positively charged and act as bioadhesives which help them to penetrate nasal mucosa and brain endothelium (negatively charged) (Fig. 8) ^95-97.

 

Figure 7:  Structure of Micelles

 

Being immunonanoparticles they are easily transported across blood brain barrier.

 

They can be orally administrated and are highly stable in acidic or neutral solution. The transfection efficiency of chitosans is highly dependent on pH. Apart from this, the size, small chitosan oligomer chains (6,12,24mer)  seemed to be effective for gene delivery and siRNA for therapeutic gene silencing but most of the time they are less cooperative and complex DNA/dsDNA reversibly. The complex formed should be of intermediate stability as more stable complex restricts the DNA transcription and siRNA gene silencing; an unstable  complex permits rapid degradation of these oligonucleotide.

 

Figure 8: Chemical structure of chitosan

 

Nanoparticles in diagnostic

Nanomaterials and true nanoscale devices are also being developed to address the need for greater sensitivity in high through put screening.

 

Nanobodies

Nanobodies are created by Belgium based (Ablynx NV) smallest available intact, antigen binding fragment of naturally occurring heavy chains. They antibodies combine the beneficial features of conventional antibodies with desirable properties of small molecule drugs. Nanobodies might be considered a next generation antibodies based therapeutic that can be used in diagnostic for diseases such as Alzhemiers diseases and cancer.

 

Nanobodies unique structure they can also address therapeutic opportunities that are beyond to reach of conventional antibodies in several area like active sites of enzyme ( protein targets) with drug format flexibility, gastro- intestinal stability, speed of delivery, ease of cost effective manufacturing, hidden epitopes. The Nanobody technology was originally developed following the discovery that camelidae (camels and llamas) possess fully functional antibodies that lack light chains ⁹⁸. These heavy-chain antibodies contain a single variable domain (VHH) and two constant domains (CH2 and CH3) ^{99, 100}. Importantly, the cloned and isolated VHH domain is a perfectly stable polypeptide harbouring the full antigen-binding capacity of the original heavy-chain antibody ¹⁰¹. These newly discovered VHH domains with their unique structural and functional properties form the basis of a new generation of therapeutic antibodies whichAblynx has named Nanobodies(Fig. 9).

 

Quantum dots

Quantum dots are nanocrystals containing 100 to 100000 atom and exhibiting unusual. “Quantam Effects” such as prolonged fluoresences. They are being investigated for use in immune staining as alternatives to fluorescent dyes ^{102, 103}. Quantum dots (QDs) absorb light and reemit in a different wavelength. Quantum dots range between 2-10nm in diameter ¹⁰⁴. Generally, quantum dots consist of a semiconductor core, over coated by a shell (e.g. ZNS) to improve optical properties and a cap enabling improved solubility in aqueous buffers ^{105, 106}.

 

 

Fig. no. 9 structure of nanobodies

 

These are silicon nanocrystals with exceptional optical properties that can be used to design probes that monitor biological experiments with greater sensitivity ^107-109. They can be made of nearly every semiconductor metal (egCds, CdSe, CdTe, Zns, Pbs) but alloys and other metals (eg Au) can also be used (Fig. 10). The most commonly used material for the core crystal is Cadmium, Selenium that exhibits bright fluorescence and high photo stability ^{110, 111}.  

Several quantum dots are commercially available Qdot Tm conjugates from the quantum dots corporation (Hayward, CA, USA) can produce photo resolution upto light times more detailed than older imaging tools.

 

Figure 10: Structure of Quantum dots

 

Gold nanoparticles

Colloidal gold and silver are used already in molecular detection and separation, where their size can be reproducibly engineered to submicron dimension for controlled chemical architecture and high surface to volume loading capacity ^{112, 113}.

 

Gold possess many properties that make it an ideal material for biomedical purpose. Gold nanoparticles are the metal of choice because gold remains an oxidized at the nanoparticle size. Other metals typically oxide, lose their nanoparticle optical properties useful for imaging and ultimately collect together to form nanoparticle ^{114, 115}. Gold nanoparticle can be used for imaging cancer, monitoring blood flow, mapping blood vessels and allow for 3D imaging (Fig. 11) ^{45, 116}.

 

Figure11: Structure of Gold Nanoparticles

 

They are also used as a connecting point to build biosensors to detect disease DNA. A gold nanoparticle can be attached to an antibody and other molecules such as DNA can be added to the nanoparticle to produce bar code. Because many copies of the antibodies and DNA can be attached to a single nanoparticles, this approach is much more sensitive and accurate than the fluorescent molecule tests used for drug discovery they need to be combined with another technology for visualization ¹¹⁷.

 

Toxicity

Particular concerns for environmental issues, as area referred to as nanotoxicology. While no adverse consequences of the application of nanotechnology to living creatures have yet been detected, yet there is apprehension within the industry over this issue ¹¹⁸. Many technology products are composed of heavy metals and other potential toxins such as carbon, titanium, cadmium and gallium. Because of their extremely small size, nanoparticle have a large surface area per unit of mass, thus enabling absorption and recruitment of exogenous toxins ^{119, 120}. Since they were explicitly designed to cross the surface membranes, organ exposure could potentially be enhanced. Thus, the intrinsic qualities of nanoparticles, which endow them with so much potential could have negative and dangerous outcomes ¹²¹.

 

FDA approval is essential for clinical application of nanotechnology and substantial regulatory problems could be encountered in the approval of nanotechnology based products. Pharmaceutical biological and devices are all regulated differentially by the FDA.

 

There is no universal “nanomaterial to fit in all the case”, each nanomaterial should be treated individual when health risk are expected. Nanomaterial designed for drug delivery or as food components need special attention.

 

New approaches

The long term goal of nanomedicine as the control and manuipulation of supramolecular assemblies in living cells in order to improve the quality of human health. To reach these long term objectives. A set of five near goal for his programs, including :

·        Development of smart biosensors that employ fluorescence resonance energy transfer or other molecular activation techniques.

·        Optimization of performance of quantum dots and other nanoparticles.

·        Movement through the clinic to FDA approval of this new family of imaging agents.

Three main areas of study including drug therapy, with particular concern for size reductions of the drug transporting particles, gene therapy, taking advantage of an endovascular model and immunotherapy, targeting. The mucosal tissues with local injection of nanoparticle.

 

A future of growth for nanomedicine

Anything use of nanobiotechnology by pharmaceutical and biotechnology industries is anticipated. The US govt. is currently investing $ billion a year in funding for nanotechnology research, while the global total is $ 4 billion per annum. Venture capitals contribution has been much less, with $ 900 million expended in the past four years and half of that going to fund nanobiotechnology projects.

 

The fact that the public contribution is so much larger than the private outlay clearly reflect a long term optimism on the part of the US and the other govt. that the venture capital sector hasn’t yet picked upon. This may be due to the fact that while the technology seems to have unlimited potential there are few products that have moved through clinical trials and received approval by American on foreign regulatory bodies.

 

While the market for nanobiotechnology products is very new, it is expected to grow rapidly. Reaching over $ 3 billion by 2008 for an annual growth rate of 28%. If this projected expansion comes to pass, nanobiotechnology will rapidly overwhelm conventional drug development and other traditional approaches.

 

Conclusion:

Nanobiotechnology has provided novel approaches to DNA extraction and amplification as well as reduced the time required for these processes to seconds. Nanomaterial are sensitive chemical and biological sensors and forms the basis used in molecular diagnostic. Nanotechnology is an emerging field that could potentially make a major impact to human health.

 

Nanomaterial promise to revolutionize medicine and are increasingly used in drug delivery application. Nanotechnology will be applied at all stages of drug development from formulation for optimal delivery of diagnostic application in clinical trials.

 

One of the main goals of drug delivery will be to more efficiently target therapies to specific tissue type. This while increase drug efficacy by sequestering a drug where it is needed and also ensure that healthy tissues are spared. To accomplish this goal, further work in need to verify that devices delivery drug to the desired tissue types across large population of patients.  

 

Acknowledgement:

The authors acknowledge Department of Biotechnology, Kalyan PG College, Sector -7, Bhilai, Chhattisgarh, India for providing necessary infrastructural facilities.

 

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Received on 28.03.2014                Modified on 25.04.2014

Accepted on 30.04.2014                © RJPT All right reserved