Nanotechnology in Medicine Beshoy Makram , Ehab Youssef , Kerolles Kamal , Kerolles Sadek , Mina Zosser , Mena Welleam , Martin Mahrous , Medhat Adly , Samouel Yahya , Simon Samir . Faculty of pharmacy Minia University . Department of Toxicology .
Key words
A B S T R A C T
Nanomedicine
The aim of this research is to count some of the enormous
Nanoparticles
applications of " Nanotechnology in the field of medicine " , or
Nanobots
so called ( Nanomedicine ) .
Nanoshells
Interaction between biological molecules with artificial
Nano robots
molecular assemblies at nanoscale ( in vivo or in vitro ) , opens
Nanotechnology
up a vast field of research and application in the field of
Noisomes
medicine .
Nanodrugs
Operating at nanoscale has many advantages , like it allows to exploit physical properties different from those observed at microscale such as the volume / surface ratio . Nanotechnology also may be used to develop normal drugs to " Nanodrugs " . where the drug distribution , targeting is improved . To deliver the drug to diseased tissues while protecting the healthy tissue . A third area of application is regenerative medicine where nanotechnology allows developing biocompatible materials which support the growth of cells used in cell therapy , or by using nanoscale robots known as " Nanobots " at DNA repair and neuron replacement . Nanotechnology in medicine contribute to develop diagnosis , therapy and monitoring . By Nanomedicine we are finally capable of making a very early diagnosis of diseases and treat the diseased cells without affecting the healthy tissues .
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1. Introduction The simplest definition of " Nanotechnology " is " The science and technology of small things " . In particular , things that are less than 100 nm in size[6] . So , Nanosciences and nanotechnologies imply studying and working with matter at ultra small scale . Therefore nanomedicine operates at the same size scale – about 100 nanometers or less – that biological molecules and structures inside living cells operate .[1,15]
For comparison[1] , 1 nanometer is one-millionth of a millimeter ( 10-9 meter ) and a single human hair is around 80,000 nanometers thick . A typical protein size lies between 3 to 10 nanometers (nm), while red blood cells are a standard size of about 6000 – 8000 nm . Nanostructures are not new and they were not first created by man . There are many examples of nanostructures in nature in the way that plants and animals have evolved. Similarly there are many natural nanoscale materials , such as catalysts , porous materials , that have unique properties particularly because of the nanoscale features. If we look closely, we can notice that many plants and animals around us have developed special features that are at the nanoscale level , like " A moth’s eye " has very small bumps on its surface . They have a hexagonal shape and are a few hundred nanometers tall and apart . Because these patterns are
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smaller than the wavelength of visible light (350 - 800nm) , the eye surface has a very low reflectance for the visible light so the moth’s eye can absorb more light[14]. The moth can see much better than humans in dim or dark conditions because these nanostructures absorb light very efficiently. In the lab, scientists have used similar man-made nanostructures to enhance the absorption of infra-red light (heat) in a type of power source ( a thermo-voltaic cell) to make them more efficient[1,6] .
2. Is the nano scale really adequate for medical technologies ? Some physical laws are different at the nanoscale, and this may be favorable for medical applications[1] : •The surface/volume ratio of particles becomes very large when size decreases, so that nanoparticles have a huge surface suitable for chemical interactions with biomolecules, for instance . Moreover, the biochemical reaction time are much shorter ( it decreases sharply with sample size ) . Accordingly using nanoparticles to make the sensing part of the analytical device ( like nano pillars or nano beads )[15] , makes the analytical devices : More faster : the biochemical reaction time is much shorter due to more surface area and small biological sample . •The ultra small size of the sensing part of the analytical device gives the opportunity for making Smaller devices , which offer a lower invasiveness and can even be implanted within the body " Device miniaturization " . More sensitive devices : because the sensing part is very small so it needs a small volume of the biological sample .
3. Medical applications of nanotechnology Nanotechnology could be used in medicine in three main classes[1] : Medical diagnosis ( In vitro , In vivo " imaging , implants or sensors " ) . Medical treatment ( Drug delivery systems " passive targeting , active targeting , destruction from within " , Drug delivery mechanical device ) . Regenerative medicine ( stem cells , biomaterials ) .
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3.1. Medical diagnosis 3.1.1. In vitro diagnosis : In vitro diagnosis for medical applications has traditionally been a laborious task ; blood and other body fluids or tissue samples are sent to a laboratory for an analysis , which could take hours , days or even weeks , depending on the technique used[13] . The many disadvantages include sample deterioration , high cost , lengthy waiting times (even for urgent cases) , inaccurate results for small sample quantities , difficulties in integrating parameters obtained by a wide variety of methods and poor standardisation of sample collection . Steadily[1] , miniaturisation , parallelisation and integration of different functions on a single device , based on techniques derived from the electronics industry , have led to the development of a new generation of devices that are smaller , faster and cheaper , do not require special skills , and provide accurate readings . These analytical devices require much smaller samples and will deliver more complete ( and more accurate ) biological data from a single measurement .[1] The requirement for smaller samples also means less invasive and less traumatic methods of extraction . Nanotechnology enables further refinement of diagnostic techniques , leading to high throughput screening ( To test one sample for numerous diseases , or screen large numbers of samples for one disease ) .[11] An in vitro diagnostic tool can be :  A single biosensor .  An integrated device containing many biosensors .
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A biosensor is a sensor that contains a biological element " such as an enzyme " capable of recognizing and signaling ( through some biochemical change ) the presence , activity or concentration of a specific biological molecule in solution . A transducer is used to convert the biochemical signal into a quantifiable signal . Key attributes of biosensors are their specificity and sensitivity. Integrated devices can measure tens to thousands of signals from one sample , thus providing the general practitioner or the surgeon with much more complementary data from his patient’s sample .
3.1.2. In vivo diagnosis : In vivo diagnostics[1] refer in general to imaging techniques, but also covers implantable devices . Nanoimaging includes several approaches using techniques for the study of in vivo molecular events and molecules manipulation . Imaging techniques cover advanced optical imaging and spectroscopy , nuclear imaging with radioactive tracers , magnetic resonance imaging , ultrasound , optical and X-ray imaging , all of which depend on identifying tracers or contrast agents that have been introduced into the body to mark the disease site . The goal of in vivo diagnostics research is to create highly sensitive , highly reliable detection agents that can also deliver and monitor therapy . This is the " find , fight and follow " concept of early diagnosis , therapy and therapy control . [11] With this strategy , the tissue of interest can firstly be imaged , using target specific contrast nanostructures . Then , combined with a pharmacologically active agent to apply therapy . Finally, monitoring of treatment effects is possible by sequential imaging .
3.1.2.1. Imaging The old imaging techniques[1] could only detect changes in the appearance of tissues when symptoms were relatively advanced . Later , contrast agents were introduced to more easily identify and map the locus of disease . Today , through the application of nanotechnology , both imaging tools and marker/contrast agents are being dramatically refined towards the end goals of detecting disease as early as possible . To make a good tumor imaging we need two things :  Something that specifically identifies a cancerous cell .  Something that enables it to be seen and gives me the exact location of it in the body .
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And both could be achieved by nanotechnology , the same nanoparticle that detect the change in the interested tissue , is also gives the exact location of that tissue in the body at the cellular level .[11] For example , antibodies that identify specific receptors found to be over-expressed in cancerous cells can be coated onto nanoparticles such as metal oxides which produce a high contrast signal on Magnetic Resonance Images (MRI) . Once inside the body , the antibodies on these nanoparticles will bind selectively to cancerous cells , effectively lighting them up for the scanner . Similarly , gold particles could be used to enhance light scattering for endoscopy techniques like colonoscopies . Nanotechnology will enable the visualisation of molecular markers that identify specific stages and types of cancers , allowing physicians to see cells and molecules undetectable through conventional imaging .[4]
3.1.2.2. Implants , Sensors Implantable devices for in vivo diagnostics is very important monitoring of circulating molecules is of great interest for some chronic diseases such as diabetes or AIDS. The miniaturisation of implanted sensors to work at the nano levels lower invasiveness and gives more accurate data , due to the increase in sensitivity of the sensory part of the implant , and it gives remote control and external transmission of data .
Examples : 1. Implant nano-chip : It is a small chip that harvest the biomarkers in blood and gives external and remote control of data inside the body . It depends in its work on the physical proprieties of the metal beads in a way that every bead has a set of antibodies to a certain protein , when all the antibodies are filled with the proteins[19] , the bead
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is bent down and gives a signal that could be identified remotely . Every bead has a set of antibodies that is different from the adjacent bead . This gives an early diagnosis for any possible tumors depending on their specific biomarkers .[8,1]
Free nanobot
Occupied nanobot
2. Bacteria sensors : There are robots that identify the type and amount of bacteria in blood stream . These small robots are in the nano scale , so they are called nanorobots or so called " Nanobots " . Nanobots could be entered in the blood stream by an IV injection . How it works ? These Nanobots collect bacteria from blood stream and when a nanobot collects maximum amount of one type of bacteria it shows a unique barcode for this type only , that could be read by an external laser scanner . Every type of bacteria has its own unique barcode . This method for bacteria diagnosis is very amazing , because it provides indication of bacterial content over the hour , it minimizes the invasiveness and the pain very much , no blood samples is needed , no more time consuming waiting for the test results . This method is considered a revolution in the medical diagnostic field[19] .
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3.2. Medical treatment Most of pathologies are treated by dispensing drugs . Some of them are small chemical molecules while others are biological ones . However the use of systemic drug administration may generate some side effects . Therefore improvements of drug administration , especially for injectable drugs , are looked for by pharma industry and by patients . Encapsulation of drugs in carriers is a possibility . Nanotechnology offers means to aim therapies directly and selectively at diseased tissues or cells , with application in cancer or inflammation for instance . The behavior of nanomaterials used for in vivo administration should be demonstrated whether they are biocompatible , or biodegradable[19] .
3.2.1. Drug delivery systems In the short and medium term[1,8] , the main use of nanoparticle medicinal products is vectorisation of active principles . Generally three vector generations are considered : •First generation vectors : nanospheres and nanocapsules . •Second generation vectors : nanoparticles coated with hydrophilic polymers such as polyethylene glycol (PEG) , PEGylated nanoparticles . •Third generation vectors : combining a biodegradable core and a polymer envelope (PEG) with a membrane recognition ligand at the surface .
Inorganic nanoparticles : Inorganic nanoparticles can be defined as particles of metal oxide or metallic composition possessing at least one length scale in the nanometer range . These nanostructures exhibit significantly novel and distinct chemical , physical, and biological properties, and functionality due to their nanoscale size[2,3] . Preparation methods : 1-The most traditional preparation method for nanoparticle synthesis is the sol-gel route which the preparation of a solution of inorganic precursor , and the control of its particle growth though thermal or pH conditions of the solution . 2-The use of the spray-drying process is a more scale-up .
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3-Another method for the preparation of nanoparticles is microemulsion processing , microemulsions are produced spontaneously without the need for significant mechanical agitation making it a rather simple technique. The technique is simple and uses inexpensive equipment that results in high yields with homogeneous particle size . TYPES OF INORGANIC NANOPARTICLES 1- Metal nanoparticles : Metal nanoparticles have been used in various biomedical applications . These nanomaterials have found important applications as chemical sensor , For example , gold nanoparticles , Silver particles [2,12] . 2- Mesoporous silica system : In the past decade, synthesis and applications of mesoporous solids have received intensive attention due to their highly ordered structures , larger pore size , and high surface area due to stable mesoporous structure and well-defined surface properties , mesoporous materials seem ideal for the encapsulation of pharmaceutical drugs .[3]
Polymers in drug delivery systems : Engineering polymeric nanostructures such as hyperbranched polymers , dendrimers and polymeric micelles are a growing area of contemporary biomaterials science , due to their unique properties and large potential in drug deliver For using polymers in drug delivery , a polymer must be biocompatible the development of drug delivery systems, must meet very specific requirements such as[2,3]: a. Biocompatibility backbone of the polymer and its degradation products . b. Mechanical strength sufficient to meet the needs of specific applications . c. Degradability with degradation kinetics matching a bio-logical process such as wound healing . d. Possibility using available equipment . e. Solubility in various solvents . f. Chemical , structural and application versatility . g. Economically acceptable shelf life .
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Polymeric nanoparticles Polymeric nanoparticles (NPs) are < 1000 nm in size and are composed of biostable polymers and copolymers . The drug molecules can be entrapped or encapsulated within the particle , physically adsorbed on the surface , or chemically linked to the surface of the particle .
Dendrimers A typical dendrimer consists of three main structural components: a. A focal core . b. Building blocks with several interior layers composed of repeating units . c. Multiple peripheral functional group .The branched units are organized in layers called "generations" , and represent the repeating monomer unit of these Macromolecules [2] .
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Dendrimers offer several featured advantages as drug carrier candidates . These advantages include: [2] (1) High density and reactivity of functional groups on the periphery of dendrimers . 2) Weight and monodispersity of dendrimers ensure reproductive . 3) Pharmacokinetics controllable size . 4) High penetration abilities of dendritic structures through the cell membrane cause increased cellular uptake level of the drugs complexed or conjugated to them . 5) The lack of immunogenicity of dendrimers makes them much safer choices than synthesized peptide carriers and natural protein carriers enhanced penetration .
Dendrimers for drug delivery
[2,3]
Two strategies are used for the application of dendrimers to drug delivery: Drug encapsulation by dendritic structure and drug conjugation to dendrimers. Firstly, the drug molecules can be physically entrapped inside the dendrimers . Secondly , the drug molecules can be covalently attached onto the surface or other functionalities to afford dendrimer-drug conjugates . Dendritic macromolecules have non-polar cavities in their interior, which ensures them capable of encapsulating hydro-phobic drug molecules . Moreover, there are large numbers of positively or negatively charged functional groups on the surface of dendrimers , which make it easy for drug molecules with opposite charges to attach . These non-covalent inclusions or complexes offer a variety of promising advantages such as enhanced water solubility drug stability , programmed release of drugs from the matrixes , and improved pharmacodynamic (PD) and pharmacokinetic (PK) behaviors .
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Today, most current research projects in nano delivery systems are focused on the third generation vectors " which contain a recognition ligand at the surface , which bind with the receptors at the tumors surface " .[1] Conventional chemotherapy employs drugs that are known to kill cancer cells effectively . But these cytotoxic drugs kill healthy cells in addition to tumor cells , leading to adverse side effects such as nausea , neuropathy, hair-loss , fatigue , and compromised immune function. Nanoparticles can be used as drug carriers for chemotherapeutics to deliver medication directly to the tumor while sparing healthy tissue . Nanocarriers present several advantages over conventional chemotherapy. They can : [1,2] 1- Protect drugs from being degraded in the body before they reach their target ( Because the drug is in the core of the nanocarrier and it has a protective layer of phospholipids at the surface ) . 2- Enhance drug absorption into tumors and the cancerous cells themselves ( Due to the recognition ligands at the surface which recognize and bind to the receptors at the tumor surface ) . 3- Allow for better control over the timing and distribution of drugs to the tissue , making it easier for oncologists to assess how well they work ( Due to the slow degradation of the drug ) . 4- Prevent drugs from interacting with normal cells, thus avoiding side effects ( Because the drug isn't released until the ligand interact with the receptors on the tumor surface , so the drug is released only on the surface of the tumor . Or by inducing the tumor to absorb the nanocarrier , so drug is released inside the tumor ) .
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3.2.1.1. Active targeting
On the horizon are nanoparticles that will actively target drugs to cancerous cells , based on the molecules that they express on their surface Active targeting could be done by two ways : ď&#x201A;ˇ By binding to the particular surface receptors on the tumor and then release the drug , so that it specifically targets cells expressing this receptor only . ď&#x201A;ˇ By inducing the cancerous cell to absorb the nanocarrier inside it and then release the drug inside the cancerous mass . So drug delivery system by nanotechnology is better than the conventional chemotherapy , because it deliver drug to diseased cells only and don't affect healthy cells , but chemotherapy is destructive for both . Active targeting can be combined with passive targeting to further reduce interaction of carried drugs with healthy tissue. Nanotechnology-enabled active and passive targeting can also increase the efficiency of a chemotherapeutic, achieving more significant tumor reduction with lower drug doses.
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3.2.1.2. Passive targeting There are now several nanocarrier-based drugs on the market , which rely on passive targeting through a process known as " Enhanced permeability and retention " . Because of their size and surface properties , certain nanoparticles can escape through blood vessel walls into tissues . In addition[1] , tumors tend to have leaky blood vessels and defective lymphatic drainage , causing nanoparticles to accumulate in them , thereby concentrating the attached cytotoxic drug where itâ&#x20AC;&#x2122;s needed , protecting healthy tissue and greatly reducing adverse side effects . Another strategy for passive targeting consists in using myeloid cells like macrophages which absorb nanoparticles and concentrate them in the site to be treated , like a Trojan horse.
3.2.1.3. Destruction from within Moving away from conventional chemotherapeutic agents that activate normal molecular mechanisms to induce cell death , researchers are exploring ways to physically destroy cancerous cells from within . One such technology " Nanoshells " is being used in the
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laboratory to thermally destroy tumors from the inside . Nanoshells can be designed to absorb light at different wavelengths , generating heat ( hyperthermia ) . Once the cancer cells take up the nanoshells ( via active targeting ) , scientists apply near-infrared light that is absorbed by the nanoshells , creating an intense heat inside the tumor that selectively kills tumor cells without disturbing neighboring healthy cells . Similarly , new targeted magnetic nanoparticles are in development that will both be visible through Magnetic Resonance Imaging (MRI) and can also destroy cells by hyperthermia . The new targeted magnetic nanoparticles do triple action : ď&#x201A;ˇ It can identify the cancerous cells ( to tell whether this cell is cancerous or not ) . ď&#x201A;ˇ It tags the cancerous cell and tell me where its location ( because it is visible through MRI ) . ď&#x201A;ˇ It destroys cancerous cells by hyperthermia . So it does : Diagnosis , Imaging , Therapy .
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3.2.2. Drug delivery (mechanical) devices
Implanted drug delivery devices can take benefit of nanotechnology . The Nanopump is a miniaturized drug delivery pump based on . The Nanopump[1] has been tested , for instance, for insulin delivery. The precision of nanofabrication and micro-techniques enable design and fabrication of ultra small devices with reservoirs , actuators , pumps to control accurately the release of pharmaceutical ingredients . Some parts of these micro-systems are at the nanoscale . Due to their small size and low invasiveness , these drug delivery devices can be implanted within the body , even in the brain .[15]
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3.3. Regenerative medicine Regenerative medicine is the process of creating living , functional tissues , to repair or replace tissue or organ function lost due to age , disease , damage , or congenital defects , By : ď&#x201A;ˇ Stimulating previously irreparable organs to heal by themselves . ď&#x201A;ˇ Grow tissues and organs in laboratory and safely implant them when the body cannot heal by itself . Regeneration of tissues can be achieved by the combination of living cells , which will provide biological functionality , and materials , which act as scaffolds to support cell proliferation .
3.3.1. DNA regeneration
DNA is the most complicated biological information source , but a single defective gene can cause a serious genetic disease . Nanotechnology can solve this problem . Future gene replacement technology can cure most of genetic defects in DNA . How it works ? Nanomechanical robot can grab , analyse and fix an individual DNA molecule . 1- DNA molecule is attached to the nanobot surface by the fixation part of the nanobot.
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2- The nanobot scans nucleotides , seeking for damaged fragments by the sensory part of the nanobot . 3- The invalid fragment is removed by excision process .[20,15,1]
DNA regenerative process :
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3.3.2. Dental and bone replacement Bone is one of the most commonly transplanted tissues . surgeons face a diverse spectrum of clinical challenges in bone reconstruction reflecting the variety of anatomic sites, defect sizes, mechanical stresses, and available soft tissue cover . Autologous bone grafting remains the gold standard for reconstruction of skeletal defects , however , this technique does have some drawbacks including limited supply , bone graft loss/resorption , short-term instability in large defects , complications associated with a second surgical site , and autograft failure rates exceeding 50% in difficult healing environments . Bone allografts ( bone transplanted from a donor) present another option . However , their clinical success does not approach that of autologous bone , with higher failure rates (30â&#x20AC;&#x201C;60% ) over 10 years in vivo with significant decreases in strength and prevalence of late rejection . As a result of these limitations , the use of synthetic implants to replace damaged bone is growing exponentially .[10] Bone regeneration requires three essential elements: 1- osteoconductive matrix (scaffold), 2- osteoconductive signals . 3- osteogenic cells that can respond to these signals and an adequate blood supply .
The first step , fabrication of strong and porous scaffolds . Natural composites or hybrid structures , such as bone and teeth , display properties that are invariably far superior to their individual constituent phases . Fabrication alone , however , will not be enough to create an optimum scaffold . In this respect , nanotechnology provides new and useful tools to engineer the scaffoldâ&#x20AC;&#x2122;s internal surfaces and to create devices for drug delivery with carefully controlled
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spatial and temporal release patterns . Synthetic scaffolds can also serve as a vehicle for the delivery of cells to build new tissue . Different techniques have been proposed to successfully seed scaffolds with cells . They can be roughly divided into two main groups: ď&#x201A;ˇ Attaching the cells to the internal scaffold surface . ď&#x201A;ˇ Or distributing them in the scaffold porosity using a gel-like vehicle . Injectable gels containing cells could also be used directly in non-load bearing applications . Seeding with skeletal stem cells has attracted much attention , but it is critical to develop the adequate chemical and physical extracellular milieu to promote differentiation toward the osteoblastic lineage . The growth of new bio-structures in a mould or directly in/on the injured body part ( teeth or bone ) , can develop from either nano-physical or nano-chemical structures . A nano-physical structure develops from a single nano-crystal , whereas a nano-chemical structure develops from an array of large reactive molecules attached to a surface . These nanostructures are used as seed molecules , or seed crystals , to drive materials to grow by themselves .[10] Researchers hope to use nano-patterned polymers to grow adult stem cells that will turn into bone . Once the process of growing tissue on patterned scaffolding is perfected , nanostructured devices can be attached to further improve bone growth rate .
4. conclusion Considering great contribution that nanotechnology has made to the field of medicine , now we can easily make an early diagnosis , a targeting therapy and monitoring for any disease without affecting the healthy cells . even better we can do all this by the same nanoparticle , just a single type of nanoparticles ( like gold nanoparticles ) can identify the cancerous cells , locate it , imaging it and then we just stimulate it by an external stimulant like infrared beam and it will eliminate the tumor and the tumor only , just like that , no more invasive ways or blood samples or biopsies or waiting long time for the results . By nanotechnology we are capable of repair any defective gene easily . We can regenerate the growth of bone and teeth instead of replacing them . We can know thy type and the amount of bacteria inside your body just by using a laser scanner , no blood
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samples needed , no pain , no time wasting . No more daily insulin shots for a diabetic patient , just a nano pump is planted under the skin and it will measure the blood glucose levels and secrete insulin according to it . It can regenerate the defected nerves in brain or totally replace it , imagine a painless and safe therapy to Alzheimer . In a little words , Nanotechnology is not the way to future , it is the future .
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[13] The present and future of nanotechnology in human health care , Nanomedicine: Nanotechnology, Biology, and Medicine 3 , S.K. Sahoo , S. Parveen , J.J. Panda , 2007 [14] WHAT IS NANOTECHNOLOGY? , Adapted from Online Materials Available from National Nanotechnology Infrastructure Network "NNIN " official site . http://www.nnin.org/nnin_edu.html [15] Nanotechnology , a Stanford Nanofabrication Facility journal , M. Deal . [16] NANOTECHNOLOGY IN MEDICINE , GAURAV MEHTA , 2010 [17] Nanomedicine: Nanotechnology, Biology, and Medicine , Yun J, Nanomaterials Technology, Singapore , 2006 [18] Application of nanomedicine in emergency medicine; Point-of-care testing and drug delivery in twenty-first century , DARU Journal of Pharmaceutical Sciences , Ali Pourmand , Mohammad Reza Pourmand , Justin Wang , Robert Shesser , 2012 [19] Nanotechnology in medicine , D. Nedra Karunaratne , J . Natn . Sci .Foundation Sri Lanka , 2007 [20] Embryonic and Induced Pluripotent Stem Cells : Understanding , Creating , and Exploiting the Nano-Niche for Regenerative Medicine , Emmajayne Kingham , Richard O.C. Oreffo , 2012
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