Nanotechnology and Drug Development & Delivery

Hello Komal,

Your answers-

1. The artificial red blood cell or "respirocyte" proposed here is a bloodborne spherical 1-micron diamondoid 1000-atm pressure vessel with active pumping powered by endogenous serum glucose, able to deliver 236 times more oxygen to the tissues per unit volume than natural red cells and to manage carbonic acidity.

The respirocyte is constructed of tough diamondoid material, employs a variety of chemical, thermal and pressure sensors, has an onboard nanocomputer which enables the device to display many complex responses and behaviors, can be remotely reprogrammed via external acoustic signals to modify existing or to install new protocols, and draws power from abundant natural serum glucose supplies, thus is capable of operating intelligently and virtually indefinitely, unlike red cells which have a natural lifespan of 4 months...

An onboard nanocomputer and numerous chemical and pressure sensors enable complex device behaviors remotely reprogrammable by the physician via externally applied acoustic signals.

Given the goal of oxygen transport from the lungs to other body tissues, the simplest possible design for an artificial respirocyte is a microscopic pressure vessel, spherical in shape for maximum compactness.

Which goes as follows-
Most proposals for durable nanostructures employ the strongest materials, such as flawless diamond or sapphire constructed atom by atom, with Young's modulus 1012 N/m2 (107 atm) and conservative working stress (~0.2 times tensile strength) of 1010 N/m2 (100,000 atm) .

Tank storage capacity is given by Van der Waals equation which takes account of the finite size of tightly packed molecules and the intermolecular forces at higher packing densities: P = [nRT/(V-nB)] - [An2/V2], with P in atm, n in moles of gas, R = 8.206 x 10-5 m3-atm/mole-°K, T = 310 °K (human body temperature), V in m3, and constants A and B determined experimentally for each gas.

2. The artificial respirocyte is a simple nanotechnological device whose primary applications include transfusable blood substitution; treatment for anemia, perinatal and neonatal disorders, and a variety of lung diseases and conditions; contribution to the success of certain aggressive cardiovascular and neurovascular procedures, tumor therapies and diagnostics; prevention of asphyxia; maintenance of artificial breathing in adverse environments; and a variety of sports, veterinary, battlefield and other applications.

This device cannot be built today. However, when future advances in the engineering of molecular machine systems permit its construction, the artificial respirocyte may find dozens of applications in therapeutic and critical care medicine, and elsewhere.

You can find great details over this at-
http://www.foresight.org/nanomedicine/Respirocytes.html
http://www.foresight.org/nanomedicine/Respirocytes1.html#Sec22

regards,
Sakshi.

Hello Shobha,
thanks for your question..

You know, the cosmetic industry can boast filing the highest number of patents for the development and use of nanoparticles. ..

Today, nanotechnologies are being employed predominantly as nanomaterials in sunscreens, emollients, soaps, shampoos, lipstick, eye shadow, aftershave products, deodorants and anti-aging products. In these common products, nanomaterials offer several advantages as a novel vehicle for topical delivery. Nanomaterials overcome issues of penetration, dosing and controlled delivery of bioactive agents.

Research in the medical field has shown where nanotechnology can help with the healing and repair of skin tissue. In the cosmetic arena it is believed that the smaller particles are more readily absorbed into the skin and as such repair damage easier and more efficiently. It is believed that as new products are developed nanotechnology may be used to prevent graying hair and combat hair loss in some cases.

Nanotechnology is elevating the development of skin care products and cosmetics to another level, making them high-tech so as to deliver increased benefits to users. In addition to improving the efficacy of cosmetics and skin care products, nanotechnology is making it possible for other ingredients to be used in the manufacturing of beauty products.

Nanotechnology in the beauty industry involves making products with nanoparticles that can go deeper below the skin’s surface to give better results.
Sunscreens and some anti-aging products are the main cosmetic products on the market currently being made using nanotechnology.

However, because of the relative newness of the technology in terms of cosmetics manufacturing there is still concern as to how safe nanotech cosmetics are and their long-term effect. Agencies such as the Federal Drug Administration (US) and The Royal Society (UK) have issued statements calling for continued testing and transparency governing research on the use of nanotechnology in cosmetics.

Some nanoparticles have received FDA approval, such as zinc oxide and titanium dioxide which have been included in sunscreen; in 1996 the FDA is reported to have concluded that “… smaller, micronized particles of titanium dioxide are not new substances and that there is no evidence demonstrating that these micronized particles are unsafe.”

However, nanoparticles, being so tiny, have the potential to penetrate unusually deeply into the skin and organs, causing exotic physical effects. Animal studies show that some nanoparticles can penetrate cells and tissues, move through the body and brain and cause biochemical damage.

Reference-
http://www.care2.com/greenliving/skin-deeper-nanotechnology-and-cosmetic...

Regards,
Sakshi

Hello Hemangi..
Thanks..
nice question...

A biosensor is a device for the detection of an analyte that combines a biological component with a physicochemical detector component. It combines a biochemical recognition/binding element (ligand) with a signal conversion unit (transducer).

How it works would be more clear, if we give a look at its components-
It consists of three parts
•The sensitive biological element (e.g. Tissues, Microorganisms, Organelles, Cell receptors, Enzymes, Antibodies, Nucleic acids, Synthetic receptors, Sensing organs etc)
•The transducer (Acts as an interface, measuring the physical change that occurs with the reaction at the bioreceptor then transforming that energy into measurable electrical output.) Physical transducers: Optical, Electrochemical, Opto-electronic, Piezoelectric, Magnetic Thermal, Mass.
•The detector element (Signals from the transducer are passed to a microprocessor where they are amplified and analyzed, The data is then converted to concentration units and transferred to a display or/and data storage device.)

The transducer converts the biochemical interactions into a measurable electronic signal.

For the introduction of biosensors in the body, many strategies can be followed depending upon its function.

Nanobiosensor developments, are giving shape to new platforms for pain-free, accurate, and selectively sensitive developments of diagnostic biosensors.
Like- By injecting a body with the quantum dots, a doctor could see where a tumor or cancer cell was by finding the injected quantum dots, an easy process because of their fluorescence. Developed nanosensor quantum dots would be specifically constructed to find only the particular cell for which the body was at risk.

Or there can be a viral Nanosensor - Virus particles are essentially biological nanoparticles. Herpes simplex virus (HSV) and adenovirus have been used to trigger the assembly of magnetic nanobeads as a nanosensor for clinically relevant viruses. This system is more sensitive than ELISA-based methods and is an improvement over PCR-based detection because it is cheaper, faster and has fewer artifacts.
You can find more details for this here-

Refrences-
http://www.azonano.com/Details.asp?ArticleID=1977
http://en.wikipedia.org/wiki/Nanosensor
http://small.buffalo.edu/data/Lec23-EE428528-SUNYBuffalo.pdf
http://nanobiowave.com/AUTOMATED_BIOCHEM_EMR.aspx

regards,
Sakshi.

1) mention the steps involved in drug development ? ( nanotechnological steps )
2) As nano drugs are nano sized how it can be handled ?? how they are get carried ?
3) Specify the storage conditions for nano partices ? why those conditions are requried ?
4) Any adverse body reactions ?? if so why ? if not why ?

Hello sir,
quite glad to answer your question...

1stly dealing with the advantages-

So, being nano in drug delivery-have innumerable advantages...
The nano enabled drug delivery system ( DDS ) over the next 5 years are forecast to dramatically reshape the way existing drugs are delivered. The benefits of nano- based DDS will be dramatic for both doctors & patients, providing lower drug toxicity, more specific targeting & reduced cost of treatments. Nanotechnology has the potential to provide formulations & routes for drug delivery, enormously broadening their therapeutic potential.

Now, taking one by one some nanodevices employed in drug delivery with their advantages-
The Nanoparticles- increase drug solubility & can lead to controlled release &/ or drug targeting. They are used in anti- cancer treatment, gene delivery, asthma inhalers, drug delivery through the eye & in oral & vaccine delivery systems.

The Nanocrystals are specially used for poorly water soluble drug compounds-by grinding them into nanocrystals, thereby increasing their surface area , which leads to an increase in dissolution rate. Also, the size of the particles allows for safe & effective passage through capillaries.

Nanoshells- which consist of a non conducting core known as silicon surrounded by a metal shell of varying thickness. They are “tunable”, in that their ability to respond to light varies with thickness of shell & core size. Nanoshells can be designed so that they either scatter or absorb light that hits them. Nanoshells designed to absorb incident light heat up & can potentially be used to target & kill cancer cells.

Nanocapsules- when encapsulation materials are produced from nanomaterials, instead of bigger microparticles, they have a large surface arae for the same volume, smaller pore size, improved solubility & different structural properties. This improves both the diffusion & degradation characteristics of the encapsulated drug material. This permits timed drug release to occur as the drug diffuses through the encapsulation material.

Next comes the polymer therapeutics which include polymer drugs, polymer drug conjugates, micelles, dendrimers, liposomes which are based on the fact that with the appropriate biodegradable linker, &/ or a cell specific targeting group, it becomes possible to deliver the drug direct to the target site.

In a short summary, I can say that due to very high surface area, nanomaterial based drugs are more effective as the penetration is concerned. Drugs are also more target specific & minimize risk of side effects to the normal cells.

Hello Amit,
Thanks,

“Why nanotechnology will be applied to all stages of drug development”, is quite an elaborate question in itself. I will have to jot down all the benefits of the nanotechnology in drug development, mentioned in my presentation. But, summarizing it all, let me present my view, in a more general way, like your question…

The potential impact of nanotechnology stems directly from the spatial & temporal scales being considered. Materials & devices engineered at the nanometer scale imply controlled manipulations of individual constituent molecules & atom in how they are arranged to form the bulk macroscopic substrates. This in turn means that nano-engineered substrates can be designed to exhibit very specific & controlled bulk chemical & physical properties as a result of the control over their molecular synthesis & assembly.

For applications to medicine & physiology, these materials & devices can be designed to interact with cells & tissues at a molecular ( i.e., subcellular) level with a high degree of functional specificity, thus allowing a degree of integration between technology & biological systems not previously attainable…

Disease & ill health are caused largely by damage at the molecular & cellular level. Today’s surgical tools are, at this scale, large &crude. From the viewpoint of the cell, even a fine scalpel is a blunt instrument more suited to tear & injure than heal & cure. Modern surgery works only because cells have a remarkable ability to regroup, bury their dead & heal over the injury.

Nanotechnology, “the manufacturing technology of the 21st century,” should let us economically build a broad range of complex molecular machines ( including molecular computers ). It will let us build fleets of computer controlled molecular tools much smaller than a human cell & built with the accuracy & precision of drug molecules. Such tools will let medicine, for the first time; intervene in a sophisticated & controlled way at the cellular & molecular level…

So, nanotechnology will be applied at all stages of drug development - from formulations for optimal delivery to diagnostic applications in clinical trials. Many of the assays based on nanobiotechnology will enable high-throughput screening. Some of nanostructures such as fullerenes are themselves drug candidates as they allow precise grafting of active chemical groups in three-dimensional orientations. Nanoparticles and nanodevices such as nanobiosensors and nanobiochips, are used to improve drug discovery and development. Nanoscale assays can contribute significantly to cost-saving in screening campaigns.

Nanobiotechnology, an integration of physical sciences, molecular engineering, biology, chemistry and biotechnology holds considerable promise of advances in pharmaceuticals and healthcare.

Nanomedicine is now within the realm of reality starting with nanodiagnostics and drug delivery facilitated by nanobiotechnology…

Reference-
http://www.azonano.com/news.asp?newsID=6039
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T64-4HCF2TD-B...

Tell me, if you like my answer & more queries..
regards,
Sakshi

Hello Amol,
A very nice question…

You know, most of nanotechnology is still unknown to us.
There is a saying that "All good fruits will turn bad". There are things that we will be misused. For example, when we discovered nuclear, we used it as a source of cheap energy, as scientists experimented more with the substance, they found out that they can use it to make deadly weapons of mass destruction…

As good as nanotechnology sounds there are drawbacks or risks associated with it. Nanotechnology not only has risks to the environment but also public health.

Manufacturing nanomaterials poses risk to human health and other organisms due to their composition, reactivity, and unique size. One of the main concerns is that some nanotubes are very similar to asbestos fibers.

Scientist have raised concern that nanoparticles might end up in the food supply causing anything from food poisoning to genetic damage. If nanoparticles can be taken up by cells, as studies have shown, they could slip into animals, plants, and ultimately our food chain and eventually to us.

Since they are manufactured to be more durable than current day materials, it begs the question of how long they ultimately will last in our landfills when nanomaterials are disposed of.

Some Drawbacks of Nanotechnology :
• In March 2004 tests conducted by environmental toxicologist Eva Oberdörster, Ph.D., with Southern Methodist University in Texas found extensive brain damage to fish exposed to fullerenes for a period of just 48 hours at a relatively moderate dose of 0.5 parts per million. The fish also exhibited changed gene markers in their livers, indicating their entire physiology was affected. In a concurrent test, the fullerenes killed water fleas, an important link in the marine food chain.
• Other nanoparticles have also been shown to have adverse effects. Research from University of California in San Diego in early 2002 revealed cadmium selenide nanoparticles, also called quantum dots, can cause cadmium poisoning in humans. In 2004 British scientist Vyvyan Howard published initial findings that indicated gold nanoparticles might move through a mother’s placenta to the fetus; and as far back as 1997 scientists at Oxford discovered nanoparticles used in sunscreen created free radicals that damaged DNA.
• Highest at risk are workers employed by manufacturers producing products that contain nanoparticles. The National Institute for Occupational Safety and Health (NIOSH)reports over 2 million Americans are exposed to high levels of nanoparticles and they believe this figure will rise to 4 million in the near future. NIOSH publishes safety guidelines and other information for those employed in the nanoindustry.
• Some have compared the situation to that of asbestos dust – another material that was assumed safe until it was learned that it can cause cancer from accumulation in the body. Today 3,000 deaths per year are still attributed to asbestos from decades-old use.

Some other disadvantages associated with it are:

1. According to research if silver nanoparticles used in socks to prevent foot odor if released in water can prove harmful to the purity of water.

2. Some nanoparticles destroy the bacteria help in breaking down the organic matter in water treatment plants.

3. The process of manufacturing the nanomaterials results in the release of certain waste products which enter the plants and air.

4. Nanoparticles have the large surface so they can easily hamper the biological processes as they get absorbed by macromolecules in an animal body.

5. Now with the use of nanotechnology various social issues for farmers and workers have come up who depend on the on the production and distribution of these natural substances. This technology replaces the natural substances.

6. Agriculture countries will face the heavy financial losses if nanoproducts replace the natural products.

7. There occurs Global monetary crisis, loss of jobs, oil becomes worthless and diamonds become worthless, atomic weapons more destructive and accessible.

8. Some kinds of carbon nanotubes can prove as harmful as asbestos inhaled in fair quantities. Sometimes, they can cause mesothelioma.

9. It is increasing risks in the field of terrorism as the anti groups or terrorists make the use of this technology and destruct the human race at the molecular level.

10. It is not suited in terms of privacy because with this technology you can design minute devices and increase the chances of more spying.

References-
http://www.techdreams.info/tag/drawbacks-of-nanotechnology/

Hope it answers your question..
regards, Sakshi

Hello shilpa,

Thanks for your question..

I have a small doubt regarding your question, whether should I tell you the fate of nanomedicines after their therapeutic action in the body or ultimately in the environment…
I’ll answer both..

The large surface area of the nanomedicines increases their contact with the tissues & their retention as well. The high retention allows the particles to be translocated into the other parts more effectively. They are further transported to circulatory system, lymphatic system & the nervous system.
The smaller particles that reach deeper into the alveolar epithelium escaping phagocytosis, may have harmful effects on the respiration system like fibrosis, emphysema, inflammation, tumors, etc.

The nanoparticles not obstructed by the lungs reach the blood vessels. From here onwards they find way to the organs like spleen, liver, kidneys, heart, bone marrow.

The further uptake of the nanoparticles by the blood cells may reduce the oxygen carrying capacity of the red blood cells.

Next, the gastrointestinal tract may be utilized for the uptake. The mucous lining of intestines being negatively charged may trap the positively charged particles. Diseases such as ulcerative colitis have been linked to the presence of nanoparticles such as that of carbon, sulfur, calcium etc.

Next, the accumulation of nanoparticles in the nervous system occurs mainly via two pathways- olfactory nerves & the blood brain barrier. The particles embedding in the brain are found to cause brain inflammation, neuronal dysfunction, & oxidative damage.

The particles not cleared by body are deposited into the organs like liver, spleen, heart & kidneys being the most important ones.

Next comes -- what happens after the prescribed use & residues of nanomedicines enter the environment.
The engineered nanomedicines may interact with already occurring environmental pollutants & change the availability & toxicity of these.

Although nanomedical products will probably enter the environment, their fate and effects are not well understood with respect to fundamental issues, such as bioavailability, bioaccumulation, toxicity, environmental transformation and interactions with other environmental contaminates, as well as the applicability of current environmental fate and transport models to nanomaterials.

So, at this point of time, the risks and benefits associated with developments in nanomedicine are largely hypothetical and illustrative of larger questions that accompany new technological developments.

So, the future of nanomedicine will depend on rational design of nanotechnology materials and tools based around a detailed and thorough understanding of biological processes rather than forcing applications for some materials currently in vogue.

References-
http://www.medscape.com/viewarticle/584380
http://www.medscape.com/viewarticle/584380_3

regards, sakshi

Hello Komal,

Thanks,

Regarding the handling of nanoparticles, or I should say, the safe handling of nanoparticles, many recommendations have been made...
We know that nanoparticles are ultrafine particles measuring between 1-100 nanometers (nm) in one dimension. In addition to the novel size of nanoparticles or structures, uses are also derived from the composition of the nanoparticles, which can be chemical or biological.
So, the concerns with safety regarding the handling of nanotechnology have arisen primarily from the recognition of several unique attributes of nanoparticles.

National Institute for Occupational Safety and Health (NIOSH), the NIH, and the EPA promote the incorporation of cautionary measures in research to minimize or eliminate exposures to nanoparticles.
While the health risks from exposure to nanoparticles are not well known and will vary depending on the composition of the particles, work practices and engineering control procedures to prevent exposure are well understood.

The following are minimum engineering, work practice and ventilation controls required when handling nanoparticles to reduce potential exposure:

•Lab coats must be worn.
•Gloves must be worn when handling nanomaterials. Because skin penetration is a concern, gloves must cover the wrist and any skin on the arm exposed by the lab coat.
•Arm sleeves are required where high levels of exposure or splashes of solutions containing nanoparticles are anticipated.
•Standard safety glasses should be worn.
•Dry nano-materials must be handled in a fume hood or biological safety cabinet. Work on the open bench with dry nanoparticles is not allowed.
•Transport of dry nanoparticles should occur in closed containers.
•Hand washing facilities must be provided in all labs. Hand washing must be performed after handling nano-materials.

So, these are some major concerns while or for handling of nanoparticles…
Reference-
http:www.cdc.gov/niosh/topics/nanotech/safenano/

Hope, it answers your question…
Best regards,
Sakshi.

Hello Bhasker,
Your question is a bit elaborate one, let me answer it one by one..

As per toxicology of nanoparticles is concerned, it will be very specific to the type of base material, size, ligands & coatings.
Yes, you are right, that nanoparticles possessing ultra fine structures show greater toxicity then fine particulates of same material on a mass basis.

But, at the same time, due to very high surface area, the nanomaterial based drugs are more effective as the penetration is concerned. The drugs are more target specific & minimize the risk of side effects concerning with the harm to the normal cells.

The high specificity of nanomedicines to the target site is based on the target molecules attached to it. Target molecules are conjugated on the nanoparticles that actively guide the drug molecules to release at a targeted site. These molecules are usually peptides, monoclonal antibodies, folate, transferrin, & aptamers.

Monoclonal antibodies serve as very good target agents for targeting the receptors of the tumor cells without affecting normal cells. Similarly, folate receptors bind folate & folate drug conjugates.
Also, transferrin, the iron containing serum glycoprotein is delivered only in erythroblasts & cancer cells to deliver transferring.
Alternatively, nanoparticles can be conjugated with the aptamers to target the prostate cancer cells.

Now, mentioning the nanobots- they will be able to distinguish between cell types, by checking their surface antigens ( they are different for each type of cell ). This is accomplished by the use of chemotactic sensors keyed to the specific antigens on the target cells.

Next, the nanocapsules ( drug encapsulated ) also have antigens that allow them to bind only with tumor tissues.
Also, drug encapsulation decreases the likelihood of significant systemic toxicity, & make it biologically unavailable during transit in systemic circulation.

Lastly, let me mention nanoshells- that are tuned to respond to near infra red light which passes harmlessly through soft tissue.
In the treatment, nanoshells convert this light into heat that destroys nearby tumor cells, & as the heating is much localized, it does not affect healthy tissues adjacent to the tumor.

So, with this small data on the specificity of nanomedicines, we can see that there is no possibility as such of translocation and toxicity to other sites, other than the targeted site.

hi Noopur..
thanks..

Now,regarding the harmful effects of Nanomedicines, research has been advancing in this direction & it’s been realized very early that not everything is safe for the use though it may look very attractive in the preliminary research...

Of the harmful effects or increased risks to these medicines, the 1st parameter & the most obvious one is the size. For the same amount of mass, nanoparticles are found to be much more toxic than the bigger ones. The large surface area of the nanomaterials increases their contact with the tissues & their retention as well. The high retention allows the particles to be translocated into the other parts more effectively. For instance, TiO2 nanoparticles with 20nm diameter having same crystalline structure as that of 250nm particles causes high inflammatory reaction in rats.
DNA damage has also been found to be significantly more for the smaller particles.
Next, the dose dependency of materials in the macro world is directly proportional to the toxicity in the macro world. In the nanoworld, effects are not found to be dependent on the mass dose but on the surface area dose. It means that smaller particles pose at low dose are more risky than bigger particles even at higher doses owing to the higher surface areas in smaller ranges.

The nanoparticles are further transported to circulatory system, lymphatic system, & the nervous system.

The nanoparticles, that reach deeper into the alveolar epithelium escape phagocytosis. The harmful effects on the respiration system include impaired macrophage clearance, fibrosis, emphysema, inflammation, tumours etc.

The further uptake of nanomedicines by blood cells reduces the oxygen carrying capacity of red blood cells & can lead to anemia.

Next, if gastrointestinal tract is utilized for the uptake, the mucous lining of intestines being negatively charged traps the positively charged particles effectively. Diseases such as cancer, Crohn’s disease, ulcerative colitis have been linked to the presence of nanoparticles.

Accumulation of nanomedicines in the nervous system, can cause embedding in the brain, found to cause brain inflammation, neuronal dysfunction, and oxidative damage.

However, researches are going on to reduce these side effects, and in the recent years, successes have been reported.

hope, its clear to you.

regards, sakshi

hi, Dixon..

first of all,sorry for replying so late,as there was some problem with my computer, i was not able to answer to any comments.

now the answer- you must have heard about "gene therapy". let me tell you in brief. There are more than 4000 known inherited genetic disorders which lack effective therapy, some of them namely- cystic fibrosis, hemophilia, muscular dystrophy, seickel cell anemia, etc.
Current methods of treatment of genetic diseases are mostly symptomatic & when analysed on the criteria of life increased, it shows very low rate of success, as well as high risk factors are involved, eg: as in case of hemophilia- where blood products are used which may be infected with AIDS virus.

So, Gene Therapy is a technique for correcting defective genes responsible for disease development either through addition of normal gene or replacement of the mutant gene, that is by addition of recombinant DNA.

Although, it is still in its infancy & undergoing clinical trials, & FDA has not yet approved any human gene therapy product for sale for various complications involved, yet there are many recent successful research developments, in cases of inherited blindness, in treatment of metastatic melanoma cancer, etc.

so, these complications would get manyfold times reduced, when aided with Nanotechnology.

Hope it answers your question..
regards.