INTRODUCTION:

‘Nanomedicine’ is defined as submicron size (<1um) modules, used for treatment, diagnosis, monitoring, and control of biological system^{. 1} ‘Nanotechnology’ is the synergy of mechanical, material sciences, microelectronics, electrical, chemical and biological screening. Nanotechnology was first discovered by Richard Feynman in 1959 (Nobel Laureate in physics, 1956) ². Nanotechnology is one of the most popular areas of scientific research, especially with regard to medical applications. Some of the new detection methods that should bring about, faster and less invasive cancer diagnoses, but once the diagnosis occur, there's still the prospect of surgery, chemotherapy or radiation treatment to destroy the cancer. Unfortunately, these treatments can carry serious side effects. Chemotherapy can cause a variety of ailments, including hair loss, digestive problems, nausea and lack of energy and mouth ulcers. ¹⁰ But nanotechnologists think they have an answer for treatment as well, and it comes in the form of targeted drug therapies.⁹ Scientists can load their cancer-detecting gold nanoparticles with anticancer drugs; they could attack the cancer exactly where it lives. Such a treatment means fewer side effects and less medication used. Nanoparticles also carry the potential for targeted and time-release drugs. A potent dose of drugs could be delivered to a specific area but engineered to release over a planned period to ensure maximum effectiveness and the patient's safety.

These treatments aim to take advantage of the power of nanotechnology and the voracious tendencies of cancer cells, which feast on everything in sight, including drug-laden nanoparticles.³

Application of Nanotechnology in Pharmacy:

An important area of application of nanotechnology includes novel drug delivery techniques, which are quicker and less risky, compared to the costs of developing new drugs

Applications of nanotechnology in the different field can be summarized as follows:

1. Nanomedicines: nanodrugs, medical devices, tissue engineering, etc.

2. Chemicals and cosmetics: nanoscale chemicals and compounds, paints, coating.

3. Materials: nanoparticles, carbon nanotubes, biopolymers, paints, coating

4. Food science: processing, nutracetical food, nanocapsules

5. Environment and energy: water and air purification filters, fuel cells, photovoltics

6. Military and security: bio-sensers, wepons, sensory enhancement

7. Electronics: semiconductor chips, memory storage, photonics, optoelectronics

8. Scientific tools: atomic force, microscopes and scanning tunneling microscope

9. Agriculture: pesticides, food production.

Nanomedicine:⁵

Nanomedicine is the medical application of nanotechnology. Nanomedicine ranges from the medical applications of nanomaterials, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology.

Cancer:⁴

The small size of nanoparticles endows them with properties that can be very useful in oncology, particularly in imaging. Quantum dots (nanoparticles with quantum confinement properties, such as size-tunable light emission), when used in conjunction with MRI (magnetic resonance imaging), can produce exceptional images of tumor sites. These nanoparticles are much brighter than organic dyes and only need one light source for excitation. This means that the use of fluorescent quantum dots could produce a higher contrast image and at a lower cost than todays organic dyes used as contrast media.

Nanoparticle Targeting: ⁶

The positive surface charge of the nanoparticle decreases the rate of opsonization of nanoparticles in the liver, thus affecting the excretory pathway. Even at a relatively small size of 5 nm, though, these particles can become compartmentalized in the peripheral tissues, and will therefore accumulate in the body over time. While advancement of research proves that targeting and distribution can be augmented by nanoparticles, the dangers of nanotoxicity become an important next step in further understanding of their medical uses.

Nanorobots:

The somewhat speculative claims about the possibility of using nanorobots in medicine, advocates say, would totally change the world of medicine once it is realized.⁷ Nanomedicine would make use of these nanorobots (e.g., Computational Genes), introduced into the body, to repair or detect damages and infections.⁸

Cell Repair Machines:

With molecular machines, there will be more direct repairs. Cell repair will utilize the same tasks that living systems already prove possible. Access to cells is possible because biologists can insert needles into cells without killing them. Thus, molecular machines are capable of entering the cell.

Approaches for nanotechnology:

Nanobiology involves research to determine the properties and structure of biological molecules at the single molecule level, as well as research into primarily molecular motors and biomachines and other molecular assemblies and intracellular bioreaction imaging and so on.

Nanocarriers:

Nanocarriers are colloidal particulate systems with size ranging between 10-1000 nm. They have been successfully utilized in the diagnosis, treatment and monitoring of various diseases.¹¹

Successful development of a drug formulation for any disease requires consideration of five parameters. This is also known as 5D-approch and comprises of disease, drug, destination, delivery system and dollar or cost of medication.

These parameters are interlinked, i.e. selection of drug as well as destination depends on the disease under investigation and similarly, selection of a delivery system depends on physicochemical properties of drugs, destination or the target area of disease.¹²

Classification of Nanocarriers:

The term ‘nanocarrier’ is meant to imply variety of systems such as polymeric nanoparticles, liposomes, polymeric micelles, dendrimers, niosomes, solid lipid nanoparticles (SLN) and magnetic nanoparticles.

Advantages of Nanocarriers:^16-19

a) Unlike conventional medications which result in formation of crests and troughs, use of controlled release polymers help in the maintenance of constant drug levels in therapeutic range.

b) Enhanced delivery which in turn leads to superior performance of drugs

c) Dosing frequency of drugs can be reduced

d) Life span of best selling drugs can be elevated by reformulating them using novel polymeric systems

e) Increase the patent protection

f) Increase the longevity in blood

g) Site-specific targeting to the diseased site

h) Enhanced intracellular penetration of drugs

Disadvantages of Nanocarriers:^20,
21

a) Involves higher manufacturing costs which may in turn lead to increase in the cost of formulation

b) Involves the use of harsh toxic solvents in the preparation process

c) May trigger immune response and allergic reactions

d) May generate free radicals and reactive oxygen species

Specific Targeted Delivery of Nanocarriers to Tumors:

The vascularity of tumors is highly heterogeneous, ranging from areas of vascular necrosis to areas which are densely vascularized in order to sustain the adequate supply of oxygen and nutrients to the growing tumor. Tumor blood vessels have several abnormalities compared to normal blood vessels, including a high proportion of proliferating endothelial cells with aberrant underlying basement membrane, increased tortuosity of blood vessels, and a deficiency in pericytes. Cancer nanotechnology is emerging as a new field of interdisciplinary research cutting across the disciplines of biology, chemistry, engineering and medicine and is expected to lead to major advances in cancer detection, diagnosis and treatment.³

Tumor micro vessels demonstrate enhanced permeability, which is regulated in part by abnormal secretion of vascular endothelium growth factor, bradykinin, nitric oxide, prostaglandins, and matrix metalloproteinases. The transport of macromolecules across tumor microvasculature may occur through open interendothelial junctions or transendothelial channels. The pore cutoff size of these transport pathways in various models has been estimated to be in the 1 m range, and in vivo measurement of extravasation of liposomes into tumor xenografts suggests a cutoff size in the 400 nm range. In general, particle extravasation is inversely proportional to size, and smaller particles (200 nm size) would be most effective for extravasating the tumor microvasculature. The tumor lymphatic system is also abnormal, resulting in fluid retention in tumors and high interstitial pressure with an outward convective interstitial fluid flow. This property is thought to promote tumor cell intravasation, resulting in tumor metastasis and blockage of nanocarrier extravasation from microvasculature into the tumor interstitium. However, the lack of an intact lymphatic system also results in retention of the nanocarriers in the tumor interstitium since these particles are not readily cleared from the interstitium. When taken together, the leaky microvasculature and the lack of intact lymphatic system results in enhanced permeation and retention (EPR) effect and “passive” cancer targeting through the accumulation of nanocarriers in the tumor at a higher concentration that is present in the plasma and in other tissues. The release of drugs from nanocarriers in this case results in a relatively higher intratumoral drug concentration translating into enhanced tumor cytotoxicity. These nanocarriers may be further modified for “active” cancer targeting by functionalizing the surface of nanocarriers with ligands such as antibodies, aptamers, peptides, or small molecules that recognize tumor-specific or tumor-associated antigens in the tumor microenvironment. When nanocarriers are targeted to the extracellular portion of transmembrane tumor antigens, they may be specifically taken up by cancer cells through receptor mediated Endocytosis. The specific targeting, intracellular uptake, and regulated therapeutic delivery of payload are properties that are derived through a rational design of nanocarriers. The application of nanotechnology to cancer therapy, including the development of “smart” nanoparticles, is indeed an exciting and promising area of investigation. In the following sections, we review some of the most important breakthrough nanotechnology platforms for cancer therapeutic applications.^{22, 23, 24, 25}

Current trends of nanotechnology for cancer therapy:

Cancer occurs at a molecular level when multiple subsets of genes undergo genetic alterations, either activation of oncogenes or inactivation of tumor suppressor genes. Then malignant proliferation of cancer cells, tissue infiltration and dysfunction of organs will appear. Tumor tissues are characterized with active angiogenesis and high vascular density which keep blood supply for their growth, but with a defective vascular architecture. Combined with poor lymphatic drainage, they contribute to what is known as the enhanced permeation and retention (EPR) effect. With the development of nanotechnology, the integration of nonmaterial into cancer therapeutics is one of the rapidly advancing fields. It can revolutionize the treatment of cancer. Nanotechnology is the creation and utilization of materials, devices, and systems through the control of matter on the nanometer scale. Nanocarrier systems can be designed to interact with target cells and tissues or respond to stimuli in well-controlled ways to induce desired physiological responses. They represent new directions for more effective diagnosis and therapy of cancer.

Nanomaterials for Cancer Therapy:

Nanoparticles used for anticancer drug delivery can be made from a variety of materials, including polymers, dendrimers, liposomes, viruses, carbon nanotubes, and metals such as iron oxide and gold.²⁶ So far, almost all the nanoparticle delivery systems which have been approved by the FDA or are currently in clinic trials are based on polymers or liposomes.²⁷

Table 1 Various nanoparticles based delivery systems with their therapeutic and diagnostic uses in cancer therapy.

Nanoparticle based delivery systems	Therapeutic and diagnostic use
Liposomes	Controlled and targeted drug delivery; Targeted gene delivery.
Nanoshells	Tumor targeting
Fullerene based derivatives	As targeting and imaging agent
Carbon nanotube	Drug gene and DNA delivery; Tumor targeting
Dendrimers	Targeted drug delivery
Quantum dots	As targeting and imaging agent
Gold nanoparticles	Targeted delivery and imaging agent
Solid lipid nanoparticle (SLN)	Controlled and targeted drug delivery
Nanowires	As targeting and imaging agent
Paramagnetic nanoparticles	As targeting and imaging agent

New drugs:

Nanoparticles:

These are submicron-sized (<1µm) colloidal particles with a therapeutic agent of interest encapsulated within their polymeric matrix or adsorbed or conjugated onto the surface.²⁸ Nanoparticles are targeted to specific sites by surface modifications, which provide specific biochemical interactions with the receptors expressed on target cells.^{22, 29} Another important function of nanoparticles is their ability to deliver drugs to the target site, crossing several biological barriers such as the blood–brain barrier. By coating the nanoparticles with polysorbates, the drug-loaded nanoparticles can be transported across the blood–brain barrier, enabling brain targeting after an intravenous injection.³⁰

Classification of Nanoparticles:

In one dimension (Thin surface coatings):

One dimensional system, such as thin films or manufactured surfaces

In Two Dimensions:

Carbon Nanotubes:

Carbon nanotubes are a new form of carbon molecule. Wound in a hexagonal network of carbon atoms, these hollow cylinders can have diameters as small as 0.7 nm and reach several millimeters in length.³¹ Each end can be opened or closed by a fullerene half-molecule. These nanotubes can have a single layer (like a straw) or several layers (like a poster rolled in a tube) of coaxial cylinders of increasing diameters in a common axis.³²

Fig. 5: Schematic representation of monolayer or multiplayer carbon nanotube.

In Three Dimensions:

Fullerenes (Carbon 60):

Fullerenes are spherical cages containing from 28 to more than 100 carbon atoms. Fullerenes are a class of materials displaying unique physical properties. They can be subjected to extreme pressures and regain their original shape when the pressure is released. These molecules do not combine with each other, thus giving them major potential for application as lubricants.

Dendrimers:³³

Dendrimers represent a new class of controlled-structure polymers with nanometric dimensions. They are considered to be basic elements for large-scale synthesis of organic and inorganic nanostructures with dimensions of 1 to 100 nm, displaying unique properties. Compatible with organic structures such as DNA, they can also be fabricated to interact with metallic nanocrystals and nanotubes or to possess an encapsulation capacity.

Quantum Dots:^{35, 36}

It represents a special form of spherical nanocrystals from 1 to 10 nm in diameter. They have been developed in the form of semiconductors, insulators, metals, magnetic materials or metallic oxides. Semiconductor QDs are emerging as a new class of fluorescent labels for biology and medicine. The broad absorption and narrow emission characteristics of the QDs make it possible to perform multicolor imaging with a single excitation source.

Advantages of Nanoparticles:

1. Increased bioavailability

2. Dose proportionality

3. Decreased toxicity

4. Smaller dosage form (i.e., smaller tablet)

5. Stable dosage forms of drugs which are either unstable or have unacceptably low bioavailability in non-nanoparticulate dosage forms.

6. Increased active agent surface area results in a faster dissolution of the active agent in an aqueous environment, such as the human body. Faster dissolution generally equates with greater bioavailability, smaller drug doses, less toxicity.

7. Reduction in fed/fasted variability.³⁴

Polymers used for nanospheres and production of nanoparticles:

1. Poly (isohexylcyanoacrylate) nanosphers (PIHCA).

2. Poly (methylcyanoacrylate).

3. Poly (ethylcyanoacrylate).

4. Poly (isobutylcyanoacrylate).

5. Hydrophilicpolymers-polyethyleneglycols, poloxamers, polysaccharides.

6. Poly (methylmethacrylate)(PMMA)

7. Poly (ethyleneoxide)-poly (L-lacticacid)/poly (βbenzyl-Laspartate).

8. Poly (ethyleneglycol) coatednanospheres.

9. Poly (γ–benzyl-L-glutamate)/poly (ethyleneoxide).

10. Poly (D, L–lactidecoglycolide) PLGA.

11. Poly (D, L- lactide).

Exqor has developed new Nanoparticles based on highly specialized proteins used by brain cells these special proteins have unique geometric structure; they are protein analogs of buckyballs (carbon fullerenes). They are designed to readily pass blood brain barrier and deliver both large and small molecules to specific targeted regions in brain. Preparation of Nanoparticles:

The different methods for preparing nanoparticles and for entrapping or adsorbing the drugs or antigens are:

1. Emulsion polymerize

2. Interfacial polymerization.

3. Denaturation of natural macromolecules in an oil emulsion.

4. Desolvation of macromolecules.

5. Solvent displacement method.

Nanodiamond:

Nanotechnology Developed originally for the surface finishing industry, diamond nanoparticles are now finding new and far-reaching applications in modern biomedical science and biotechnologies. Due to its excellent biocompatibility, diamond has been called the Biomaterial of the 21st Century and medical diamond coatings are already heavily researched for implants and prostheses. Nanoscale diamond is also being discussed as a promising cellular biomarker and a non-toxic alternative to heavy metal quantum dots.

Further extending the nanomedical use of diamond, researchers now have demonstrated a nanodiamond-embedded device that could be used to deliver chemotherapy drugs locally to sites where cancerous tumors have been surgically removed.

Fig. 5: The patch resembles plastic wrap, exhibiting innate flexibility and a thin physical profile. (Image: Mark Chen/Robert Lam, Northwestern University).

Gold Nanoparticles:^{37, 38}

Gold nanoparticles are a popular choice for medical research, diagnostic testing and cancer treatment, but there are numerous types of nanoparticles in use and in development. In other words, scientists are so wrapped up in what they can do; they are not asking if they should do it. In a study published in the July 2007 issue of Analytical Chemistry, scientists from Purdue University detailed their use of gold nanoparticles to detect breast cancer. Their work, along with similar studies at other universities, has the potential to radically change breast cancer detection. The procedure works by identifying the proteins found on the exteriors of cancer cells. Different types of cancer have different proteins on their surfaces that serve as unique markers. Nanorods, gold nanoparticles shaped like rods, use specialized antibodies to latch onto the protein markers for breast cancer, or for another cancer type. After the nanorods bind to proteins in a blood sample, scientists examine how they scatter light. Each protein-nanorod combination scatters light in a unique way, allowing for precise diagnoses.

CONCLUSION:

Cancer nanotechnology field has the potential to better monitor therapeutic efficacy, provide novel methods for detecting and profiling early stage cancers, and for enabling surgeons to delineate tumor margins and sentinel lymph nodes. Nanomaterials have unique features that are attractive, and can be applied to biosensing. The development of various nanomaterials and nanotechnology has enabled detection of cancer biomarkers with great precision and sensitivity that could not be achieved before. Many studies are being conducted on developing sensing mechanisms that will push down the detection limit as far down as possible. It is therefore highly anticipated that in the near future, nanotechnology shall help to detect cancer at an early stage and monitor the disease with much greater precision. It must be however noted that these new technologies must be validated critically before applying them for clinical diagnosis. Ultimately, if the nanotechnology researchers can establish methods to detect tumors at a very early stage, that is, before tumors begin to vascularize and metastasize, cancer will become a disease that will become amenable to complete cure via surgical resection.

REFERENCES:

1. Jain S, Jain NK. Liposomes as drug carrier, In: Controlled and novel drug delivery. CBS publisher, New Delhi. 2^nd edition; 2002.

2. James R Baker et al. The Synthesis and testing of anticancer therapeutic nanodevices. Biomedical micro devices. 3; 2001: 61-69.

3. Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer 5; 2005:161–171.

4. Cavalcanti A et al.: "Nanorobot architecture for medical target identification"; 2008.

5. Freitas RA "What is Nanomedicine?" Nanomedicine: Nanotech. Biol. Med.; 2005.

6. LaVan DA, McGuire T, Langer R. "Small-scale systems for in vivo drug delivery". Nat Biotechnol; 2003.

7. Zheng G et al. "Multiplexed electrical detection of cancer markers with nanowire sensor arrays". Nat Biotechnol; 2005.

8. Wagner V et al. "The emerging Nanomedicine landscape". Nat Biotechnol; 2006.

9. "Nanotechnology kills cancer cells." BBC News; Aug. 2, 2005.

10. "General side effects of chemotherapy drugs." Cancer Research UK; May 8, 2007.

11. Oberdorster GE, Oberdorster and Oberdorster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect; 2005: 823-39.

12. Panchagnula R et al. Fixed dose combinations for tuberculosis: Lessons learned from clinical, formulation and regulatory perspective. Methods Find Exp Clinical Pharmacology; 2004: 703-21.

13. Maggi L, Bruni R and Conte U. High molecular weight polyethylene oxides (PEOs) as an alternative to HPMC in controlled release dosage forms. Int J Pharm; 2000: 229-38.

14. Potoski J. Timely synthetic support for medicinal chemists. Drug Discovery Today; 2005: 115-20.

15. Uhrich KE et al. Polymeric systems for controlled drug release. Chem Rev, 1999: 3181-98.

16. Mainardes RM et al. Colloidal carriers for ophthalmic drug delivery. Curr Drug Targets; 2005: 363-71.

17. Varde NK and Pack DW. Microspheres for controlled release drug delivery. Expert Opin Biol Ther; 2004: 35-51.

18. Bhardwaj TR et al. Natural gums and modified natural gums as sustained-release carriers. Drug Dev Ind Pharm. 2000:1025-38.

19. Okada H and Toguchi H. Biodegradable microspheres in drug delivery. Crit Rev Ther Drug Carrier Syst; 1995:1-99.

20. Moghimi SM, Hunter AC and Murray JC. Nanomedicine: current status and future prospects. FASEB J; 2005: 311-30.

21. Lanone S and Boczkowski J. Biomedical applications and potential health risks of nanomaterials: molecular mechanisms. Curr Mol Med; 2006: 651-63.

22. Parveen S and Sahoo SK. Polymeric nanoparticles for cancer therapy. Drug Target; 2008: 108–123.

23. Sengupta S et al. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system; 2005: 568–572.

24. Bharali DJ et al. Nanoparticles and cancer therapy: a concise review with Emphasis on dendrimers. Int. J. Nanomed; 2009: 1-7.

25. Sparreboom A et al. Comparative preclinical and clinical pharmacokinetics of a Cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin. Cancer Res.; 2005: 4136–4143.

26. Dilipkumar Pal and Amit Kumar Nayak. Nanotechnology for Targeted Delivery in Cancer Therapeutics. Int. J of Pharma. Sc. Rev. and Res; 2010: 1-5.

27. Qiu LY et al. Polymer architecture and drug delivery. Pharm Res.; 2006.

28. Sahoo SK and Labhasetwar V. Nanotech approaches to drug delivery and imaging. Drug Discovery Today; 2003: 1112–1120.

29. Misra R and Sahoo SK. Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy. Eur. J. of Pharm. Sci.; 2010: 152–163.

30. Wang X et al. Application of nanotechnology in cancer therapy and imaging. CA Cancer J. Clin; 2008: 97–110.

31. Hett A. Nanotechnology: small matter, many unknowns; 2004.

32. Iijima S. Helicle microtubule of graphite carbon. Nature; 1991.

33. Tomalia DA. Dendrimer as quantized building blocks for nanoscale synthetic organic chemistry. Aldrichimica Acta.; 2004.

34. Edward PT and Michele MS. Application of nanotechnology: A case study in the pharmaceutical area; 2004.

35. Nie S et al. Nanotechnology applications in cancer. Annu. Rev. Biomed. Eng.; 2007.

36. Grodzinski P et al. Nanotechnology for cancer diagnostics: promises and Challenges. Expert Rev. Mol. Diagn; 2006.

37. “Gold Nanorods Identify Metastatic Tumor Cells." National Cancer Institute; July 2007.

38. Physorg, “Gold nanoparticles may pan out as tool for cancer diagnosis." July 31, 2007.

Received on 16.07.2012 Modified on 02.08.2012

Research J. Pharm. and Tech. 5(9): September 2012; Page 1161-1167