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Nano technology is a multidisciplinary field, which recently has emerged as one of the most propitious field in cancer treatment. Nano technology is definitely a medical boon for diagnosis, treatment and prevention of cancer disease. It supports and expands the scientific advances in genomic and proteomics and builds on our understanding of the molecular underpinnings of cancer and its treatment. The various nanotechnological approaches in cancer treatment have been encompassed in the current article. One of them includes localized delivery of heat and the localized imaging of biological materials through nanoparticles. The delivery may be in vitro or in vivo and is useful for the localized treatment of cancer and disorders involving over proliferation of tissue. Other approach relates to a novel process of manufacture of nanoparticles of substantially water insoluble materials from emulsions. These emulsions have the ability to form a single liquid phase upon dilution of the external phase, instantly producing dispersible solid nanoparticles. The formed nanoparticles can be used in a wide range of therapeutic treatments of cancer. Additional approach comprises of solid tumors having an acidic extra cellular environment and an altered pH gradient across their cell compartments. Nanoparticles responsive to the pH gradients are promising for cancer drug delivery. Such pH-responsive nanoparticles consist of a corona and a core, one or both of which respond to the external pH to change their soluble/insoluble or charge states, thereby they have therapeutic advantages over the conventional pH-insensitive counterparts. An alternative advancement discloses a method/system utilizing interaction of electromagnetic pulses or ultrasonic radiation with nano- and micro particles for enhancement of drug delivery in solid tumors. These particles can be attached to antibodies directed against antigens in tumor vasculature and selectively delivered to tumor blood vessel wall. A widespread understanding of these new technologies can provide essential breakthroughs in the fight against cancer.
Keywords: Nanoparticles, cancer, dendrimers, nanoemulsion
In ancient Greek 'Nano' means dwarf1.Â Nano technology is the creation of useful materials, devices and systems through the manipulation of miniscule matter (including anything with at least one dimension less than 100 nanometers). The emerging field of nano technology involves scientists from many different disciplines, including physicists, chemists, engineers and biologists. R. P. Feynman, a physicist, initially used the Nanoscale. In his talk, 1959, called "There's plenty of room at the bottom. But there's not that much room - to put every atom in its place - the vision articulated by some nanotechnologists - would require magic fingers". He was one of the first people to suggest that scaling down to nano level and starting from the bottom was the key to future technology and advancement.2, 3
Tiny man-made nanoparticles have been used to successfully smuggle a powerful cancer drug into tumor cells leaving healthy cells unharmed. When tested in mice, the Nan structure-based therapy was 10 times as effective at delaying tumor growth and far less toxic than the drug given alone. Researchers believe the therapy could transform many cancers from killer into chronic, treatable diseases.4,5 The major goals in designing nanoparticles as a delivery system are to control particle size, surface properties and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutically optimal rate and dose regimen. Though liposome have been used as potential carriers with unique advantages including protecting drugs from degradation, targeting to site of action and reduction toxicity or side effects, their applications are limited due to inherent problems such as low encapsulation efficiency, rapid leakage of water-soluble drug in the presence of blood components and poor storage stability. On the other hand, polymeric nanoparticles offer some specific advantages over liposome. For instance, they help to increase the stability of drugs/proteins and possess useful controlled release properties. The purpose of the chemotherapy and radiation is to kill the tumor cells as these cells are more susceptible to the actions of these drugs and methods because of their growth at a much faster rate than healthy cells, at least in adults. Research efforts to improve chemotherapy over the past 25 years have led to an improvement in patient survival but there is still a need for improvement.6, 7 Current research areas include development of carriers to allow alternative dosing routes, new therapeutic targets such as blood vessels fueling tumor growth and targeted therapeutics that are more specific in their activity. Several nano biotechnologies mostly based on nanoparticles, have been used to facilitate drug delivery in cancer. The magic of nanoparticles mesmerizes everyone because of their multifunctional character and they have given us hope for the recovery from this disease. Although we are practicing better drug delivery paths into the body, we ultimately seek more accurate protocols to eradicate cancer from our society.Â This review will primarily address new methods for delivering drugs, both old and new, with a focus on nano particle formulations and ones that specifically target tumors.
The Vision for Nano particles in the Treatment of Cancer:
Nano technology is the creation and utilization of materials, devices, and systems through the control of matter on the nanometer-length scale, i.e. at the level of atoms, molecules, and supramolecular structures8. These technologies have been applied to improve drug delivery and to overcome some of the problems of drug delivery for cancer treatment. Several nanobiotechnologies mostly based on Nan particles, have been used to facilitate drug delivery in cancer. The magic of Nan particles mesmerizes everyone because of their multifunctional character and they have given us hope for the recovery from this disease. Although we are practicing better drug delivery paths into the body, we ultimately seek more accurate protocols to eradicate cancer from our society. This review focuses on progress in treatment of cancer through delivery of anticancer agents via Nan particles. In addition, it pays attention to development of different types of Nanoparticles for cancer drug delivery.
The general mechanism metaphorically represents the popular Trojan horse trickery. It is based on the principle that all living cells require folic acid to replicate but cancer cells have particularly strong appetite for it, displaying up to 1000 more docking sites called folate receptors on their membranes. By attaching five folic acid molecules to branches of the dendrimer, the researchers were able to lure the cancer cells into accepting the whole package across the membrane and into the cell including the toxic drug, which then kills of the cell. The approaches stated henceforth are the most recent Nan particle advancements used in cancer treatment: 9
Thermal approach of nanoparticles
This method has primary goal of curing cancer growth by producing heat. It is a further object of the present invention to provide methods for using these materials which are minimally invasive and efficacious without systemic side effects8. In the therapeutic embodiment, methods are described in which particles are administered to cells and/or tissue, which upon their exposure to light, effect the in vitro or in vivo, local heating of their immediate environment. In the preferred embodiment, the particles consist of a dielectric or semiconductor core and a conducting shell, the dimension of the particles is on a scale of tens to hundreds of nanometers, and the radiation used is infrared radiation, this preferred embodiment is used to treat cancer10,11. In an alternative embodiment, the method is applied to treat non-malignant tumors. In either of these embodiments, the method may be the sole method or it may be used in combination with another therapy. The nanoparticles consist of a silica core and a gold shell. In an alternative embodiment, the nanoparticles consist of a gold sulfide core and a gold shell12. In a further embodiment of the general method, the nano particles are targeted to a desired location through the use of appropriate chemical schemes. In the preferred embodiment, antigen-antibody binding is used for targeting.13, 14
According to this aspect, this invention provides a method of making nanoparticles of substantially insoluble water compounds and more specifically, nanoparticles of a water insoluble pharmaceutical compound (or "drug") from an emulsion in which a solution of said material forms the globules of the dispersed phase. These emulsions are readily transformed into a single uniform liquid phase, in which nanoparticles of the diagnostic or therapeutic agent are suspended, upon further dilution with the external or continuous phase. The resulting dispersed solid nanoparticles are generally less than 200 nm average diameters. The approach of miniemulsion can also be employed in cancer treatment. Miniemulsion polymerization process is typically preformed by subjecting a system of monomer, water, surfactant and a highly water insoluble compound, so-called hydrophobe, to high shear fields. In the present invention, comparing with nanoparticles prepared by emulsion polymerization, poly (n-butyl cyanoacrylate) (PBCA) nanoparticles prepared by miniemulsion polymerization process are higher loading and encapsulation efficiencies for hydrophobic monomers, such as paclitaxel and flutamide. An advantageous feature of this invention is that therapeutic or diagnostic nanoparticles so produced can be utilized for intravascular injections to treat systemic diseases. Another advantageous feature is that extra vascular injections containing these particles can provide controlled release of the drug at the site of injection for prolonged drug effects, and minimize multiple dosing. Yet another advantage of this invention is improved drug transport across absorption barriers such as mucosal gastrointestinal barriers, nasal, pulmonary, ophthalmic, and vaginal membranes, and other distribution barriers, such as the blood--tissue and blood--tumor barriers of various organs and tissues. For example, anti-cancer nanoparticles of less than 50 nm diameter can migrate through the compromised, more permeable vascular bed to reach tumor tissues. Once the nanoparticles are in the tumor tissue they will provide local cytotoxic action against the tumor cells. In the case of highly protected organs such as the brain, with its tight vascular bed surrounding the normal tissues, drug nanoparticles will preferentially concentrate in the tumor tissue, with minimal or no toxicity to the healthy brain tissue. A further advantage of this invention is the improved oral bioavailability of poorly absorbed drugs.15
pH responsive nanoparticles
Solid tumors have an acidic extracellular environment and an altered pH gradient across their cell compartments. Nanoparticles responsive to the pH gradients are promising for cancer drug delivery. Such pH-responsive nanoparticles consist of a corona and a core, one or both of which respond to the external pH to change their soluble/insoluble or charge states [16-18]. Nanoparticles whose coronas become positively charged or become soluble to make their targeting groups available for binding at the tumor extracellular pH have been developed for promoting cellular targeting and internalization. Nanoparticles whose cores become soluble or change their structures to release the carried drugs at the tumor extracellular pH or lysosomal pH have been developed for fast drug release into the extracellular fluid or cytosol. Such pH-responsive nanoparticles have therapeutic advantages over the conventional pH-insensitive counterparts. The novel core-shell polymer nanoparticles are designed with their lower critical solution temperature (LCST) being dependent on the ambient pH. This value is above the nominal physiological temperature of 37Â°C at pH 7.4, but decreases to a temperature below the physiological temperature with a small decrease in pH. The resulting change in LCST causes the core-shell nanoparticles to deform and precipitate in an acidic environment, triggering the release the chemotherapeutics at low pH. In addition, a biological signal has been conjugated to the shell of the nanoparticles, which can recognize tumor cells. This system may be able to target drugs to tumor cells and release the drugs intracellularly.19-22
Nanoparticles used in combination with radiations
The present invention discloses a method/system utilizing interaction of electromagnetic pulses or ultrasonic radiation with nano- and microparticles for enhancement of drug delivery in solid tumors. These particles can be combined to antibodies to target the antigens existing in the tumor vasculature. Cavitation induced by ultrasonic waves or local heating of the particles by pulsed electromagnetic radiation results in perforation of tumor blood vessels, microconvection in the interstitium, and perforation of cancer cell membrane, and therefore, provides enhanced delivery of macromolecular therapeutic agents from blood into cancer cells with minimal thermal and mechanical damage to normal tissues.23-25
Drug Delivery For Cancer Treatment:
Core features of cancer cell
-Abnormal growth control
- Improved cell survival
-Unlimited replicated potential
Transport of an anticancer drug in interestium26 will be governed by physiological (i.e. pressure) and physiochemical (i.e. composition, structure and charge) properties of the interestium and by the physiochemical properties of molecules (size, configuration, charge and hydrophobicity) itself. Thus, to deliver27 therapeutic agents to tumor cells in vivo, one must overcome the following problems:
Â·Â Drug resistance at the tumour level due to physiological barriers (non cellular based mechanisms)
Â·Â Drug resistance at the cellular level (cellular mechanisms),
Â·Â Distribution, biotransformation and clearance of anticancer drugs in the body.
A strategy could be to associate antitumor drugs with colloidal nanoparticles, with the aim to overcome non-cellular and cellular based mechanisms of resistance and to increase selectivity of drugs towards cancer cells while reducing their toxicity towards normal tissues. There are different drug delivery strategies that have been used to fight with cancer which are discussed in this paper.
Drug Delivery Strategies Used To Fight Cancers:
There are a variety of different delivery strategies28 that are either currently being used or are in the testing stage to treat human cancers which are discussed in this paper.
TABLE 1 : Table for Different drug delivery strategies.
Various methods for cancer treatment:
Direct Introduction of anticancer drugs into tumour
Injection Directly into the tumour
Tumour necrosis therapy
Injection into the arterial blood supply of cancer
Local injection into the tumour for radiopotentiation
Localized delivery of anticancer drugs by electroporation (Electrochemotherapy)
Local delivery by anticancer drugs implants
Routes of Drug delivery
Subcutaneous injection or implant
Transdermal drug delivery
Vascular route: intravenous, intra-arterial
Systematic delivery targeted to tumour
Heat-activated targeted drug delivery
Tissue-selective drug delivery for cancer using carrier-mediated transport systems
Tumour-activated prodrug therapy for targeted delivery of chemotherapy
Pressure-induced filtration of drug across vessels to tumour
Promoting selective permeation of the anticancer agent into the tumour
Two-step targeting using bispecific antibody
Site-specific delivery and light-activation of anticancer proteins
Drug delivery targeted to blood vessels of tumour
Drugs to induce clotting in blood vessels of tumour
Vascular targeting agents
Special formulations and carriers of anticancer drugs
Albumin based drug carriers
Delivery of proteins and peptides for cancer therapy
Fatty acids as targeting vectors linked to active drugs
Pegylated liposome's (enclosed in a polyethylene glycol bilayer)
Polyethylene glycol (PEG) technology
Single-chain antigen-binding technology
Transmembrane drug delivery to intracellular targetsÂ
Transduction of proteins and Peptides
Vitamins as carriers for anticancer agents
Genetically modified bacteria
Pathways For Nanoparticles In Cancer Drug Delivery:
Nanotechnology has tremendous potential to make an important contribution in cancer prevention, detection, diagnosis, imaging and treatment. It can target a tumor, carry imaging capability to document the presence of tumor, sense pathophysiological defects in tumor cells, deliver therapeutic genes or drugs based on tumor characteristics, respond to external triggers to release the agent and document the tumor response and identify residual tumor cells. Nanoparticles are important because of their nanoscaled structure but nanoparticles29 in cancer are still bigger than many anticancer drugs. Their "large" size can make it difficult for them to evade organs such as the liver, spleen, and lungs, which are constantly clearing foreign materials from the body. In addition, they must be able to take advantage of subtle differences in cells to distinguish between normal and cancerous tissues. Indeed, it is only recently that researchers have begun to successfully engineer nanoparticles that can effectively evade the immune system and actively target tumors. Active tumor targeting of nanoparticles involves attaching molecules, known collectively as ligands to the outsides of nanoparticles. These ligands are special in that they can recognize and bind to complementary molecules, or receptors, found on the surface of tumor cells. When such targeting molecules are added to a drug delivery nanoparticle, more of the anticancer drug finds and enters the tumor cell, increasing the efficacy of the treatment and reducing toxic effects on surrounding normal tissues. Although the past 30 years of innovation in nanotechnology has removed much of the "magic" to yield 21st century "smart bombs" capable of carrying a whole host of new anticancer drugs directly to tumors, we are still searching for the ideal delivery nanosystem. Nanotechnology studies30 are not new. In essence, all drug molecules can be considered as Nanoengineered structures. What is new is the inclusion of a number of other nano-based approaches to medical studies.
Future Herbal Nanoparticles For Cancer:
The whole world is practicing herbal medicine to avoid maximum side effects and for better treatment. The science of Ayurveda31 is supposed to add a step on to curative aspects of cancers. There are many herbs like Aswagandha, Amla, Basil, Rakta vrntaka (Tomato), Neem, Turmeric etc with anticancerous properties. Antioxidants play an important role in mitigating the damaging effects of oxidative stress on cells. Lycopene, a carotenoid, has received considerable scientific interest in recent years. They have demonstrated a very special role in the curing of cancer. In the past several years, two lines of emerging evidence have supported a role for lycopene in the prevention of certain malignancies, especially prostate cancer32 Tomato is a rich source of lycopene. The first, antioxidant properties of lycopene (Lycopersicon esculentum) have been established33,34. Given the relatively high concentrations of lycopene in the tissues of many individuals, and the potential role of oxidative stress in the formation or progression of cancers, a potential anticancer influence of lycopene has been hypothesized. Secondly, a number of epidemiologic studies have suggested that individuals with a relatively high intake of lycopene, particularly from tomato products, have a lower risk of prostate cancer.35,36 In the future, the concept of herbal nanoparticles for cancer drug delivery may also fascinate some potential research groups and potentially create attention-grabbing results.
Development And Commercialization Of Nanomaterials:
Drug delivery techniques were established to deliver or control the amount, rate and, sometimes location of a drug in the body to optimize its therapeutic effect, convenience and dose. Combining a well established drug formulation with a new delivery system is a relatively low risk activity and can be used to enhance a company's product portfolio by extending the drug's commercial life-cycle. Although not exhausting, this is a representative selection reflecting current industrial trends. Most companies are developing pharmaceutical applications, mainly for drug delivery. Most major and established pharmaceutical companies have internal research programs on drug delivery that are on formulations or dispersions containing components down to nano sizes. With the total global investment in nanotechnologies currently at â‚¬ 5 billion, the global market is estimated to reach over â‚¬ 1 trillion by 2011-2015. Nano and Micro technologies are part of the latest advanced solutions and new paradigm for decreasing the discovery and development time for new drugs and potentially reducing the development costs.Â
Companies Involved With The Commercialization Of Nanomaterials For Bio- And Medical Applications:
Examples of companies37 commercializing nanomaterials for bio- and medical applications are given in Table.
Table 2 . Companies commercializing nanomaterials for bio- and medical applications.
Major area of activity
Advectus Life Science Inc.
Polymeric nanoparticles engineered to carry anti-tumor drug across the blood-brain barrier
Alnis Biosciences,Â Inc.
Biodegradable polymeric nanoparticles for drug delivery
Nanoporous ceramic materials for endotoxin
Biophan Technologies, Inc.
Nanomagnetic /carbon composite materials to shield medical devices from RF fields
Capsulation Nanoscience AG
Pharmaceutical coating to improve solubility of drugs
Layer-by-layer poly-electrolyte coating, 8-50 nm
Reducing size of the drug particles to 50-100 nm
Semiconductor quantum dots with amine or carboxyl groups on the surface, emission from 350-2500 nm
Tracking and separation of different cell type
Magnetic core surrounded by a polymeric layer coated with antibodies for capturing cell
Antimicrobial nano emulsions
NanoCarrier Co., Ltd
Micellar nanoparticles for encapsulation of drugs, proteins, DNA
Polybutyilcyanocrylate nanoparticles are coated with drug and then with surfactant can go across the blood brain barrier
Gold nanoparticles for biological markers
Gold nanoparticles bio-conjugates for TEM and/or fluorescent microscopy
DNA barcode attached to each nanoprobes for identification purposes, PCR used to amplify the signals, also catalytic silver deposition to amplify the signal using surface plasmon resonance
NanoMed Pharmaceutical, Inc.
Nanoparticles for drug delivery
Tools Of Nanotechnology: 38, 39
Some of the tools of nanotechnology having applications in cancer treatment are the following:
Cantilevers: Tiny bars anchored at one end can be engineered to bind to molecules associated with cancer. These molecules may bind to altered DNA proteins that are present in certain types of cancer monitoring the bending of cantilevers; it would be possible to tell whether the cancer molecules are present and hence detect early molecular events in the development of.
Nanopores: Nanopores (holes) allow DNA to pass through one strand at a time and hence DNA sequencing can be made more efficient. Thus the shape and electrical properties of each base on the strand can be monitored. As these properties are unique for each of the four bases that make up the genetic code, the passage of DNA through a nano pore can be used to decipher the encoded information, including errors in the code known to be associated with cancer.
Nanotubes: Nanotubes are smaller than Nanopores. Nanotubes & carbon rods, about half the diameter of a molecule of DNA, will also help identify DNA changes associated with. It helps to exactly pin point location of the changes. Mutated regions associated with cancer are first tagged with bulky molecules. Using a nano tube tip, resembling the needle on a record player, the physical shape of the DNA can be traced. A computer translates this information into topographical map. The bulky molecules identify the regions on the map where mutations are present. Since the location of mutations can influence the effects they have on a cell, these techniques will be important in predicting disease.
Quantum Dotes (QD): These are tiny crystals that glow when these are stimulated by ultraviolet light. The latex beads filled with these crystals when stimulated by light, the colors they emit act as dyes that light up the sequence of interest. By combining different sized quantum dotes within a single bead, probes can be created that release a distinct spectrum of various colors and intensities of lights, serving as sort of spectral bar code.
Nanoshells (NS): These are another recent invention. NS are miniscule beads coated with gold. By manipulating the thickness of the layers making up the NS, the beads can be designed that absorb specific wavelength of light. The most useful nanoshells are those that absorb near infrared light that can easily penetrate several centimeters in human tissues. Absorption of light by nanoshells creates an intense heat that is lethal to cells. Nanoshells can be linked to antibodies that recognize cancer cells. In laboratory cultures, the heat generated by the light-absorbing nanoshells has successfully killed tumor cells while leaving neighboring cells intact.
Dendrimer: A number of nanoparticles that will facilitate drug delivery are being developed. One such molecule that has potential to link treatment with detection and diagnostic is known as dendrimer. These have branching shape which gives them vast amounts of surface area to which therapeutic agents or other biologically active molecules can be attached. A single dendrimer can carry a molecule that recognizes cancer cells, a therapeutic agent to kill those cells and a molecule that recognizes the signals of cell death. It is hoped that dendrimers can be manipulated to release their contents only in the presence of certain trigger molecules associated with cancer. Following drug releases, the dendrimers may also report back whether they are successfully killing their targets.Â The technologies mentioned above are in the various stages of discovery and development. Some of the technologies like quantum dots, nano pores and other devices may be available for detection and diagnosis and for clinical use within next ten years.
Challenges Of Technology
Today, much of the science on the nanoscale is basic research, designed to reach a better understanding of how matter behaves on this small scale. The surface area of nano-materials being large, the phenomena like friction and sticking are more important than they are in large systems. These factors will affect the use of nanomaterials both inside and outside the body. Nanostructures being so small; the body may clear them too rapidly to be effective in detection or imaging. Larger nanoparticles may accumulate in vital organs, creating a toxicity problem.
Composition and method for cancer treatment using targeted single walled carbon nanotubes.40
Composition and methods of RNAi therapeutics for treatment of cancer and other neovascularization diseases.41
Nanoparticulate compositions of angiogenesis inhibitors.42
Gamma radiation sterilized nanoparticulate docetaxel compositions and methods of making same.43
Methods of enhancing radiation effects with metal nanoparticles.44
Tumor environment-induced ligand-expressing nanocarrier system.45
Nanoparticulate sorafenibÂ formulations.46
Delivery system for diagnostic and therapeutic agents.47
Methotrexate-modified nanoparticles and related methods.48
Nanotechnology will radically change the way we diagnose, treat and prevent cancer to help meet the goal of eliminating suffering and death from cancer. Although most of the technologies described are promising and fit well with the current methods of treatment, there are still safety concerns associated with the introduction of nanoparticles in the human body. These will require further studies before some of the products can be approved. The most promising methods of drug delivery in cancer will be those that combine diagnostics with treatment. These will enable personalized management of cancer and provide an integrated protocol for diagnosis and follow up that is so important in management of cancer patients. There are still many advances needed to improve nanoparticles for treatment of cancers. Future efforts will focus on identifying the mechanism and location of action for the vector and determining the general applicability of the vector to treat all stages of tumors in preclinical models. Further studies are focused on expanding the selection of drugs to deliver novel nanoparticle vectors. Hopefully, this will allow the development of innovative new strategies for cancer cures.
Acknowledgements: On behalf of all authors I would like to thank our Director, Dr.K.Pundarikakshudu for constant encouragement for good publications.