Advances in nanotechnology for cancer therapeutics

There might be disease who commands even worse prognosis than various type of cancer, but evading all that, cancer still subjects to widespread fear and taboos, despite of constant research and urge to improve the diagnosis and treatment of it. Cancer in itself is a horrid disease and had expressed that consistently over last five decades or so. In a review generated by Globocon (experts in bioinformatics in cancer) it has been found that more than 10 million people are annually affected from various type of cancers, out of which breast cancer individually accounts for a whopping 25 per cent just behind cervical cancer (29 per cent). Breast cancer is characterized by uncontrolled growth of cells in the areas like - the ducts, the lobules and even in tissues between these two and known to develop by various multistep (0,I,II,III,IV) of carcinogenesis, developing from a berated cell signalling and makes it a highly incomprehensible and complex disease. In the early stages via dedicated research diagnosis of cancer has been developed based on identification of morphological characters of tumour cells via radiological and histopathological studies. Also the treatment was done via chemotherapy radiology or even surgery. However, breast cancer cannot be completely treated / cured beyond a certain stage of its development (stage II). This is the reason why early diagnosis and treatment of cancer remains a technological bottleneck. Apart from above mentioned methodologies of treatment, a new and fully potential field of nanotechnology offers a very effective diagnostic and treatment. ”Nanotechnology is primarily matter manipulation at atomic and molecular scale i.e. over a size range of 1-10 nm. In the perspective of breast cancer it is inter disciplinary subjects entailing the concepts and fundamentals of the field like science, engineering and medicine”

Primary requisite for cancer therapy is to achieve the desired drug concentration at tumour site and destroying cancer cells without damaging normal cells. Thus the whole process of nanotechnology is to develop single substances having potential of diagnosis and treatment of cancer, which can be done utilizing ligand targeted therapeutic strategies, immunotoxins, radioimmunotherapeutics and drug immunoconjugates. Targeted cancer therapy aims at ensuring that, the drug should reach the site of tumour without losing its constituent in circulation via Enhanced permeability and retention effect (EPM) by crossing complex biological membranes and also selectively kill tumour cells only. This needs to be done simultaneously with improvement in patient survival, increase in intracellular drug concentration and inducing dose-limiting toxicity. Nanoparticles delivery of drug at target sites of cancer is done by either passive targeting or active targeting.

Passive targeting
Passive targeting is primarily accumulation of drug/drug carrier system at desired sites utilizing physicochemical and pharmacological properties of drug. This method effectively increase drug bioavailability and efficacy as it makes use of anatomical and functional differences between normal and tumour vasculature. Tumour vasculature unlike normal vasculature have large gaps in between endothelial cells of blood vessels (600-800 nm) formed by process of angiogenesis in the preliminary stage of tumour development. This leaky properties is due to enhanced level of vascular mediators like bradykinin, nitrous oxide, prostaglandin. This leaky behaviour along with poor lymphatic drainage induces “Enhanced permeability and retention effect [EPR]” in tumour cells and in their environment.  Apart from this, certain hyperproliferative cells due to high metabolic rate causes increase acid production in their vicinity (by glycolysis) and brings down the pH-7.4

Active targeting
Active targeting approach involves coupling of drug with “homing” moiety like monoclonal antibody or ligand which delivers drug at pathological site via molecular recognition mechanism clearly different from passive targeting which depends upon EPR effect. While developing ternary drug complex of this potential following things should be considered, firstly corresponding antigen should be present exclusively on tumour cells, also they should respond against antigen specific present on all tumour cells, and lastly antigen-antibody complex should not be shed in the circulation.

Tools of nanotech

Liposomes: These are very versatile tool in biology, biochemistry and medicine. They are primarily aimed at drug delivery specific to the cancer cells. For example, Polyethyleneglycated (PEG) liposomal Doxorubicin and Daunorubicin. They have an added advantage of prolonged circulation as they have very miniscule plasma interaction or for that matter with macrophages. An extended effort is done to incorporate polyethyleneglycated immune-liposomes carrying expression gene that would aberrate the cell signaling and prevent the uncontrolled cell division.

Dendimers: This is an extensively branch molecule which can be moulded into any shape (sphere, square etc.) such that it is symmetric around the core.This type of structure makeup makes it a potential tool for nanotechnology especially in breast cancer as it can be used for site specific drug delivery and gene delivery. They can also be used for imaging purpose as they would help in determining the size and site of tumours.

Nanocantilivers: These are tools that primarily acts by analyzing and measuring biochemical and biomolecular interaction and is used extensively as a tool for diagnosis and genomic research. They include tiny bars engineered to be anchored at a site close to tumour tissue, they contain receptor on their surface which binds to altered DNA proteins generated by tumour cells of breast. This generates assigned by bend in nano-cantilever which can be optically measured. The extent of bent is an identification of amount of protein binding to receptors.

Carbon nanotubes: These are primarily allotropes of carbon with a cylindrical nanostructure have been constructed with length to diameter ratio up to 132,000,000:1.  These can also be used for diagnosis of breast cancer as it help in discriminating between different proteins present in serum samples and also in drug delivery. They are of two types Multiwalled Nanotubes (MWNTs) and Singlewalled Nanotubes (SWNTs). SWNTs has in particular a high applied absorbance i.e, in range of infrared, which might help in heating up and killing up of tumour cells of breast, which have selectively been inserted into nanotubes. Also, MWNTs has been used for bioimaging purposes, also drug incorporated into MWNTs show more effective internalization into cells than free drug.

Quantum dot: Quantum dot is a portion of matter whose exciters are certified into all dimensions. Their electronic properties is intermediate to semiconductor and discrete molecules, they have broad absorption and competently narrow emission range hence help in multicellular imaging with single excitation. They are completely resistant to photo bleaching. These properties make them perfectly suited for both diagnosis and drug targeting. They earlier were suspected to here a toxicological profile which was later completely dismissed.  Also surface can be engineered to improve QD, solubility sensitivity, and specificity, etc.

Polymeric micelle: Polymeric micelle is an arrangement of amphillic surfactant in a 3-D pattern such that the hydrophilic head is in centre and hydrophobic tail is passed out. This happens only when surfactant concentration exceeds critical micelle concentration. Doxorubicin load polymeric micelles have shown encouraging results against various types of tumours as it treats restenosis by accumulating vascular lesions, also antibody conjugated polymeric micelle (immuno micelles) having incorporated Taxol have selectively shown to bind to cancer cells in vivo.

Nanoparticles
Nanoparticles are submicron-sized colloidal particles with a therapeutic agent of interest encapsulated within their polymeric matrix or adsorbed or conjugated onto the surface. Nanoparticles are targeted to specific sites by surface modifications, which provide specific biochemical interactions with the receptors expressed on target cell. 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 . Recently, it has developed several different potential nanocarrier systems for the treatment of cancer, like  designing epithelial growth factor antibody-conjugated rapamycin-loaded nanoparticles and showed the enhanced efficacy of these formulated immunonanoparticles in MCF 7 breast cancer-cell line.

Nanotech-mediated novel cancer therapy
Nanotechnology-based gene therapy is based on the concept that specific exogenous genes can be incorporated into the tumour cell genome to produce a tumouricidal effect. It represents one of the most rapidly developing areas in preclinical and clinical cancer research. The problem associated with the viral vector is the toxicity, immune and inflammatory responses, gene control and targeting issue; in addition, there is always a fear of the virus recovering and causing disease. To overcome this, much interest has been shown in non-viral mediated gene transfer techniques. The advantage of using non-viral vectors is repeated administration at a very low cost and less immune reaction, owing to their non-toxicity. The most widely used non-viral vectors are liposome-mediated cationic polymers and nanoparticles. The physical properties of nanoparticles, including their morphology, size, charge density and colloidal stability, are important parameters for determining the overall efficacy of nanoparticles to act as potential nonviral gene delivery vehicles.

Nanotech-based photodynamic therapy
Nanotechnology-based photodynamic therapy involves the administration of a photosensitizing drug. PDT relies on activation of a photo sensitizer, which – when activated by a specific wavelength of light – induces the release of reactive oxygen species that can kill tumor cells.  Directly, as well as the tumor-associated vasculature, singlet oxygen is highly reactive. Polymeric nano particles offer a solution to this problem by enabling the delivery of a high quantity of photo sensitizers to tumor cells via tumor-specific ligands. Additional advantages of PDT are that it can be used repeatedly without producing immunosuppressive and myelosuppressive effects and can be administered even after surgery, chemotherapy or radiotherapy.

Nanotechnology-based radiotherapy andRadio frequency therapy deals with an  enhancement of radiation dose by high atomic number (Z) materials has long been of interest. It has been reported that loading high Z materials into the tumour could result in greater photoelectric absorption within the tumour than in surrounding tissues, and thereby enhance the dose delivered to a tumour during radiation therapy. Gold nanoparticles have been actively investigated in a wide variety of biomedical applications because of their biocompatibility and ease of conjugation to biomolecules. Although radiofrequency ablation has been used in the treatment of cancer, cardiac conduction abnormalities and neurological lesions, it is most commonly used in cancer therapies. Unresectable malignant hepatic lesions are the most common tumour treated; with this procedure.  Radiofrequency ablation is an established approach to destroying tumours that has traditionally involved the insertion of probes into tumours.

Nanotech-based cancer theragnostics
Combining diagnosis and therapy in one process is an emerging biomedical method referred to as theragnostics. The primary goal of theragnostics is to selectively target-specific (diseased) tissues or cells to increase diagnostic and therapeutic accuracy .With the help of theragnostics, we can bring together key stages of a medical treatment, such as diagnosis and therapy, and make a treatment shorter, safer and more efficient. Biocompatible nanoparticles are currently under development as cancer theragnostic agents that would enable non-invasive diagnosis and precise cancer therapy. Several recent reviews have proved that magnetic nanoparticles can simultaneously act as diagnostic molecular imaging agents and as drug carrier.

Micro RNAs (mi RNAS) are small, evolutionarily conserved, non-coding RNAs of 18–25 nucleotides in length that have an important function in gene regulation. Micro RNAs as cancer gene can be used as it was found that a mi RNA cluster was frequently deleted or down regulated in chronic lymphocytic leukemia. This discovery suggested that non-coding genes were contributing to the development of cancer, and paved the way for the closer investigation of mi RNA loss or amplification in tumours. Mi RNA as cancer classifiers is used as it was found that aberrant mi RNA levels reflect the physiological state of cancer cells and can be detected by mi RNA expression profiling and harnessed for the purpose of diagnosis and prognosis. mi RNAs as drugs and drug targets can be used owing to the ability of mi RNAs to simultaneously target multiple genes and pathways that are involved in cellular proliferation and survival.