|Year : 2015 | Volume
| Issue : 1 | Page : 1-9
Unique roles of nanotechnology in medicine and cancer-II
F Alam, M Naim, M Aziz, N Yadav
Department of Pathology, J.N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
|Date of Web Publication||3-Feb-2016|
Department of Pathology, J.N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Applications of nanotechnology in medicine and cancer are becoming increasingly popular. Common nanomaterials and devices applicable in cancer medicine are classifiable as liposomes, polymeric-micelles, dendrimers, nano-cantilevers, carbon nanotubes, quantum dots, magnetic-nanoparticles, gold nanoparticles (AuNPs) and certain miscellaneous nanoparticles. Here, we present review of the structure, function and utilities of the various approved, under trial and pretrial nanodevices applicable in the cancer care and medicine. The liposomes are phospholipid-vesicles made use in carrying drugs to the target site minimizing the bio-distribution toxicity and a number of such theranostics have been approved for clinical practice. Newly worked out liposomes and polymeric micelles are under the trail phases for nano-therapeutic utility. A multifunctional dendrimer conjugate with imaging, targeting and drug molecules of paclitaxel has been recently synthesized for cancer theranostic applications. Nano-cantilever based assays are likely going to replace the conventions methods of chemical pathological investigations. Carbon nanotubes are emerging for utility in regenerative and cancer medicine. Quantum dots hold great promise for the micro-metastasis and intra-operative tumor imaging. Important applications of magnetic nanoparticles are in the cardiac stents, photodynamic therapy and liver metastasis imaging. The AuNPs have been employed for cell imaging, computed tomography and cancer therapy. Besides these categories, miscellaneous other nanoparticles are being discovered for utility in the cancer diagnosis and disease management. However, the use of nanoparticles should be cautious since the toxic effects of nanoparticles are not well-known. The use of nanoparticles in the clinical practice and their toxicity profile require further extensive research.
Keywords: Cancer, clinical applications, nanoparticles, theranostic
|How to cite this article:|
Alam F, Naim M, Aziz M, Yadav N. Unique roles of nanotechnology in medicine and cancer-II. Indian J Cancer 2015;52:1-9
| » Introduction|| |
Applications of nanotechnology in various disciplines of medicine particularly cancer care are becoming increasingly popular so much so that the process of replacing traditional health-care by nanomedicine had already begun. Nanomedicine focuses on the formulations of imaging, diagnostic and therapeutic agents, which can be carried by biocompatible nanoparticles, for the purpose of cancer/disease management. One of the major advantages, which nanomedicine offers is the specific site targeted delivery of the theranostic agents, lowering the risk of toxicity to the normal tissues around the lesion and other organs of the patient. The scientific basis of the nanoparticle utilities in cancer medicine had been earlier reviewed. Nanomaterials and devices, which have been worked out and presently applicable in cancer/disease imaging, diagnosis and therapy (theranostics) are classifiable on the basis of the carrying nanoparticles as liposomes, polymeric-micelles, dendrimers, nano-cantilevers, carbon nanotubes, quantum dots, magnetic-nanoparticles, gold nanoparticles (AuNPs) and miscellaneous nanoparticles based nano-theranostic products. Here, we present review of the structure, function and utilities of the various approved, under trial and pretrial nanodevices applicable in the cancer care and medicine.
| » Liposomes|| |
The liposomes are 50-100 nm size, single or multi lamellar phospholipid-vesicles having anionic, cationic or neutral charges and composed of lipid layers surrounding a central aqueous space or core., The nanoliposomes are used for encapsulating the lipophilic and hydrophilic drugs within their lipid layers or in the aqueous core, for delivery to the specific target site, thus, minimizing bio-distribution toxicity. Liposome based theranostics have advantages of cell specific targeting, pH and reductive environmental sensitivity, temperature sensitivity and long circulation half-life due to the surface modifiable lipid composition. However, there are issues of stability, batch to batch reproducibility and sterilization limiting their wider utilities. Liposome based theranostic products had been in a good number approved for the clinical practice and now widely used for cancer/diseases managements [Table 1], besides the new ones, which are under trail [Table 2].
|Table 1: The liposome based nanodrugs available in the clinical practice in cancer care|
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| » Polymeric Micelles|| |
These are nanoparticles of 10-100 nm size made up of polymer chains having a hydrophobic or ionic core and shell structure capable of carrying the drug, diagnostic, or imaging molecules and the shell is capable of interacting for stability in the fluid vehicle. The lipophilic anticancer drugs, as paclitaxel, although potent microtubule growth inhibitor but has low water solubility (0.0015 mg/ml), therefore, on intravenous (i.v.) administration may undergo rapid drug aggregation and cause capillary embolisms. By encapsulation of such drugs in micelles, the solubility may be increased to the magnitude of 0.0015-2 mg/ml to prevent drug aggregation and embolism., Polymeric micelles are presently under the trails for use in nanotherapy [Table 3].
|Table 3: The polymeric micelles based nanodrugs in the clinical use*/and under trial|
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| » Dendrimers|| |
The dendrimers are polymers of regularly branched macromolecules measuring 2-10 nm in size and spherical in shape. Dendrimers having an isohydrophillic end-group like a carboxyl group are water soluble. Dendrimers are easily modifiable and can be loaded with drugs in their core cavities through hydrophobic interactions, hydrogen bonds, or chemical linkages. It is also possible to design a water-soluble dendrimer with internal hydrophobicity allowing it to carry a hydrophobic drug in its interior. The most commonly studied system has been the family of polyamidoamine dendrimers, but the list of the variety of building blocks is fast growing. A multifunctional dendrimer conjugated with imaging molecule of fluorescein isothiocyanate, folate receptor expressing cancer cell targeting molecule of folic acid and chemo-therapeutic drug molecule of paclitaxel was recently synthesized for cancer theranostic applications. The amino groups were partially acetylated to improve the solubility and to prevent its non-specific targeting and the functionalities (imaging agent, biomarker and drug) were conjugated to the residual non-acetylated primary amino groups. Fluorescein was attached using thiourea bond while folic acid was covalently conjugated via condensation reaction between the γ-carboxyl group of the folic acid and the primary amino group of the dendrimer. Finally, paclitaxel was attached-covalently through an ester bond to facilitate easy cleavage. This dendrimer-conjugate acted as a pro-drug that remains inactive until the drug is released from the carrier. The remaining primary amino groups were converted to-OH to prevent nonspecific targeting during delivery. Drug-free dendrimers were not cytotoxic in vitro and the drug-loaded dendrimers had no effect on folate receptor-negative cells. Dendrimers conjugation; thus may minimize the methotraxate toxicity limiting the toxic drug release from the conjugate in the intercellular compartment of the targeted cell. Methotrexate-carrying dendrimers recognizing the cells expressing the folate receptors had in vivo demonstrated successful targeted drug delivery to the cancer cells. These dendrimer conjugates also carried fluorescein as a tracking or imaging agent in addition to the desired drug and biomarker. Dendrimers conjugates are presently under the focus for theranostic applications in the cancer/disease managements [Table 4] and [Table 5].,
|Table 4: The dendrimer drug carriers in the preclinical developmental stage|
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|Table 5: The dendrimer nano applications as MRI contrast agents under preclinical development|
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| » Nanocantilevers|| |
The nanocantilevers are lithographic semi-conductors producing flexible microscopic beams resembling a row in the diving boards. Cantilevers may be coated with the molecules for detection by the microarray methods, providing indispensable tool for detection of cancer expressions, molecular diagnosis and genome research and drug discovery. The tiny bars anchored at one end of cantilever can be engineered to bind diagnostic molecules, which in turn may bind to the specific deoxyribonucleic acid (DNA) proteins expressed by certain types of cancer. When this bio-specific interaction occurs between a receptor immobilized on the cantilever and a ligand in solution, the cantilever bends, which is detectable optically to tell whether cancer molecules are present, thereby, helps early molecular diagnosis of cancer. The deflection of cantilever beam depends on the amount of DNA protein bound to the cantilever surface. The deflection can be observed directly using laser light or by measurement of perturbations in their resonant vibration frequency. Wu γ, used micro-cantilevers to detect single-nucleotide polymorphisms in a 10-mer DNA target oligonucleotide without the use of extrinsic fluorescent or radioactive labeling. They coated the surface of the micro-cantilever with antibodies specific to prostate specific antigen (PSA) a prostate cancer marker found in the blood of the patient having prostate cancer. When the PSA-coated micro-cantilever was made to interact with the blood sample of the prostate cancer patient the antigen antibody complex formed and the cantilever bent due to the adsorbed mass of the antigen antibody complex molecules. The nanometer bending of cantilever was detected optically by a low power laser beam with sub-nanometer precision using a photo detector. This nanocantilever based assay was more sensitive than the conventional biochemical techniques for detection of PSA and could detect antigen levels lower than the clinically relevant threshold value. The technique is good and potentially better than enzyme-linked immunosorbent assay. Moreover, the cost per assay is less as there are no requirements for any fluorescent tags or radiolabel molecules. The break through potential of the nanocantilevers lie in their extraordinary multiplexing capability. The cantilevers presently under the focus for utility in nanomedicine are shown below [Table 6].
|Table 6: Cantilever applications relating medicine and cancer presently under the focus|
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| » Carbon Nanotubes|| |
CNTs are fibrous carbon materials with cylindrical structure of the nanometer size. Each cylinder comprises of a rolled graphene sheet having honeycomb arrangements of benzene rings oriented in the same plane. CNTs made of single graphene sheet (single walled) and several graphene-sheets (multi walled) have high mechanical strength, thermal resistance, electrical and thermal conductivities and large surface useful for specific binding of the medicine, peptide and nucleic acid molecules., The functionalized CNTs can permeate cell membranes by mechanisms like the endocytosis for intracellular targeting. For these novel characteristics, CNTs have utility in the scaffolds to artificially develop the cells and tissues for a cure of the disease injured organs in regenerative medicine. Appropriate scaffolds are required for regeneration of specific tissues and organs with respect to required cells, genes and proteins, cytokines, or growth factors expressions etc. There have been several previous reports regarding such scaffolds. The vascular endothelial cells show proliferation and also regulate thrombo-genesis on the CNT-polycarbonate-urethane composite scaffolds. CNTs scaffolds have been used for neuronal proliferation. CNT-polycarbonate urethane composite films have shown good results for chondrocytes adhesion and cartilage regeneration. Combinations of collagen with CNTs improved the properties of the scaffolds. The CNTs may also be useful for strengthening and extending the lives of different biomaterials used in various orthopedic procedures. The CNTs are also useful as enhancers of existing biomaterials in the cancer diagnosis and therapy.,,,,,,,,,,
There is scope for improving sensing capabilities of the markers such as PSA, carcino-embryonic antigen, carbohydrate antigen 19-9 and alpha-fetoprotein, by use of CNTs, for quick sensing of the earliest evolving cancer-cells.,,,,,,, The high near-infrared optical absorbance of single-wall CNTs under laser irradiation produces heat useful for thermo-therapeutic destruction of the selectively CNT internalized cancer cells. CNTs, thus, are emerging as the nano-applications of great utility in the regenerative and cancer medicine [Table 7].
|Table 7: The carbon nanotubes based applications used in regenerative medicine|
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| » Quantum Dots|| |
QD is spherical crystalline semiconductor nanoparticle of <10 nm size made of 200-1000 atoms. Structurally QD consists of a semiconductor core coated by shell having optical properties, covered by a cap enabling solubility in the aqueous buffers. The proto-type QD has been cadmium selenide. Recently, QDs have attracted research attention in view of their scientific and technological applications in microelectronics, optoelectronics and cell imaging.,,,
These semiconductors are characterized by composition-dependent band-gap energy. The band-gap energy is the minimal-energy required to excite an electron from its orbit to a higher level. As the election relaxes and returns back to the ground orbit, a photon gets emitted, leading to a visible fluorescence. The band gap energy is dependent on the size of the semiconductor nanoparticle; hence the optical characteristics of QD can be tuned by adjusting its size. Increase in the QD size improves optical penetration of the tissue and reduces the background fluorescence at near infrared wave lengths. The QDs demonstrate 10-100 times improved signal brightness, compared with the other fluorescent proteins and organic dyes. They also display greater resistance against photo-bleaching; thus, affording longer stability to the probes. In addition, single QD light source is capable of exciting multiple expressions simultaneously producing different identifiable fluorescence colors. This broad absorption and narrow emission characteristics of the QDs, make it possible, to perform multicolor imaging with a single excitation source. QD imaging have been used for detection of breast cancer metastasis/micro-metastasis, pancreatic cancer, ovarian cancer and prostate cancer.,, The QDs can directly transfer energy to oxygen by photodynamic reactions, but, act better synergistically in conjugation with routine photosensitizers used for photodynamic therapy of cancer cells. QDs may also be used as versatile nano-scale scaffolds for designing multifunctional imaging cum therapeutic nanoparticles. The QDs because of their intense fluorescent signals and multiplexing capabilities also hold great promise for intra-operative tumor imaging [Table 8].
| » Magnetic Nanoparticles|| |
These are magnetic nanomaterials. The iron oxides either magnetite (Fe3O4) or maghemite (γ- Gamma-Fe2O3) are the most often used magnetic nanoparticles (10-100 nm) size used in the biomedical operations. One of their main envisaged applications has been the targeted chemotherapeutic-drug delivery to the tumors. Magnetic nanoparticles coated with the drug are injected intravenously and can be retained at the tumor site by application of an external magnetic field gradient, to ensure requisite prolonged release of drug at the tumor site., An important extension of this technique is the use of implanted magnetized cardiac stents., Another interesting therapeutic application is in the field of cancer hyperthermic  and photodynamic therapy. The super-paramagnetic nanoparticles are useful contrast agents for magnetic resonance imaging (MRI) to better enhance the image-contrast between normal and diseased tissue and indicate the status of organ function and blood flow. Small super-paramagnetic iron oxides have been developed for use in imaging of the liver metastases and to distinguish loops of bowel from the other abdominal structures. Magnetic nano applications presently under consideration in cancer medicine are listed below [Table 9].
|Table 9: Magnetic nanoparticle applications under clinical trials currently, and available in the market for use|
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| » AuNPs|| |
AuNPs particles of <50 nm size are versatile nanoparticles and can be prepared in the different geometries such as nanospheres, nanoshells, nanorods and nanocages. These are widely used as conjugates for attaching the oligonucleotides, antibodies and proteins etc., for the biotechnological applications. On binding with the analytes the physicochemical properties of AuNPs such as surface plasmon resonance (SPR), conductivity and the redox behavior are altered leading to detectable signals. They are also useful as platforms for therapeutic agents due to their high surface area allowing binding of drugs and targeting agents. The spherical AuNPs have better useful attributes of size-shape related opto electronic properties, surface-to volume ratio, SPR, efficiency to quench fluorescence, excellent biocompatibility, low toxicity, range of colors (brown, orange, red and purple) in aqueous solution with the increase of core-size 1-100 nm and size relative absorption peak at 500-550 nm. The AuNPs play a critical role in the “bio-barcode assay,” which is an ultra-sensitive method for detecting the target proteins and nucleic acids. The optical and electronic properties of AuNPs have been employed for cell imaging using the computed tomography (CT), dark-field light scattering, optical coherence tomography (OCT), photothermal heterodyne imaging and Raman spectroscopy techniques. AuNPs based therapy is usable both by the passive and active targeting mechanisms. Effective targeting and delivery strategies using AuNPs have been developed for therapeutic applications in photothermal therapy, genetic regulation and drug treatment. AuNPs have also been exploited as attractive large surface area scaffolds for making transfection agents for gene therapy of cancer and genetic disorders. Loading of drugs onto AuNP can be done either by non-covalent interactions or covalent conjugation. AuNPs, thus, are incredibly materials for the next generation biomedical applications [Table 10] and [Table 11]..
|Table 10: Biomedical applications of different types of gold nanoparticles|
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| » Other Miscellaneous Nanoparticles|| |
Other nanoparticles are also under investigations for diagnostic and therapeutic nano carrying capabilities. Drugs conjugated with the polysorbate-80 coated poly butyl cyanoacrylate nanoparticles can be easily transported across the blood-brain barrier, enabling the drug targeting to brain. Epithelial growth factor antibody-conjugated rapamycin-loaded polymeric PLGA poly (lactic-co-glycolic acid) immunonanoparticles showed enhanced therapeutic efficacy in the Michigan Cancer Foundation-7 (MCF- 7) breast cancer-cell line. Misra and Sahoo  improved the therapeutic efficacy of doxorubicin by directly targeting the drug to the nucleus of breast cancer cells by conjugating a nuclear localization sequence to the surface of PLGA nanoparticles. Mohanty and Sahoo  formulated a nanoparticulate delivery system using glycerol monooleate and pluronic F-127 which solubilized curcumin in aqueous media at clinically relevant concentrations, protected it from hydrolytic degradation and in vivo biotransformation and delivered curcumin in a controlled manner.
Multifunctional or multimodal nanoparticles (MMNPs) are nanoparticles that combine several different functional capabilities in a single stable unit. For example, a core nanoparticle could be linked to specific targeting ligands that recognize the unique surface signature on their target cells. Simultaneously, the same particle can be attached with an imaging agent to monitor its transport progress, a moiety to evaluate the therapeutic efficacy of a drug or a therapeutic agent. In short, the function of the multifunctional nanoparticle depends upon the component attached. With multiple components such as fluorescent molecules, tumor targeting moieties, anticancer drugs, or small interfering ribonucleic acid available, the possibilities are numerous. MMNPs in bio-imaging and bio-sensing are a rapidly growing research fields as these particles can be detected using the multiple imaging modalities, i.e., MRI, X-ray, ultrasound and fluorescence, unlike their single-modal predecessors. The use of MMNPs as contrast agents will enable intra-operative imaging as well as improve pre-operative imaging, offering new approaches to visualization and accurate resection of tumors. Silica based nanoparticles have been developed for the purposes of bio imaging and bio-sensing. Silica is a good candidate for this work because it is a good host material for agents such as fluorescent dyes, metal ions and drugs. The silica matrix is transparent and allows excitation and emission light to pass through efficiently. Encapsulation by silica also provides enhanced photo-stability for optical agents. The surface of silica particles can be modified easily to attach bio molecules; it is water dispersible, resistant to microbes, biocompatible and resistant to swelling due to changes in solvent polarity. These characteristics of silica have led to its use in the production of several MMNPs.
The strategies for generating nano multi-functionalities share common approaches irrespective of the nature of NPs and involve encapsulation, covalent conjugation, or non-covalent adsorption of various moieties to allow the NPs to recognize or locate the tumor, deliver a load or kill the tumor cells and permit visualization or imaging. Synergistic effects could be achieved by conjugating different peptides or by loading with multidrug regimens. More complicated schemes could be devised with the use of heat-labile or protease-susceptible tethers to engineer the smart NPs for targeted drug release. DNA with heat-labile hydrogen bonding between complementary strands may serve as a heat-labile linker. Protease susceptible linkers could be the substrates for tumor-specific or tumor environment-specific enzymes. Tumor-specific processes and environments may be exploited to trigger the release of therapeutic agent by enzymatic activation of NPs via bonds that are sensitive to degradation under certain conditions (e.g., abnormal pH, oxygen levels, unique biomarkers, extracellular matrix remodeling and proteolytic enzymes over-expressed in tumors). Although, these are the general strategies, inducing the NPs to actually perform in vivo as predicted by theory and addressing the biocompatibility, bio-stability and bio-distribution issues require extensive research. Few promising nanoparticles that are in various stages of pre-clinical development having been summarized [Table 12].
|Table 12: Mode of actions of nanoparticle application systems under observations and research|
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| » Toxicity|| |
However, the use of nanoparticles in cancer and medicine should be cautious in view of the potential health risks that they may pose because the toxic effects of nanoparticles are not studied in detail and not yet well-known, except a few observations reported so far.
| » Conclusion|| |
Nanomaterials and devices applicable in cancer medicine, thus, are classifiable on the basis of the carrying nanoparticles. The liposome based theranostic products had been in a good number approved for clinical practice and now widely used for cancer medicine, besides the emerging new ones which are under the trails. Polymeric micelles are presently under the trails in nanotherapy. Dendrimer conjugates including the multifunctional ones carrying the imaging, targeting and chemo-therapeutic molecules in single nanoparticles are presently under the focus for theranostic cancer applications. Nano-cantilever based assays are likely going to replace the conventions assay methods of chemical pathology. CNTs are emerging nano applications of great utility in the regenerative and cancer medicine. QDs hold great promise for the micro-metastasis and intraoperative tumor imaging. Important applications of magnetic nanoparticles and super para magnetic nanoparticles are in the magnetized cardiac stents, cancer hyperthermic and photodynamic therapy and liver metastasis imaging. The AuNPs have been employed for cell imaging CT, dark-field light scattering OCT, photo thermal heterodyne imaging, Raman spectroscopy techniques and AuNPs based cancer therapy. Besides these defined categories miscellaneous other nanoparticles are being discovered for utility in the cancer diagnosis and disease management.
However, the use of nanoparticles should be cautious in view of the potential health risks that they may pose since the toxic effects of nanoparticles are not well-known. The use of nanoparticles in the clinical practice and their toxicity profile require further extensive research.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12]