|Year : 2017 | Volume
| Issue : 1 | Page : 1-7
Role of nanotechnology in theranostics and personalized medicines
Siddharth Vats, Meemansha Singh, Sana Siraj, Himani Singh, Swati Tandon
Institute of Biosciences and Technology, Shri RamSwaroop Memorial University, Barabanki, Uttar Pradesh, India
|Date of Submission||06-Jul-2016|
|Date of Acceptance||14-Oct-2016|
|Date of Web Publication||1-Feb-2017|
Institute of Biological Sciences and Technology, Shri Ram Swaroop Memorial University, Lucknow Deva Road, Barabanki - 225 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Various researches have been conducted for the improvement of diagnostics and therapeutic systems of health care. Novel and advanced technologies focus more on diagnosing and identifying diseases and then providing an effective therapy conjugated with the diagnostic agents itself. Theranostics based on nanotherpay with personalized medicines do have better prognosis and prevent turning up of curable disease into fatal one due to late diagnosis, especially for the common poor from the third world nations. In the treatment of cancers, various biofluids and tumors are isolated and then analyzed for various biomarkers such as soluble markers, immune histocomplexes, proteins as products from mutated genes, altered proteins, antigens, or differently expressed proteins. Providing treatment on right time depends very much on right-time diagnosis with high specificity and accuracy. Improved diagnosis helps in prescreening the profile of target molecules to develop biomarkers based on disease-specific therapy. With making it the less expensive, with less off-target toxicity and high efficacy and specificity, with real-time analysis for thorough observation and guidance and studying effects and side effects to develop further therapeutic options. This review focuses more on personalized medicines with theranostic approach.
Keywords: Nanoparticles, nanotechnology, personalized medicines, theranostics
|How to cite this article:|
Vats S, Singh M, Siraj S, Singh H, Tandon S. Role of nanotechnology in theranostics and personalized medicines
. J Health Res Rev 2017;4:1-7
|How to cite this URL:|
Vats S, Singh M, Siraj S, Singh H, Tandon S. Role of nanotechnology in theranostics and personalized medicines
. J Health Res Rev [serial online] 2017 [cited 2020 Sep 24];4:1-7. Available from: http://www.jhrr.org/text.asp?2017/4/1/1/199328
| Introduction|| |
It was in the year 1998 when the term “Theranostics” was used by John Funkhouser for the first time. The Food and Drug Administration has observed a decline in number of innovative modern scientific tools used in medical and health-care system in the year 2004 and made an appeal to make collective efforts toward modernizing scientific tools. People in the third world countries and in developing countries find it hard to have access to health services and especially the marginalized section of the society. It is not only the lack of money but also late diagnosis and then followed by a late treatment, which worsens the health and leads to further loss of money and raised health-care cost. Moreover, it is a vicious cycle where ill health and poverty contribute more to each other. Cost and affordability are the two important determinants for a good health-care system. The ever-increasing cost in the sector of health care has put tremendous pressure on the budget allotted to health care. The major chunk of this budget gets allotted to the treatment section while the diagnostics sector has to bear the restrictions. This in turn puts large pressure on the diagnostic arm to be updated and innovative with more focus on product enhancement. Pharmaceutical industries are also going through efficiency enhancement phase with rising voices, demanding more proof for safety and efficacy. Pharmaceutical industries and diagnostic industries are now coming together for developing diagnostics tests also providing applications of therapies. In addition, this kind of therapy involving diagnostics and treatment together for more specificity toward diseases and patients by the use of single agent is called theranostics as shown in [Figure 1] of graphical abstract., Moreover, this type of health-care approach where the delivery of both therapeutic and diagnostic agents such as imaging agents to the same targeted location using a single delivery platform is termed theranostic medicine. Most of the medicine system uses the term Rx/Dx for the theranostic treatment strategy, where Rx stands for targeted therapeutic and Dx stands for companion diagnostic. Theranostics involves combinations of molecular-based therapeutics, biosensors, in vitro prognostics and diagnostics, molecular imaging, bioelectronics, image-guided therapy, translational medicines, and system biology. Theranostics aims toward real-time understanding and monitoring the response of the medicines on the patients during treatment for reducing the off-target toxicity and enhancing safety level. This also prevents patients from undergoing unnecessary treatments and helps the patients in reducing the avoidable cost for the treatment. Theranostics provides an excellent opportunity for drug manufacturing pharmaceutical companies and companies associated with manufacturing diagnostics kits and instruments  to work together and reduce the overall cost associated with health-care systems and treatments. Cancer cells spread by forming leaky vasculatures around themselves and get transferred through flowing blood. Targeted, sustained, and specific “enhanced permeability and retention” (EPR) delivery system (vehicles such as liposomes, nanoparticles, and polymer particles; carrying chemical/biochemical agents or drugs) aimed at cancer tissues can revolutionize the cancer treatment. During the take-off stages of theranostics, EPR delivery systems were loaded with particles that can be easily detected by positron emission tomography (PET), near-infrared fluorescence, computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT),, etc., as shown in [Figure 2].
|Figure 1: Graphical abstract: Nanotechnology in theranostics and personalised medicines|
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| Molecular Theranostics|| |
Molecular theranostics involves development of the molecule-specific diagnostics tests and tendering them with target-based therapy. Molecular theranostics forms an important part of personalized medicine. A molecule targeting drug associated with a diagnostics tests termed as “companion” diagnostics tests is specifically designed to have a real-time assessment of the given therapy. It helps in developing a clear understanding about the treatment chosen and both benefits and side effects associated with that treatment. Keeping Rx/Dx approach in mind, the treatment involves designing a molecular diagnostic test and targeted therapy learning from each other, collaborative and interdependent based on patient's disease subtype, and his/her genetic profile. Not just this, the companion diagnostic tool also provides a clear understanding about the state of the disease, its progression rate, optimum drug concentration and type, safety and toxicity related to the therapy applied. Picard et al. detailed about the theranostics health-care system for the diagnostics and treatment of infectious diseases. Munakata et al. studied β2-adrenergic receptor gene (ADRB2) as a target molecule for β2-agonists. ADRB2 haplotypes (54) and diplotypes (42) were studied as target molecule and to find their role in asthma in Japan. From the study, it was observed that the single nucleotide polymorphisms and ADRB2 haplotypes and diplotypes present in Japan were different from those of Caucasians and African Americans. Hence, this suggests that the treatment suitable for Caucasians and African Americans may not be that effective in treating asthma in Japanese people. By keeping this in mind, they suggested to develop molecular theranostic techniques. Ultrasound imaging techniques have been used worldwide for the screening of various kinds of cancers of neck, breast, abdomen, and other soft tissues. This technique also paved path for understanding and monitoring the therapy progress. Use of microbubbles has been suggested by Kiessling et al., for increasing the efficacy of the ultrasound imaging because the microbubbles act as vascular contrasting agents for improving the characterization and detection of inflammation, lesions related to cancers, and pathologies related to heart. Ultrasound has great sensitivity toward bubble detection and that can be further enhanced by binding peptides, other targeting moieties, and antibodies on its surface. Microbubbles targeted against the selectins, integrins, epidermal growth factor receptor-2, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, etc., were able to bind to tumor blood vessels and atherosclerotic plaques. Microbubbles have also found use in the evaluation of myocardial perfusion and functioning of heart to detection of various heart-related problems such as vesicoureteric reflux. Microbubbles used in ultrasound imaging-based theranostic techniques keep diameter of bubbles in the range of 1–4 µm so that they can stay confined to the vascular compartments. The bubbles can be stabilized by the use of shell prepared with phospholipids, polymers such as proteins. Both passively targeted and actively targeted bubbles based on ultrasound imaging techniques are used depending on cellular and tissue specificity. Passively targeted approach exploits the intrinsic properties of the bubbles while actively target approach focuses more upon types of attachment (covalent/noncovalent) of targeting moieties on the stabilizing shells.
Theranostics and personalized medicines
Personalized medicine means patient's tissue specific targeting of diseases. For personalized medicines, variability of each individual has to be considered before developing a suitable treatment strategy. And for that, the use of theranostics is inevitable for early diagnosis and therapeutic applications for screening of patients depending on the responses developed by the patients toward the therapy. In addition, patients with better results and favorable outcome can be continued with the same therapy while the patients with less response can then be treated with some other therapy. It will increase the safety profile because individual specific protocols will maximize the benefits and chances of treatment., Personalized medicine can be very successful in the case of treatment or control of cancers. Most of the anticancer therapeutics falls into three major modes of actions. First, those molecules having the ability to specifically binding to a specific biomolecular target or molecular products obtained from altered gene expression or pathways, and are key for differentiation of cancer cells from normal cells and killing of them. Second strategy includes supporting host immune response in removal or killing of tumor/malignant cells, and third, by increasing the permeation ability of drugs or anticancer agents only in the malignant cells, specifically with no off toxic effects. Anticancer agents can work by invading the cancer cells (small chemical agents) or by attaching to the surface proteins present on the cancer cells. Most of the small chemical agents mainly attack cellular processes related to growth or divisions such as DNA replications, tubulin polymerization, and enzyme-catalyzed biochemical reactions. In the invasive mode of actions, there is also use of small nucleic acid sequences-based hybridization, where the sequence can bind to the complementary sequence or to the gene product (RNAs) playing an important role in metastasis and growth of tumor cells and tissues. Receptor-based therapies involve binding of the anticancer agents to the cellular surface proteins. Nicolaides et al. have also stated that small chemical entities for the treatment of the cancers have seen a tremendous growth with the approval of various agents with similar functions. The imatinib (anti-BCR-ABL fusion proteins tyrosine kinase inhibitor), crizotinib (ALK inhibitor), and vemurafenib (Mutant BRAF inhibitors) were used to treat patients suffering from cancers.
Diseases, processes, and their monitoring
To apply theranostics, it is of utmost important to have knowledge of the key biological processes related to diseases, metabolomics, and out of various monitoring methods which one is more suitable for a particular disease. To study the metabolism related to the diseases, metabonomics and chemometrics approach can be combined. In metabonomics, biofluids and tissues samples were processed on spectroscopy and nuclear magnetic resonance spectroscopy. These biochemical data obtained from the different tests are compared with other databank according to the phenotype, disease diagnosis, and drug safety, analyzed and measured, and profiled for complex systems.In vitro tests combined with in vivo testing such as molecular imaging are applied for personalized cancer therapy. Mutation types and type's quantity of that gene were expressed into specific proteins, which vary with the type of cancer type. To focus on the type of cancer and stages of cancers, molecular imaging is a principle strategy tool. In molecular imaging, encoding is performed with PET/MRI sensible reporter genes, which shows affinity to radiotraced fluorochromes/radiotracers or magnetically tagged antibodies, followed by bioorthogonal chemical reporter strategy.In vivo imaging techniques provide better understanding of cancer than in vitro assays because of its manner of time-resolved and spatial-resolved functioning and minimal invasiveness. This noninvasiveness diagnosis ability of molecular imaging is suitable for body parts such as brain and lungs, where performing operations is quite challenging. Techniques such as fluorescence molecular tomography, CT, MRI, and PET are used either separately or in combination with each other for better data analysis and visual aspects. Each technique has its own limitations and advantages; each has their specific probes for performing the tests. Development of a universal nanoprobe that can be employed for all platforms will be the full exploitations of benefits that hybrid platform holds. Designing of nanoprobes can hold therapeutic agents such as DNA or drugs paving path for theranostics.
| Theranostics With Imaging Techniques|| |
Therapeutic strategies such as chemotherapy, hyperthermia, gene therapy, and radiation in cancer treatment are combined with diagnostic tools or probes such as contrasts agents involved in MRI, such as T1 and T2, contrast agents based on nuclear imaging techniques such as PET using 18 F and SPECT, using iodine-123, iodine-131, technetium-99 m; fluorescent markers such as dyes of organic nature and inorganic quantum dots. All the agents used in these imaging probes if conjugated on the surface of the available therapeutic agents/delivery vehicles cannot just only facilitate better imaging but also real-time trafficking pathway, therapeutic efficiency and kinetics study. By all this, better treatment and diagnostics can be provided for the patients., The current situation of the advancement in the field of nonmaterial-based diagnostics and therapy is provided in [Table 1].
|Table 1: Different levels of advancement for micro/nanobubble in the health-care sector|
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Nanocarriers for theranostics
Nanocarriers have significantly revolutionized the health-care system. There are various studies that emphasized on the availability of nanocarriers such as micelles, liposomes, polymers, dendrimers, metallic and nonmetallic inorganic nanoparticles, nanobubbles, carbon nanotubes (CNTs), and others for effective and better lived, controlled, and tissue/cells specific diagnosis and drug/gene delivery system.,, Drastic and major advancements in the field of theranostics are majorly contributed by advances and improvement in the area of nanomaterials, imaging modalities, cell/tissue/diseases specific formulations able to bypass blood–brain barriers and in molecular biochemistry. The main approach for any nanoparticle-based theranostics was to evade body's immune response, has the ability to perform systemic circulations and finally diagnosing and delivering the drug conjugated with the carrier at target site across the blood brain barrier, with getting guided by some imaging techniques. To prevent side effects and toxicity of the drug toward nontarget tissues, theranostics, researchers are developing stimuli-responsive drug delivery systems, with better coordination with the diagnostic ability of the systems.
Therapeutic application of nanobubbles associated with ultrasound
Ultrasound waves of high frequency were able to perform thrombolysis, similar results were observed by Alexandrov et al., (2004), for using Doppler ultrasound waves and tissue plasminogen activator to improve the recanalization of the arteries in the stroke patients. This effect was because of synergistic effects of microbubbles and ultrasound causing bubble to oscillate and cavitations to perform thrombolysis. Besides strong thrombolytic actions of ultrasound associated nanobubble, synergistic actions have been noted in drug delivery across biological barriers too. It was Kinoshita et al., who demonstrated the potential effects of microbubbles and concentrated acoustic energy of ultrasound together carrying trastuzumab across the drug delivery barriers such as blood–brain barriers. Theranostic applications of the nano- or micro-bubbles can be attributed to their ability to be visualized in the living tissues and hold high sensitivity. Ionic microbubbles had been used for combining vascular endothelial growth factor (VEGF) encoding plasmid DNA for the treatment of ischemic hind limbs in rats. The expression of VEGF was enhanced and induced therapeutic arteriogenesis in the skeletal muscles.
| Nanoparticle-Based Theranostics|| |
Modern nanosystems can improve drug diagnosis and delivery and can also monitor therapeutic responses to the provided medication. Nanostructures such as quantum dots, iron oxide nanoparticles (IONPs), CNTs, gold/silica nanoparticles have specific and remarkable surface properties highly tunable as per the requirement and allow them to perform action once they reach to their target location, giving a boost and improvement in the progress of personalized medicine. Nanoparticles with diverse chemical material, surface properties, nature, composition, characteristics thus can be engineered into different desired sizes and shapes. Nanoparticles have different morphologies which when used in living organism their structural study is called nanomedicine. For enhanced biological imaging and delivery of cancer drugs to targeted location nanoparticles are used. Researchers are working to synthesize a theranostic platform based on multifunctional nanoparticles at Emory University are having specificity toward receptor and good imaging capability. Metallic nanoparticles, long circulating nanocarriers, liposomes, micelles, lipid solid nanoparticle, and polymeric nanoparticles can accumulate themselves in the affected areas and provide most successful nanotechnology-based treatment.,
Metals such as gold (Au), silver (Ag), zinc (Zn), and titanium have been used as anticancer agents. A company named CytImmune has used gold nanoparticles to kill cancer tumors. A tumor-killing agent called tumor necrosis factor-alpha (TNF-α) was attached to a gold nanoparticle along with polyethylene glycol and thiol derivative (PEG-THIOL), which hides the TNF-bearing nanoparticle from the immune system. The PEG-THIOL allows the nanoparticle to flow in the bloodstream without being attacked. The TNF combined nanoparticle accumulates in the tumor cells with no negative effects on rest of the body cells. CytImmune involves combination of two techniques. First, the nanoparticle is designed too big so that blood vessels located near tumor cells allow the nanoparticle to exit the blood stream at the tumor site. Second, they attach TNF-α to nanoparticle along with PEG-THIOL hiding the nanoparticle from the body immune system. Once the nanoparticle reaches the cancer tumor, TNF binds the nanoparticle to cancer cells. The mixture of a gold nanoparticle, TNF, and PEG-THIOL is called aurmine. The phase1 clinical trial had proved to be successful; therefore, CytImmune is planning a second trial with aurmine with other chemotherapy drugs.
Iron oxide nanoparticles
IONPs stand for iron oxide particles having diameter in the range of (1–100) nm. IONPs can bind to proteins, drugs, antibodies, and nucleotides and targeted toward a cell or tissue or organ or tumor guided by external magnetic field. Magnetic IONP-based nanoconstructs are targeted to cellular receptors such as urokinase plasminogen activator receptor. This nanoconstruct enables penetration of drug-carrying nanoparticles into endothelial cell layer of the cancerous cells or tissues or tumor, for the killing of tumor stromal fibroblasts and improves the efficacy of drug delivery carried out by receptor-mediated endocytosis. These nanoparticles (IONPs) find important application in cancer imaging and treatment because of their high biocompatibility and spatial imaging capability. It has wider use in diagnosis, MRI, multimodal imaging, chemotherapy, and gene delivery. Furthermore, IONPs have a long blood retention time, biodegradability, and low toxicity (Harisinghani et al. 1999. IONPs also find use in MRI for their ability as contrast agents in the field of bioimaging. Therapeutically, studies of Gilchrist et al. suggested that lymphatic tumor cells can be heated by activating localized IONPs via an alternating magnetic field. Several IONPs formulations have been employed in for the diagnostics as well in the treatment of cancer of breast and pancreas. IONPs on conjugation with HER2 antibody herceptin (trastuzumab) can bind to breast cancer cells expressing the HER2 receptors. With cytotoxic molecules such as doxorubicin, it can display high antitumor activity when attacked to the tumor magnetically. Recently, synergistic application of IONPs formulations and anticancer drugs such as gemcitabine and doxorubicin has been tested on the N6 L (target tumor cells) and has shown good results.
| Gold Nanoparticles|| |
Under various conditions, gold nanoparticles (gold collides) are synthesized by using various reducing reagents by their controlled reduction of aqueous solutions. Commonly used reducing agent is citrate because of its ability to produce gold nanospheres of monodisperse nature. For treatment of cancer, genetic and protein biomarkers are used in the development of cancer nanotechnology for personalized oncology. Gold nanoparticles are investigated in areas such as in vitro and in vivo imaging, cancer therapy and drug delivery. For proteins such as p53, oligonucleotide-capped gold nanoparticles have been employed and are detected by the use of atomic force microscope (AFM), SPR imaging, Raman spectroscopy, and scanometric assay.,,, Very minute concentration of picomolar to femtomolar, of DNA targets are detected in some researches. In real time for the detection of streptavidin-biotin interaction in human blood cells, gold nanoshells are used. Using same samples, newly developed nanosensors are tested by the permission of the NCI Alliance for nanotechnology in cancer. Extending similar stand to broader range would be highly beneficial to cancer patients because diagnosing of cancer is difficult. Gold nanorods provide luminescence imaging of cancer cells in a three-dimensional phantom with signal intensity brighter and better from the 2 photon autofluorescence-based emission.
| Carbon Nanotubes|| |
CNTs (allotropes of carbon) are cylindrical in structure and have smart optical, chemical, and electrical properties making them widely usable for drug delivery to kill tumor cells., These carbon atoms are graphene sheets rolled in a cylinder that can have open or capped end. CNTs made of single graphene sheet turns to single-walled nanotubes whereas multiple grapheme sheets make up multiwalled CNTs (MWNTs). All these CNTs because of their large surface area can adsorb conjugating with different therapeutic molecules. Thus CNTs are surface engineered to increase their dispersibility in aqueous medium for appropriate binding of functional groups to desired therapeutic molecule. To treat the diseases, CNTs can help in penetrating the target cell by the therapeutic molecule attached to them. According to some studies, the cellular uptake of CNTs is confirmed but mechanism is not yet confirmed. Because of their needle-like shape, the penetration by CNTs might be into cellular components without causing apparent cell damage. To overcome this, a nanoinjector was introduced using AFM tip and functionalized MWNTs attached to model by sulfide linkages. When the MWNTs nanoinjector transports into the cell the sulfide bonds break and therapeutic molecule is transported to the cytosol. The position of nanotubes to cell membrane resembles the uptake of CNTs to that of nanoneedles (without causing cell death) (Myung et al., 2011)., CNTs provide varied application in transfer of drug molecules to the targeted cell varying from micro to macro in sizes introducing them in drug delivery research and explore their potential in forthcoming years.
| Liposomes Drug Delivery|| |
Liposomes are spherical shaped and contain at least one lipid layer. Mostly, phospholipid-phosphatidylcholine is found in liposomes may also include some other lipids such phosphatidylethanolamine. Liposomes are drug carrier vehicles loaded with variety of molecules such as large molecules of drugs, proteins, genes (in gene therapy), and nucleotides. Liposomes are created and processed in different sizes, compositions, and their functioning. Liposomes formulated as anti-cancer drugs and anti-fungal agents are now been commercialized to expand the therapeutic use of nanoparticles in cancer extending vast area in curing the cancer in possibly better manner., For liposomal components to be associated with the target cell, they interact cells in many different ways while when used in drug delivery there are major factors that influence their behaviors like if cholesterol is not included in vesicles membrane liposomes will leak. Large liposomes can be cleared easily than smaller ones. Half-life of liposomes is directly proportional to the dose of lipids. In addition, uncharged liposomal systems are not rapidly cleared than charged systems. The wide use of liposomal drug delivery is in the treatment of systematic fungal infections with amphotericin B. They are also used in multiple areas of interest such as liposomes for respiratory drug delivery systems, liposomes in nucleic acid therapy, liposomes in eye disorders, in tumor therapy, and many more. Liposomes when used for cancer therapy include incapsulation of antineoplastic agents such as doxorubicin and methotrexate, and delivery of N-acetylmuramyl-L-alanine-D-isoglutamine (the immune modulators). Liposomal drug delivery system showed higher efficacy and reduced toxicity of the drug for the target cell.,
| Conclusion|| |
Theranostic-based personalized medicine has more success rate than conventional medicine systems. Various attributes of personalized theranostic medicinal system help have a better understanding of the patients and help study real-time response of therapeutic outcome. Nanoformulations in curing cancer have been proved to be effectively useful. Multiple therapeutic agents can be delivered by nanocarriers to tumor sites that increase the effectiveness of therapy. Liposomes, metallic nanoparticles, CNTs, and quantum dots are examples of nanoformulations that can be used for cancer theranostics. For superior theranostic applications and utilization, all the three agents used in imaging, therapeutics, and targeting need some more extensive research and a tailored for specific applications as a personalized medicines. Theranostics holds a bright future with continuous advancement in technology, research and innovations, for betterment of theranostics nanoparticles in their solubility, excretions, longer circulation time, and better coordination with delivery vehicles of higher efficiency.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
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