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Nanomaterials--Recent Development and Fascinating Clinical Prospects: A Short Review.

Introduction

Nanomaterials have attracted immense attention in recent researches. This is a broad and interdisciplinary area of research and development activity that has been growing rapidly worldwide since the past few years. It has the potential for revolutionizing the ways in which materials are created and the range and nature of functionalities that can be accessed. The changes in physical properties at nano-level, preparation of sample, fabrication of device etc. evoke meaningful response to the development of nanoscience. Nanoscale materials are defined as a set of substances where at least one dimension is less than approximately 100 nanometers. A nanometer is one millionth of a millimeter--approximately 100,000 times smaller than the diameter of a human hair. Nanomaterials are of immense interest because at this scale unique optical, magnetic, electrical, and other properties emerge. These emergent properties have the potential for great impacts in electronics, medicine, and other fields.

The first discovered nanomaterials was prepared by vacuum evaporation of iron in inert gas and condensed in cooled substrates. Thereafter, many methods have been developed to fabricate nanoparticles that include inorganic ceramics and organic compounds (such as arc plasma torch to produce metallic powder) [1]. Some nanomaterials occur naturally, but of particular interest are engineered nanomaterials (EN), which are designed for, and are already being used in many commercial products and processes. ENs are designed at the molecular (nanometre) level to take advantage of their small size and novel properties which are generally not seen in their conventional, bulk counterparts [2]. The two main reasons why materials at the nano-scale can have different properties are increased relative surface area and quantum effects. Owing to their extremely small size (at least one dimension 100 nm or less), nanomaterials can exhibit one dimensional (e.g. surface films), two dimensional (e.g. strands or fibers), or three dimensional (e.g. particles) structures. Besides, they can exist in single, fused, aggregated or agglomerated forms with spherical, tubular, and irregular shapes. Common types of nanomaterials include nanotubes, dendrimers, quantum dots and fullerenes.

With an emphasis on clinical applications, we will highlight the nanostructures platforms that are effectively designed to integrate various aspects of cell engineering and therapy. Multiple nanoscale platforms have been developed for this purpose, such as carbon nanotubes, metallic nanoparticles, dendrimers, quantum dots, liposomes, polymeric nanoparticles, peptide based nanoparticles, nanogels etc. However, development of such platforms faces several challenges which need to be accounted--the control of the particle size, biocompatibility issue and high target specificity for delivery of drugs or advanced functionality and further functionality control.

Metallic nanoparticles: Many methods have been employed to prepare metallic nanoparticles and are discussed in details by Lue (2007) [1]. The methods include (i) Sol-gel method silver, iron nanoparticles are prepared by this method. This method offers benefit of yielding high purity, isotropic and low temperature annealing. (ii) Hydrosol fluid method- the pure metallic suspension particles (e.g. noble metals) can be prepared by this method. The process has an advantage of having relatively narrow size distribution where average diameter of 20A can be achieved. (iii) Vacuum deposition method and (iv) Ball milling method- hard and brittle ceramic materials can be ball-milled into nanoparticles [1]. Apart from metallic nanoparticles, several researchers emphasized on polymer based nanoparticles, originating from natural/synthetic resources owing to their relatively easy processibility and immense scope for clinical applications. Synthetic non-degradable polymer based nanostructures have limited use as they impose risk of toxicity in humans. Therefore, nanomaterials that undergo degradation process, received much more attention from the researchers. There are protein based (e.g. gelatin) nanoparticles and polysaccharide based nanoparticles and the common methods for the preparation of such nanostructures include emulsification, desolvation, coacervation and electrospray drying. The details of the types of nanoparticles and their preparation are nicely described by Sundar et al [3].

Characterization

Nanoparticle characterizations usually play crucial role in exploring the mystery of various interesting behavior at nanoscale level. Aspect like the size of the particles, morphology, structures are all important when their role are required to be investigated for clinical applications. The size, morphology and surface charge of nanoparticles are examined using advanced microscopic techniques as scanning electron microscopy (SEM), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The parameters such as average particle diameter, their size distribution and charge have impact on the physical stability and the in vivo distribution of the nanoparticles [3]. All characterization steps are summarized in Table 1.

Applications

Drug delivery

Conventional dosage forms suffer limitation as they usually exhibit low bioavailability and degradation of drug in the body before reaching site of action. To achieve desired efficacy of drug, it is expected that the drug should maintain minimum 'therapeutic range'. Only controlled drug release may offer such effect. Moreover, drug delivery system should be designed to ensure the drug distribution in a fashion that its fraction produces effect at the target site precisely at cellular and subcellular level providing desired kinetics for specific duration. Therefore, there has always been focus at the targeted delivery. Nanomaterials eventually bring immense promises in the area of targeted drug delivery [4]. As discussed, nanosystems usually offer benefits over micro or larger scale delivery system because smaller size nanostructures can be easily accepted by cellular system and hence offer easy transport across membrane. Nanostructured carriers are capable of overcoming anatomical barrier (e.g. blood brain barrier, branching pathways of pulmonary system) and thus allowing therapeutic molecules to reach the target sites.

Polymeric nanoparticles have gained considerable attention for their potential in controlled and targeted drug delivery system. Nanoparticles can be made from silica, carbon, gold, silver, platinum and polymers of synthetic and natural origin. However, the synthetic polymers such as PLA, PGA, PCL [5, 6] and natural polymers like chitosan [7], gelatin[8], collagen[8, 9], and alginate[10] have been exploited in formulating promising drug delivery systems over other categories due to their excellent biocompatibility, biodegradability, easy processibility and their ability to be functionalized. The important characteristics that usually determine the potential of nanoparticles based drug delivery system are particle size, encapsulation efficiency and zeta potential [11]. As size plays crucial role, smaller particle size is needed for rapid dissolution. Drug incorporation in the nanoparticles involves chemical conjugation of drug with polymer matrix and physical adsorption over polymer surface. Zeta potential indicates stability and particles with more than +30 mV and lesser than -30mV are basically considered stable [3].

Tissue Engineering

Stem cells have unique capabilities of self-renewal and multilineage differentiation to serve as versatile cell source, while nanomaterials, of late, have emerged as promising candidates in producing scaffolds capable of better mimicking the nanostructure with natural extracellular matrix in order to augment and or replace defective tissues [12]. Saravanan et al showed that Keratin based nanoparticles can be exploited as potential biomimetic substrate for bone tissue engineering applications [13]. Further, feasibility of ectopic bone formation in a 3D fibrin construct mixed with bone morphogenic protein-2 (BMP-2) loaded in nano-carriers for the osteogenic differentiation of human mesenchymal stem cells (hMSCs) has been assessed and indicated that the osteogenic differentiation of hMSCs embedded in the fibrin construct was affected significantly by the stimulation of growth factors loaded in nanoparticles [14]. Other areas of tissue engineering have been explored using nanomaterials provided significant outcome [15-17].

Cancer management

Significant advances have been made on the study and research of nanomaterials using bioactive polymers with controlled geometry, physicochemical properties, and surface charge and resulted in improved biocompatibility and active targeting of tumour tissues [18]. Cancer is the uncontrolled growth of tissues and their rapid invasion without proper development and differentiation. A huge amount of research has already been carried out in the field of cancer, resulting in a number of available diagnostic and treatment options. To devise a successful treatment regime, it is important to consider the major limitations of several therapeutic agents such as poor solubility, rapid deactivation, unfavourable pharmacokinetics and limited biodistribution. A wide range of nanomaterials has been introduced in an effort to devise more comprehensive and versatile diagnostic and treatment solutions for malignancies [18]. From a chemical view point, the nanostructures commonly employed in cancer management include lipid nanostructures (e.g. liposomes) [19], biopolymeric nanoparticles (e.g. protein nanoparticles), polymeric nanostructures (e.g. dendrimers), metallic nanostructures (e.g. gold nanoparticles), semiconductor nanoparticles (e.g.quantum dots) and composite nanoparticles [20]. However, strategies used in nanocarrier based therapeutics in cancer mainly include triggered (such as changes in temperature, pH, light, enzyme levels, ultrasound etc.), targeted (such as utilizing antigen-antibody or specific receptor mediated endocytosis due to peptide overexpression in cancer) and combinations. Various attempts have been made so far to manage different cancer ailments (such as colon, breast cancer) [21-23].

Future prospects

Rapid development of nanomaterials will result in tremendous benefits for modern life such as nanoscale visualization, insights into living systems, development of targeted drug transport and interestingly in regenerative medicine and other miscellaneous benefits. However, it is also necessary to keep in mind that applications of nanomaterials should not cause adverse effects on human health. In this context, to prevent the potential hazards complete characterization should therefore be elucidated under strict biological conditions. However, challenges in the ever growing field of nanomaterials still remain:

1. More focus on preparation and stability of bio based nanoparticles.

2. Proper characterization to meet the requirements of application in biological environment.

3. Designing modes for large scale manufacturing of potential nanomaterials

4. Manufacture and applications of nanomaterials need to be regulated through multifunctional activities among academia, industries and regulatory bodies.

Researchers across disciplines are working tirelessly to mitigate the outstanding challenges of nanomaterial fabrication and characterization, as well as improving their bio-compatibility. Simultaneously, the rapid development of functional medical imaging modalities like magnetic resonance [24], positron emission tomography [25] and photoacoustics (or optoacoustics) [26, 27] are pushing forward the frontiers of molecular imaging in-vivo, a confluence of these technologies indeed make us hopeful about the translation of nanomaterials to routine clinical practice in not-so-far off future.

References

[1.]. J.T. Lue, Physical Properties of Nanomaterials. Encyclopedia of Nanoscience and Nanotechnology. Vol. X. Ed H.S. Nalwa, American Scientific Publishers, 1-46 (2007).

[2.] K. Savolainen, L. Pylkkanen, H. Norppa, G. Falck, H. Lindberg, T. Tuomi, M. Vippola, H. Alenius, K. Hameri, J. Koivisto, D. Brouwer, D. Mark, D. Bard, M. Berges, E. Jankowska., "Nanotechnologies, engineered nanomaterials and occupational health and safety--A review", Safety Science, 48, 957-963 (2010).

[3.] S. Sundar, J. Kundu, and S.C. Kundu, "Biopolymeric nanoparticles", Science and Technology of Adv Mater, 11,014104 (2010).

[4.] L. Yan, and X. Chen, 7--Nanomaterials for Drug Delivery, in Nanocrystalline Materials (Second Edition), S.-C Tjong, Editor. 2014, Elsevier: Oxford. p. 221-268.

[5.] R.M Mainardes, N.M. Khalil, and M.P.D. Gremiao, "Intranasal delivery of zidovudine by PLA and PLA-PEG blend nanoparticles", Int J of Pharmaceutics, 395, 266-271(2010).

[6.] D.Lin, Q. Jiang, Q. Cheng, Y. Huang, P Huang, S. Han, S. Guo, Z. Liang, and A. Dong, "Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and in vivo siRNA delivery", Acta Biomaterialia, 9, 7746-7757 (2013).

[7.] H. Koo, K. H. Min, S. C. Lee, J. H. Park, K. Park, S. Y. Jeong, K. Choi, I. C. Kwon, and K. Kim, Enhanced drug-loading and therapeutic efficacy of hydrotropic oligomer-conjugated glycol chitosan nanoparticles for tumor-targeted paclitaxel delivery, J Controlled Release, 172, 823-831(2013).

[8.] A.O. Elzoghby, "Gelatin-based nanoparticles as drug and gene delivery systems: Reviewing three decades of research" J Controlled Release, 172, 1075-1091(2013).

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[10.] A. Martinez, I. Iglesias, R. Lozano, J.M. Teijon, and M.D. Blanco, "Synthesis and characterization of thiolated alginate-albumin nanoparticles stabilized by disulfide bonds. Evaluation as drug delivery systems", Carbohydrate Polym, 83, 1311-1321 (2011).

[11.] M. Kaasalainen, E. Makila, J. Riikonen, M. Kovalainen, K. Jarvinen, K.H. Herzig, V.P. Lehto,and J. Salonen, "Effect of isotonic solutions and peptide adsorption on zeta potential of porous silicon nanoparticle drug delivery formulations", Int J Pharmaceutics, 2012. 431, 230-236 (2012).

[12.] M. Peter, N.S. Binulal, S. Soumya, S.V. Nair, T. Furuike, H. Tamura, and R. Jayakumar, "Nanocomposite scaffolds of bioactive glass ceramic nanoparticles disseminated chitosan matrix for tissue engineering applications", Carbohydrate Polym, 79, 284-289 (2010).

[13.] S. Saravanan, D.K. Sameera, A. Moorthi, and N. Selvamurugan, "Chitosan scaffolds containing chicken feather keratin nanoparticles for bone tissue engineering", Int J Biological Macromolecules, 62, 481-486 (2013)

[14.] K.-H. Park, H. Kim, S. Moon, K. Na, "Bone morphogenic protein-2 (BMP-2) loaded nanoparticles mixed with human mesenchymal stem cell in fibrin hydrogel for bone tissue engineering", J Biosci Bioeng, 108, 530-537 (2009).

[15.] B. M. Mattix, T. R.. Olsen, M. Casco, L. Reese, J. T. Poole, J. Z.hang, R P. Visconti, A. Simionescu, D. T. Simionescu, and F. Alexis, "Janus magnetic cellular spheroids for vascular tissue engineering", Biomaterials, 35, 949-960 (2014).

[16.] H. Chen, Y. Zeng, W. Liu, S. Zhao, J. Wu, and Y. Du "Multifaceted applications of nanomaterials in cell engineering and therapy", Biotechnol Adv, 31, 638-653(2013).

[17.] G. Imparato, F. Urciuolo, C. Casale, and P.A. Nett, The role of microscaffold properties in controlling the collagen assembly in 3D dermis equivalent using modular tissue engineering. Biomaterials, 34, 7851-7861 (2013).

[18.] S. Nazir, T. Hussain, A. Ayub, U. Rashid, A. J. Mac-Robert, "Nanomaterials in combating cancer: Therapeutic applications and developments", Nanomed Nanotechnol Biol Med, 10, 19-34 (2014).

[19.] V. Ermolayev, X.L. Dean-Ben, S.Mandal, V. Ntziachristos, and D. Razansky, Simultaneous visualization of tumour oxygenation, neovascularization and contrast agent perfusion by real-time three-dimensional optoacoustic tomography, European Radiology, 26, 1843-1851 (2016).

[20.] M. Slingerland, H.-J Guchelaar, H. Rosing, M.E. Scheulen, L. J.C. van Warmerdam, JH. Beijnen, and H. Gelderblom, "Bioequivalence of Liposome-Entrapped Paclitaxel Easy-To-Use (LEP-ETU) Formulation and Paclitaxel in Polyethoxylated Castor Oil: A Randomized, Two-Period Crossover Study in Patients with Advanced Cancer", Clinical Therapeutics, 35, 1946-1954 (2013).

[21.] S. Hatziantoniou, K. Dimas, A. Georgopoulos, N. Sotiriadou, and C. Demetzos "Cytotoxic and antitumor activity of liposome-incorporated sclareol against cancer cell lines and human colon cancer xenografts", Pharmacological Res, 2006. 53, 80-87 (2006).

[22.] X. Zeng,, R. Morgenstern, and A.M. Nystrom, "Nanoparticle-directed sub-cellular localization of doxorubicin and the sensitization breast cancer cells by circumventing GST-Mediated drug resistance", Biomaterials, 35, 1227-1239 (2014).

[23.] AD. Seidman, AK. Conlin, A. Bach, M. E. Moynahan, D. Lake, A. Forero, G S. Wright, M.H. Hackney, A. Clawson, L. Norton, "Randomized Phase II Trial of Weekly vs. Every 2 Weeks vs. Every 3 Weeks Nanoparticle Albumin-Bound Paclitaxel With Bevacizumab as First-Line Chemotherapy for Metastatic Breast Cancer", Clin. Breast Cancer, 13, 239-246 (2013).

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[25.] S.S. Gambhir, "Molecular imaging of cancer with positron emission tomography." Nature Rev Cancer 2, 683-693(2002)

[26.] S. Mandal, X. L. Dean-Ben, N. C. Burton, and D. Razansky, "Extending Biological Imaging to the Fifth Dimension: Evolution of volumetric small animal multispectral optoacoustic tomography", IEEE pulse 6, no. 3 (2015): 4753.

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Subhamoy Mandal (1), Goutam Thakur (2) *

(1) Institute for Biological and Medical Imaging, Technical University of Munich, D-85764, Neuherberg, Germany

(2) Department of Biomedical Engineering, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, India

Received 24 April 2017; Accepted 11 November 2017; Published online 31 December 2017

* Coresponding author: Dr. Goutam Thakur; goutam. thakur@manipal. edu
Table 1: Overview of Nanoparticle characterization processes [Data
from Reference (3)]

             Methods

Particle     Techniques Dynamic light Scattering
size

             Nanoparticle tracking analysis

Particle     Scanning Electron microscopy (SEM)
morphology

             Transmission electron microscopy  (TEM)

             Atomic force Microscopy (ATM)

Particle     Zeta  potential
stability

Particle     X-ray  diffraction
Structure

             FTIR

             Remarks

Particle     widely used to determine the size of Brownian
size         nanoparticles in colloidal suspensions in the nano and
             submicron ranges, able to analyze samples containing
             broad distributions of species of widely differing
             molecular masses and can examine very small amounts of
             the higher mass species

             Able to determine the size distribution profile of
             small particles in a liquid suspension. can also be
             used in conjunction with an ultramicroscope that allows
             small particles m liquid suspension to be visualized mo
             ring under Brownian motion.

Particle     Here nanoparticle solution should be first converted
morphology   into a dry powder, followed by coating with a
             conductive metal, using a sputter coater. The sample is
             then scanned with a focused fine beam of electrons,
             rendering surface characteristics of the sample from
             the secondaiv elections emitted from the sample surface

             Here nanoparticles dispersion is deposited onto support
             grids or films The surface characteristics of the
             sample are obtained when a beam of elections is
             transmitted through an ultra-thin sample

             It has the ability to scan at ambient condition and
             even capture image from non-conducting samples without
             any specific treatment

Particle     Laser Doppler anemometry is the technique used to
stability    measure the zeta potential. The colloidal stability is
             basically analyzed through zeta potential of
             nanoparticles and most colloidal particles possess
             negative zeta potential values ranging from about -100
             to -5 mV. Nature of material encapsulation and surface
             coating ability of nanomaterials can also be estimated
             from zeta potential.

Particle     Investigates the structure of crystalline materials,
Structure    from atomic arrangement to crystallite size and
             imperfections and also analyzes the phase composition,
             crystallite size and shape, lattice distortions and
             faulting, composition variations, orientation and in
             situ structure development of the nanoparticles.

             Provides information about the structural details of
             proteins in solution with greater spatial and temporal
             resolution
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Author:Mandal, Subhamoy; Thakur, Goutam
Publication:Trends in Biomaterials and Artificial Organs
Date:Apr 1, 2017
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