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CANCER NANOTHERANOSTICS: AN ADVANCED APPROACH FOR
CANCER IMAGING AND THERAPY
Khadeeja Nizamudeen1, Sowparnika Treasa Sabu*
2 and Shaiju S. Dharan
3
1Student, 5
th Year PharmD, Ezhuthachan College of Pharmaceutical Sciences.
2Assistant Professor, Department of Pharmacy Practice, Ezhuthachan College of
Pharmaceutical Sciences.
3Principal, Ezhuthachan College of Pharmaceuitcal Sciences.
ABSTRACT
Background: Despite the wide range of knowledge and information
about cancer and advances in its treatment, still it is among the leading
cause of mortality. In this regard, nanomedicines can play a vital role
by improving the bio-distribution and the target site delivery of
chemotherapeutics. Nanotheranostics is an emerging science that holds
tremendous potential as a contrivance by integrating therapy and
imaging in a single probe for cancer diagnosis and treatment thus
offering the advantage like tumor-specific drug delivery and at the
same time reduced side effects to normal tissues. The recent surge in
nanomedicine research has also paved the way for multimodal
theranostic nanoprobe towards personalized therapy through
interaction with a specific biological system. Potential applications of
nanotheranostic medicines are assessment of drug biodistribution, site-targeted drug delivery,
and visualization of drug release at the delivery site. These applications help to optimize the
strategies based on triggered drug release and the prediction of therapeutic responses. In the
near future, nanotheranostics are the practical solution for cancer and other lethal diseases to
cure or at least treat them in the early stage. Method: This paper was prepared by referring
research and review article from various sites like Pubmed, Google Scholar, Research Gate,
Springer Link, Frontiers journal, Bentham Science, Online library Wiley, Tandfonline,
Europe PMC and IJPSR journal. The search was made by using keywords like cancer,
nanotheranostics, challenges, treatment, applications and nanocarriers. Observation:
Nanotheranostics is one of the biggest scientific breakthroughs in nanomedicine. Most of the
World Journal of Pharmaceutical Research SJIF Impact Factor 8.084
Volume 9, Issue 15, 1357-1391. Review Article ISSN 2277– 7105
*Corresponding Author
Sowparnika Treasa Sabu
Assistant Professor,
Department of Pharmacy
Practice, Ezhuthachan
College of Pharmaceutical
Sciences.
Article Received on
17 October 2020,
Revised on 07 Nov. 2020,
Accepted on 27 Nov. 2020
DOI: 10.20959/wjpr202015-19351
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currently available diagnosis and therapies are invasive, time-consuming, and associated with
severe toxic side effects. Nanotheranostics, on the other hand, has the potential to bridge this
gap by harnessing the capabilities of nanotechnology and nanomaterials for combined
therapeutics and diagnostics with markedly enhanced efficacy. The ability to engineer
nanomaterials to interact with cancer cells at the molecular level can significantly improve
the effectiveness and specificity of therapy to cancers that are currently difficult to treat. This
paper presents an overview of the nanotheranostics approach in cancer management and a
different nanomaterials used in theranostics and the possible challenges of translation of
nanotheranostics in to clinics.
KEYWORDS: Cancer, Nanotheranostics, Challenges, Treatment, Applications,
Nanocarriers.
INTRODUCTION
Cancer is a multi-factorial disease primarily characterized by uncontrolled proliferation of
cells, local tissue invasion and their ability to metastasize. It remains the third leading cause
of death in the world after heart and infectious diseases.[1]
Cancer treatment relies on the use
of surgery, radiotherapy and chemotherapy from which chemotherapy is the common
approach to the chronic management of cancer. However, in the majority of cases, surgery
and radiotherapy are used in combination with chemotherapy.[2]
However cancer therapies
are largely limited by inability to bypass biological barriers, nonspecific delivery and poor
biodistribution of drugs, ineffectiveness against metastatic disease, drug resistance of cancers,
and lack of an effective modality for treatment monitoring.[3]
Nanotheranostics is a burgeoning field which makes use of nanotechnology for diagnosis and
therapy of cancer with promises to overcome these challenges by enabling the engineered
nanomedicines to navigate the body in very specific ways, i.e., nanotechnology facilitates
controlled, tumor specific drug accumulation and release.[4]
There are different types of
nanomaterials composed of either inorganic or polymer based nanoparticles to be useful for
nanotheranostics applications such as to diagnose and treat diseases and monitoring the
therapeutic response in vivo at molecular level; to enhance the control, evaluation and
optimization of drug delivery and release; to target the drug by conjugating theranostic
nanoplatforms with biological ligands.
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Nanoparticles can be customized (loaded with a mélange of therapeutic drugs and diagnostic
probes) to develop theranostic properties, thereby constructing nanotheranostic agents.
Nanotheranostic agents have emerged as a prudent ploy for synchronized cancer intervention
and detection of the „route and reach‟ of the drugs. This paper summarizes the advantages of
nanotechnology in cancer therapy, various nanocarriers used in cancer imaging and therapy,
application of nanoparticles in the diagnosis and treatment of cancer, challenges for the
translation of nanotheranostics in to clinics.
Advantages of nanotechnology in cancer treatment:[5]
● The ultra-small size of the nanoparticles enables them to escape clearance by kidneys
● They easily permeate through the abnormally leaky blood vessels of tumor tissues and
accumulate inside the cells.
● Their high surface area increases their loading capacity for therapeutic and imaging
agents.
● They have the ability to selectively accumulate in the diseased tissues.
● They are safe and can undergo biodegradation into non-toxic by-product6.
● They increase the time period in which a drug remains active in the body.
● They can also lead to reduction in the drug volume and also site specificity, avoids the
problem of accumulation in healthy tissues.
● They provide the capacity for the personalized medicine, as the drug therapeutic efficacy
can be easily monitored as the nanoparticle contains both drug and imaging elements in
them.
1. Tumour microenvironment for nanotheranostics
Delivering an effective treatment to the tumor site, researchers reproduce the tumor
microenvironment aiming at creating the most appropriate and realistic scenario for the action
of anticancer therapies. The accumulation of nanosystems in solid tumors owing to the
enhanced permeability and retention (EPR) effect.[7]
Intratumoral distribution of
nanoparticles is highly variable and it is affected by intrinsic factors, such as interstitial fluid
pressure (IFP), blood flow, diffusion, and stroma thickness.[8]
In addition, tumor
microenvironment presents different physico-chemical characteristics compared to normal
healthy cells, such as acidic pH, hypoxia, active efflux pumps, hyperthermia, altered redox
potential, and overexpressed molecular biomarkers (e.g., oncogenic proteins).[9]
Table 1
highlights the effects of components of tumour microenvironment on tumour development.
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Table 1: The effects of tumour microenvironment components on tumour development.
TME Components Effect on tumour
development References
Activation of the Immune
system
Impairment of anti-tumor
immunity through LECs loss
of function
Garnier et al., 2019[10]
M2-type monocytes (also
known as TAM) activation
through IL-4, IL-10, TGF-β,
GM-CSF, Annexin A1, etc.
Goswami et al., 2017[11]
Lymphoangiogenesis VEGF secretion in TME Garnier et al., 2019
Formation of lymph vessels by
LECs Garnier et al., 2019
Aerobic glycolysis
(Warburg effect) Reactive Oxygen Species Gwangwa et al., 2018
[12]
Genomic instability Gwangwa et al., 2018
Hypoxia HIF activation Vaupel and Multhof., 2018[13]
Inflammation Activation of B and regulatory
lymphocytes
Labiano et al., 2015[14]
,Steven
and Seliger 2018[15]
Desmoplasia Induction of EMT and
formation of cancer stem cells
Pearson et al., 2019,[16]
Vahidian et al., 2019[17]
TME, tumor microenvironment; LECS, lymphatic endothelial cells; TAM, tumor associated
macrophages; IL, interleukin; TGF, tumor growth factor; GM-CSF, granulocyte-
macrophage colony stimulating factor; VEGF, Vascular endothelial growth factor;HIF,
hypoxia induced factor;EMT, epithelial to mesenchymal transition.
Recent nanotheranostics formulations follow a similar trend in taking the most advantage by
integrating stimuli-responsive agents/lipids and anticancer drugs. For example, a light-
responsive graphene was combined with an anticancer drug (doxorubicin) and a pH-sensitive
disulfide-bond linked hyaluronic acid to form a nanogel.[18]
In the case of lipid-based
nanosystems, the development of pH-sensitive liposomes takes advantage of the polymorphic
phase behavior of unsaturated phosphatidylethanolamine (PE), such as DOPE (dioleoyl
phosphatidyl ethanolamine), which forms an inverted hexagonal phase (HII) rather than
bilayers.[19]
The stabilization of liposomes into bilayers is accomplished by using an acid
lipid, such as oleic acid (OA), linoleic acid (LA), and CHEMS (cholesteryl hemisuccinate).
Indeed, both IFP and acidic pH are conditioning factors for the delivery of nanoparticles into
the tumor target.
A nanotheranostic system based on defect-rich clay was developed, combining a pH-sensitive
MRI diagnostic tool to detect the tumor tissue and both acid-enhanced PTT and
chemotherapy, to eliminate cancerous cells20
. This triple action allowed for the reduction of
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the dose administered in vivo, guaranteeing complete tumor elimination, after near-infrared
(NIR) range laser irradiation (808 nm) and consequent release of 5-fluorouracil (5-FU), the
chemotherapeutic drug.[21]
Considering an in vitro assay, this specifically targeted
nanosystem was selective toward BxPC3 pancreatic cancer cells, promoting a synergistic
therapeutic effect.[22]
Targeting the tumor microenvironment based on nanoplatforms can
improve tumor accumulation of drugs, enhance overall treatment efficiency, and provide
flexible and precise external control of the time, area, and dosage of therapy compared to
single therapy models.
2. Nanotheranostic agents for cancer imaging
Nanotheranostics can be classified based on the nanoplatform delivery system employed or
by the agents coupled with drugs to provide imaging functions. They can be constructed by
either organic materials (liposomes, polymeric micelles, dendrimers, etc), inorganic ones
(iron oxide, gold, mesoporous silica, etc), or organic inorganic hybrid materials.
An overview of the different types of nanotheranostics is discussed below:
2.1. Liposome and micelle based theranostics
Lipid-based nanoparticles (LNPs) are synthesized from lipids containing a hydrophilic head
group and lipophilic tail that spontaneously form spheres at critical concentrations[23,24]
Liposomes are spherical vesicles with concentric phospholipid bilayers enclosing aqueous
compartment whereas micelles or polymeric micelles are nanosized (typically in the range of
20–100 nm) spherical structures, composed of amphiphilic block copolymers, which self-
assembles to form a core/shell structure in aqueous media.[25]
Among the diversity of lipid-
based nanosystems available today, liposomes are definitely the most well-known and
versatile ones due to their unique properties and it present numerous advantages, namely
biocompatibility, biodegradability in terms of their main constituents, low toxicity, and the
ability to incorporate both hydrophilic and hydrophobic compounds. The most commonly
used phospholipid in the preparation of liposomes are polyethylene glycol and
phosophotidylcholine.[26]
Polyethylene glycol (PEG) exhibit stealth effect as they are
electrically neutral and is not recognized by the reticuloendothelial cells (RES) of liver or
spleen.
Due to stealth effect, the liposomal drugs exhibit reduced clearance and prolonged plasma
half life.[27]
Yoshihisa et al., studied the stability and biological behaviour of in vitro system
of doxorubicin entrapped in doxil, polyethylene glycol conjugated liposomes was examined
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amd compared with those of DXR entrapped in the NK911, polymer miscelles. According to
their findings, the PEG-liposomes localize immediately only around the tumor vessel after
extravasation, which was absent in case of normal tissues. Diagnosis by theranostic
liposomes can be done by utilizing magnetic resonance imaging (MRI), positron emission
tomography (PET) imaging, single-photon emission computed tomography (SPECT) and
near infrared resonance (NIR) fluorescent imaging28
. The imaging agents can be entrapped
within the hydrophobic core or linked covalently to the surface of the liposomes and the
therapeutic agent can be either encapsulated in the lipophilic core or embedded in the
lipophilic bilayer shell. The liposomes can then be further conjugated with molecular probe
for targeting. Such multi-functional liposomes may circulate for prolonged periods in the
blood, evading host defenses, and gradually release drug by targeting and simultaneously
facilitate in vitro or in vivo imaging.[29]
Thus the liposomes possesses the ability ro deliver
anticancer drug more efficiently.
Similarly, micelles are emerging as powerful, multifunctional nanotherapeutic platforms for
cancer imaging and therapeutic applications and as theranostic delivery systems in cancer
management[30]
Besides their ability to carry a diversity of chemotherapeutic compounds,
they have also been explored as delivery systems of a great variety of diagnostic agents,
including 64
Cu[118]
and 14
C isotopes,[119]
quantum dots (QDs)K,[120]
gadolinium (Gd)-based
contrast agents,[117]
SPIONs,[121]
and fluorescent probes.[31,32,33,34]
Taking all these factors into
consideration, liposomes emerge as a highly promising theranostic tool, with a broad
spectrum of clinical applications in cancer management.
2.2 Polymer and dendrimer based theranostics
Polymer is a large molecule composed of repeating units organized in a chain like molecular
architecture exhibiting a multiplicity of compositions, structures and properties. Natural
polymers such as chitosan, albumin and heparin have been used for the delivery of drugs.[35]
The synthetic polymers include polycyanoacrylate (PCA), poly-D,L- glycolide (PLG),
polylacetic acid (PLA), polylactide-co-glycolide (PLGA), poly(isohexyl cyano acrylate)
(PIHCA) or polybutyl cyanoacrylate (PBCA) are the most commonly used polymers in the
synthesis of nanoparticles .
Due to its biocompatibility, versatility and multi functionality and offer a suitable platform
for tumor imaging and therapy it have been widely studied.[36]
A number of polymeric
platforms have been applied in cancer therapy to enhance anticancer agents‟ efficacy,
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prolong drug circulation half-life, and provide stimuli-responsive drug release and targeting
delivery. Some of these polymer-based nanocarriers are currently under various stages of
clinical development.[37]
Sailor and Park has synthesized multifunctional polymer system co-
encapsulated with a hydrophobic therapeutic agent (doxorubicin) and either hydrophobic
superparamagnetic nanocrystals or hydrophobic quantum dots, using an oil-in-water emulsion
and a subsequent solvent evaporation technique and a folate group was coupled onto the
surface of the polymeric hybrid nanoparticles to target cancer cells‟ folate receptor[38]
Like
polymer nano particles, dendrimer-based NPs have also been mployed as nanotheranostic
agents because of their unique characteristics which a single dendrimer can act as a platform
for imaging and targeting agents to identify cancer cells.[39,40]
Dendrimers are nano-sized, hyper branched, radially symmetric molecules with well-defined
homogenous and monodisperse structure that has typically symmetric core, an inner shell and
an outer shell. Dendrimers having promising potentials to perform controlled and specified
drug delivery. The drug dendrimer conjugate has high solubility, reduced systemic toxicity
and selective accumulation in the tumour cells.[41]
Zhang and his group have synthesized an
ethylenediamine core poly (amido amine) (PAMAM) generation five dendrimer which has a
diameter of about 5 nm and more than 100 functional primary amines on the surface that has
the potential to be used for targeting, imaging, and intracellular drug delivery, by covalently
attaching to folic acid, fluorescein, and methotrexate in proper ratio[42]
This multifaceted
theranostic preparation, showed 100-fold higher cytotoxicity than free methotrexate.
2.3. Noble metal based theranostics
Noble metal nanoparticles present optical properties, which can be easily tuned to desirable
wavelengths according to their shape, and composition enabling their imaging and
photothermal applications under native tissue. Noble metals like gold, silver, and/or platinum
have been extensively studied as theranostics due to their unique and distinctive
characteristics such as high surface-to-volume ratio, broad optical properties, ease of
synthesis, and facile surface chemistry and functionalization.[43]
These NPs can also be easily
functionalized with various moieties, such as antibodies, peptides, and/or DNA/RNA to
specifically target different cells and with biocompatible polymers.
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2.3.1. Gold-based theranostics
Through the advantageous chemical and physical properties like superior biocompatibility
and well-established strategies for surface modification (i.e. gold-thiol bonding), gold-based
nanomaterials have been investigated as theranostic nanoplatforms.[44]
The ability to
functionalize the surface of gold with organic molecules allows for the preparation of
nanoparticles which can specifically interact with any physiological system polymer-
functionalized metallic nanoparticles featuring a gold core are, in fact, suitable for traditional
characterization methods in solution and, therefore, present an attractive opportunity for
manufacturing drug delivery vehicles with tuneable properties. Jacob et al., developed a 2nm
gold nanoparticles of paclitaxel with the attachment of a flexible hexaethylene glycol linker
at C-7 position of paclitaxel followed by coupling of the resulting linear analogue to phenol-
terminated gold nanocrystals.[45]
The synthetic strategy yielded a hybrid structure with an
extremely high content of organic shell (67 wt. %), a narrow polydispersity index (1.02), and
a well-defined number of drug molecules (73 ± 4) per metallic particle. This well-defined
chemical structure of drug-functionalized nanoparticles may allow one to more accurately
define their efficacy and therapeutic utility.
One of the most attractive attributes of gold nanomaterials (GNMs) is the tunable optical
property that mediates the localized surface plasmon resonance (LSPR). The LSPR of gold
nanomaterials can be adjusted by tuning their morphology; gold (Au) NP, nanorod (AuNR),
nanoshell, and nanocage exhibit distinctive optical and thermal properties, which can readily
upgrade gold nanomaterials to be prospective theranostic agents.[46]
Apart from this they have intrinsic disadvantages like high cost of production and an issue of
tability in physiological conditions. For clinical translation of gold nanomaterials, more stable
surface chemistry is greatly required.
2.3.2. Silver based theranostics
The cytotoxicity of silver nanoparticles (Ag NPs) effectuated by conjugating with various
chemicals, biomolecules, and anticancer drugs via covalent or non-covalent bonds. For
instance, Mukherjee and his coworker have developed bio-synthesized silver based
nanoparticles (b-AgNps) from reduction of silver nitrate (AgNO3).[47]
The formed
nanoparticle exhibited multifunctional characteristics for targeted drug delivery and
fluorescence imaging of cells that could be utilized to detect the localization of drug
molecules inside the cancer. Thus, there is a strong hope in silver based nanoparticles for
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their use as theranostic agents in cancer diagnosis and therapy[48]
The only limitation that
withholds Ag Nps from extensive application in cancer therapy and diagnosis is its poor
biocompatibility to the in vivo system. This can be overcome by capping Ag Nps with stem
latex from a medicinal plant, Euphorbia nivulia.[49]
2.5. Carbon nanotubes and fullerenes
Carbon nanotubes (CNTs) are cylindrical tubes composed solely of carbon and can either be
formed as single-walled (consists of a single graphene cylinder) with a diameter of 0.8 - 2 nm
or multi-walled (comprises several concentric graphene cylinders) with a diameter of 5-20
nm. CNT are unique because the bonding between the atoms is very strong and the tubes can
have extreme aspect ratios. There are many different types of carbon nanotubes, but they are
normally categorized as either single-walled (SWNT) or multi-walled nanotubes (MWNT). A
single-walled carbon nanotube is just like a regular straw. It has only one layer, or wall.
Multi-walled carbon nanotubes are a collection of nested tubes of continuously increasing
diameters. They can range from one outer and one inner tube (a double-walled nanotube) to
as many as 100 tubes (walls) or more.
Physico-chemical features such as high surface area, ultra-light weight, pseudoaromatic
structure, tunable surface chemistry, ease of drug loading, fluorescence detectability and
photoacoustic effects makes the different nanocarbons such as carbon nanotubes, graphene,
fullerene, nanodiamond and carbon nanoparticles (CNPs) as delivery vehicles for imaging
and therapeutic agents.[50]
Recent expansion of surface engineering and bioconjugation
techniques has accelerated the growth of multi-functional (Carbon Nanotubes) CNT-based
platforms.
CNTs can easily penetrate biological barriers like a „nanoneedle‟ facilitating the
internalization of various cargos inside the cells that would not otherwise be taken up.[51]
A
promising result has been found in a study done by encapsulating Doxorubicin as
chemotherapeutic agent and gadolinium-based contrast agents for MRI imaging within the
lipid bilayer of fullerene liposomes to target interleukin (IL-13) receptors in brain cancer
therapy. After verifying the selective binding of fullerene liposome based theranostics to the
IL-13 receptor, its antitumor effect was tested in mice bearing brain tumors and better
shrinkage of the tumor was observed.[52]
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2.6. Quantum Dots(QD’s)
Quantum dots (QD) are very small semiconductor particles, so small that their optical and
electronic properties differ from those of larger particles. They are a central theme in
nanotechnology.[53]
Many types of quantum dot will emit light of specific frequencies if
electricity or light is applied to them, and these frequencies can be precisely tuned by
changing the dots' size, shape and material, giving rise to many applications. To improve QD
solubility, sensitivity, specificity, and visualization in the target tissue, the surface of QD can
be modified by ligand exchange with simple thiol-containing molecules, dendrons, peptides,
and encapsulation by a layer of amphiphilic copolymers. This strategy not only helps to
facilitate solubilization, but also provides a linker for bioconjugation of peptides, antibodies,
oligonucleotides, or small molecule drugs, thereby multi-functionalizing the QDs for tumor
targeting, tumor imaging and drug delivery.[54]
QD based theranostic agents can be prepared by loading QDs via physical adsorption such as
methotrexate (MTX) loaded QDs or co-encapsulation of QDs and drug into lipid micelles.[55]
Tamara et al., formulated a tumor-targeted, pH-responsive quantum dot-mucin1 aptamer
doxorubicin (QD-MUC1-DOX) conjugate for the chemotherapy of ovarian cancer.[56]
The
conversion of doxorubicin to quantum dots provided the stability of complex in the systemic
circulation and drug release in the acidic environment inside cancer cell. As the quantum dots
possess fluorscence behaviour, the efficacy of the treatment can be visualized by fluorscence
imaging.[56]
2.7. Magnetic nanoparticles based theranostics
Magnetic NP-based theranostics, along with their magnetic property as nanostructured
contrast probes for MRI, are beneficial due to their biocompatibility, cost-effectiveness and
their large surface area to volume ratio that enables loading of a wide range of functionalities,
such as targeting, imaging and therapeutic features, onto their surfaces. Among the magnetic
NPs, superparamagnetic iron oxide nanoparticles (SPIONPs), mainly magnetite and
maghemite, are the most commonly used nanomaterials.[57]
The main drawback of magnetic nanoparticles is their poor water solubility and intracellular
aggregation. In order to overcome the forementioned problem hydrophilic polymers are
added to passivate the nanocrystal surface that would typically protect particles from
aggregation. For instance, Santra and his coworkers utilized poly (acryl amide) (PAA) to
coencapsulate a lipophilic NIR dye and the anticancer drug taxol within hydrophobic pockets,
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resulting in a theranostic nanocarrier for dual fluorescence and MR-based imaging and
monitoring of drug delivery. Foliate; furthermore, was conjugated onto PAA-IONPs, yielding
targeting functionality aimed at the targeted killing of foliate receptor-overexpressing cancer
cells, demonstrated by optical/MR imaging. In addition, their work pointed out that
incorporating polymer could somehow alleviate the poor water solubility problem of
magnetic nanoparticles.[58]
2.8. Silica based nanotheranostics
Silica-based nanoparticles (SiNPs) have constant physical properties similar to those of bulk
materials, except that the total surface area increases as the size decreases. Indeed, of its
higher surface area, their well-defined tunable nanostructures and well-established siloxane
chemistry it is predominate in nanobiomedicine. There are two types of silica nanoparticles,
solid silica nanoparticles and mesoporous silica nanoparticles. Methods such as sol-gel
synthesis and microemulsion have been employed to prepare silica based nanoparticles for
diagnostic imaging and therapeutic applications.[59]
A wide variety of imaging, targeting ligands and therapeutic agents, such as
superparamagnetic iron oxide nanoparticles, and Gd complexes for MRI imaging, quantum
dots, genes, chemotherapeutic drugs like Doxorubicin, Captothecin, Paclitaxel, have been
loaded/grafted/encapsulated into mesoporous silica based nanotheranosticss which are
expected to satisfy the clinical requirements following the systematic investigation of their
biological effects and bio-safety, and finally find their applications in clinical practices to
benefit human beings.[60]
Chen and his coworker reported development of trifunctionalized
MSNs for theranostic application that combined imaging, targeting, and therapeutic agent in
one single-particle platform. This theranostic platform exhibited excellent targeting of human
glioblastoma cells and minimal collateral damage, but highly potent therapeutic effects[61]
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Figure 1: Various types of nanoparticles used for cancer imaging.
Table 2: Salient features of various nanoparticles used as delivery vehicles in
nanotheranostics.
Sl. No: Nanocarriers Salient features for using as
delivery vehicle in nanotheranostics References
1 Liposome
nanoparticles
They can entrap hydrophobic
agents within the lipid bilayers and
encapsulate hydrophilic agents
inside the center aqueous
compartment, which protects the
agents from degradation.
High agent-loading efficiency
High stability in biological
environments
Controllable release kinetics and
biocompatibility
David W Deamer et
al.,2010[62]
2 Polymer
nanoparticles
● Excellent biocompatibility
● Biodegradability
● Structural versatility
Clawson et al.,201[63]
● They are able to enhance drug
efficacy compared with free drug
via improved encapsulation and
delivery
● Prolonged circulation half life
● Sustained or triggered drug release
Brewer et
al.,201[64]
,Wang et
al.,2016[65]
● By passive targeting they can
accumulate atspecific disease sites
by enhanced permeability and
Farokhzad et
al.,2009,[66]
Timko et
al.,2011[67]
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retention effect(EPR)
● Accumulate the specific disease
sites through active targeting by
incorporation of targeting moieties
specific for a receptor or cell
surface ligand at the region of
interest
3 Dendrimers
● Monodisperse and controllable
size
● Modifiable surface
● Functionality
● Multivalency
● Water solubility
● Available internal cavity for drug
delivery
Ray S et al.,2018[68]
● Capable of carrying different kinds
of drugs by forming covalent or
non covalent bonds within the core
Kesharwani et
al.,2014[69]
● The presence of various anchoring
groups increases its versatility for
interacting with different ligands
for targeting, drug loading and
encapsulating contrast agents.
● The terminal groups can be
modified to attach to other
biomolecules and reduce their
toxicity to benign tissues.
Zhao Y et al.,2010[70]
4 Gold nanoparticles
● Excellent surface plasmon
resonance (SPR) characteristics
● Strong biocompatibility.
● .Nontoxic
I. H. El-Sayed et
al.,2006[71]
, J.-L. Li et
al.,2009[72]
● Chemical stability
● High affinities to biomolecules
H. J. Huisman et
al.,2005,[73]
C. J. Ackerson et
al.,2005,[74]
● Large surface area
● Low hydrodynamic mean size
● Suitable for photodynamictherapy
● Scaffold for additional agents
● Ease of surface modification
Raquel Vinhas et
al.,2015[75]
5. Silver nanoparticles
● Adjustable size and shape
● Enhanced stability of surface-
bound nucleic acids
● High-density surface ligand
attachment
● Transmembrane delivery without
harsh transfection agents
● Protection of the attached
therapeutics from degradation
● Potential for improved
Nadezhda Ivanova et
al.,2018[76]
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timed/controlled intracellular drug-
delivery.
● AgNPs can cause apoptosis or
necrosis by destroying the
ultrastructure of cancer cells,
inducing ROS production and
DNA damage, inactivating
enzymes, as well as regulating
signaling pathways.
Eom H-J et al 2010[77]
Homayouni-Tabrizi
M et al.,2019[78]
● AgNPs can also block the invasion
and metastasis of tumor cells by
inhibiting angiogenesis
Bethu MS et
al.,2018[79]
6 Carbon based
nanoparticles
● Ultra high functionalization and
loading capacity
● High penetration capacity to
biological barriers
● Imaging probe on its on with high
spatial resolution
Raquel Vinhas et
al.,2015
● Excellent electrical properties of
CNTs coupled with their nanoscale
dimensions result in the
construction of nanoscale
electronic circuitry.
● Carbon nanotubes also display
strong luminescence from field
emission, which could be used in
lighting elements..
Choi WB et
al.,2007[80]
Endo M et al.,2008[81]
● They are known to have low
threshold electric fields for field
emission.
Bonard JM et
al.,1999,[82]
Ajayan
PM et al.,2001,[83]
7 Quantum dots
● Have unique optical and electronic
properties such as bright and
intensive fluorescence.
● Good chemical and photo-stability
● High quantum yield
● Size-and structure based tunable
light emission.
● Different types of QDs can be
excited with the same light
wavelength, and their narrow
emission bands can be detected
simultaneously for multiple
assays..
Cristian T Matea et
al.,2017,[84]
● High molar extinction co-efficient
● Potential for synergestic
application in diagnostics and
therapeutic application
Raquel Vinhas et
al.,2015
8 Magnetic
nanoparticles
● Non-virulence
● Non-immunogenicity
● They have great specific surface
Vedernikova et
al.,2015,[85]
Akbarzadeh et
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area
● They can be used as vector after
modification
● Excellent biocompatibility
● Superparamagnetism
● Can be used in tumour
thermotherapy as they produce
thermal effect under the action of
alternating magnetic field
● Can be exploited for magnetic
separation
● Excellent biodegradability
● Low cytotoxicity
● The ability to be modified by
multiple targeted ligands or
antibodies
● Ease to prepare
● They can enter cells through
endocytosis
al.,2012[86]
9 Silica nanoparticles
Large surface area
Systemic stability
Excellent biocompatibility
Controllable porosity
Surface reactivity
Ease of functionalization
Raquel Vinhas et
al.,2015
Resistance to pH changes
Large multifunctionality
High hydrophobicity
Zhigang Xu et
al.,2017[87]
3. Triggered nanotheranostic delivery
In addition to passive accumulation and active tumor-specific targeting strategies, another
important approach for tumor-localized drug release is to design„ smart‟ nanotheranostics,
which, can respond to an extrinsic stimulus (e.g. Temperature, magnetic field, ultrasound, and
light) or an intrinsic trigger (e.g. pH, glucose, redox potential, and lysosomal enzymes) which
is specific to the disease environment.[88]
3.1. Temperature responsive nanotheranostics
Temperature responsive liposomal (TSL) formulations highly promise to increase the drug
concentration and its bioavailability in the tumor. But, the need for monitoring the drug
release process has led to the development of MRI encapsulated TSLs, which allows drug
delivery under imaging guidance. When drug and a contrast agent (CA) release occurs
simultaneously, the observed MRI contrast change can be used for quantification of the drug
release.[89]
TSLs release drugs encapsulated in the liposome lumen at the melting phase
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transition temperature (Tm) of the bilayer. At Tm, the lipid membrane undergoes a gel to a
liquid-crystalline phase transition because of structural changes in the liposomal membrane.
This is accompanied by transient membrane defects, which facilitate the rapid release of
liposomal contents.[90]
3.2. PH responsive nanotheranostics
The pH of cancer cells is lower than that of normal cells as a result of increased lactic acid
production.[91]
The acid is also released to extracellular regions lowering the pH to bellow
7.4. This characteristic of cancer cells allows for pH responsive nanocarriers containing both
imaging and therapeutic agents to specifically deliver into cancer cells and release their
contents.
3.3. Magnetic field responsive nanotheranostics
Magnetic nanoparticles have the capability to produce heat under externally applied magnetic
field.[92]
MNP-based hyperthermia could be utilized to generate intense local heating within
polymeric matrices thereby creating voids for the release of encapsulated drugs. One example
of an activable drug-delivery system by a magnetic field used dextran-coated IONPs with
MRI capability and conjugated fluorescein-labeled 18 base-pair oligonucleotide duplexes to
the particle. Upon electromagnetic field activation, the duplex structure of the fluorescein-
labeled oligonucleotides melted and released the fluorescein, which served as the model drug,
into the tumor model.[93]
4. Applications of nanotheranostics in cancer therapy
The ultimate goal of the theranostic field is to gain the ability to image and monitor the
diseased tissue, delivery kinetics, and drug efficacy. The applications of nanotheranostics in
the treatment of various types of cancers are presented below.
4.1. Metastases
Metastasis is the spread of cancer cells to new areas of the body, often by way of the lymph
system or bloodstream. A metastatic cancer, or metastatic tumor, is one that has spread from
the primary site of origin, or where it started, into different areas of the body. Tumors formed
from cells that have spread are called secondary tumors. The cancer may have spread to areas
near the primary site, called regional metastasis, or to parts of the body that are farther away,
called distant metastasis.The metastatic sub-clone invades the local extracellular matrix, next
entering the blood or lymph vessels.[93]
It circulates as an embolus and following
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extravasation, it follows the path from formation of micro-metastasis to generation of macro-
metastatic mass using extensive growth process.[94]
The limited existing treatment strategies
aim to prevent metastatic disease or to reverse it. Metastases primarily develop during the late
stages of cancer and accounts for greater than 90% of all cancer related deaths.[95]
At the current time there is a large spectrum of treatment strategies have been designed for
the treatment of metastasized cancers, but due to the complexity of tumor progression, tumor
composition, and drug resistance mechanisms these are unable to improve the prognosis apart
from improving survival. Biofunctionalized nanoparticles loaded with drugs can be tailored
to overcome these biological barriers and to improve efficacy while reducing morbidity.[96]
Conceptually, a highly sensitive nano-biomolecule consists in a responsive nanoparticle that
has attached a delivery carrier with affinity for unique surface receptor proteins located inside
the cellular wall.[97]
In this way, the carrier is able to concentrate the desired active molecule
only in the desired tissue. This ability for nanoparticles to accumulate in large concentrations
in targeted tissues or cells may be accomplished through either one or both means of
targeting: passive or active.
In passive targeting, the nanoparticle is directed in the desired cell or tissue via blood flow.
To function as passive targets and to last systemically for longer periods of time nanoparticles
must be between 10 and 100 nanometers in size.[98]
The effects of passive targeting may be
enhanced by using drug-loaded nanoparticles to obtain high selectivity to a target tissue or
cell. This process is termed active targeting.
The diversity in the usage of nano-structure materials results from their versatility in
functionalization. However, there is still limited knowledge about effects of long-term
administration of nanocarriers. There are concerns regarding the effect of nanotechnology-
based treatment solutions as promoter of the metastatic process. Following exposure of tumor
cells to nanoparticles as therapy strategy for non-metastatic disease, the fate of the few
residual malignant cells should be considered of utmost importance[99]
Although side effects
of different nanocarriers on both healthy and primary tumor cells still need intensive research,
all data suggest nanotechnology is a promising tool for modulation, counteracting and
efficiently treating the metastatic process and masses.
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4.2. Multidrug resistance
Multidrug resistance (MDR) is the phenomenon in which exposure of tumor cells to a single
cytotoxic agent accounts for cross-resistance to other structurally unrelated classes of
cytotoxic agents.[100]
ATP-binding cassette (ABC) transporters are transmembrane proteins
that utilize the energy of ATP hydrolysis to shuttle various substrates across the cell
membrane. Normally, ABC transporters function as pumps that extrude toxins and drugs out
of the cell. P-glycoprotein (P-gp) is one of the most well-described ABC transporters and is
overexpressed in the plasma membrane of MDR tumor cells.[101]
P-gp is capable of effluxing
various anticancer drugs, such as doxorubicin and paclitaxel, out of the cells. P-gp inhibitors
(e.g., verapamil) have been developed to overcome P-gp-mediated MDR. However, some P-
gp inhibitors do not have good selectivity and also block normal cell function of P-gp, for
example, in the intestines or at the blood–brain barrier (BBB), and therefore increase
toxicity.Drug resistance which allows tumors to evade chemotherapeutic agents, has emerged
as a major obstacle that limits the efficacy of chemotherapy.[102]
Nanoparticles have been developed to enhance the intracellular concentration of drugs in
cancer cells while avoiding toxicity in normal cells using both passive and active targeting.
The nanosize particles can pass through leaky and hyperpermeable tumor vasculature and
accumulate in the tumor vicinity utilizing the enhanced permeability and retention (EPR)
effect. The clearance of nanoparticles via lymphatics is generally seriously compromised in
neoplastic tissues, so that an additional retention of nanoparticles in the tumor interstitium has
been observed.
Different mechanisms can be employed for uptake of theranostic nanomedicines into the
tumor. Irrespective of the exact mode of cellular entry, endocytosed nanomedicines
eventually end up in lysosomes, and thus are carried relatively deep into cells, far beyond the
reach of trans-membrane localized drug efflux pumps. In theory, this strategy, therefore
ensures efficient delivery of chemotherapeutic agents into the cytoplasm of cells, without
being sensed and removed by MDR proteins as opposed to free (i.e. non-nanomedicine-
associated) chemotherapeutic drugs, which upon passive diffusion across the cellular
membrane are rapidly sensed and effluxed by MDR proteins.[103]
4.3 Solid tumors
Solid tumors are abnormal mass of tissue that usually does not contain cysts or liquid areas.
Solid tumors may be benign (not cancerous), or malignant (cancerous). Different types of
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solid tumors are named for the type of cells that form them. Examples of solid tumors are
sarcomas, carcinomas, and lymphomas. When these tumors reach a critical size, diffusion of
chemotherapeutic agents into the tumor becomes impaired. Thus new strategies that
overcome this problem should be designed. Owing to their small size, nanotheranostics,
especially those conjugated with targeting ligands have the ability to deliver the therapeutic
agent deep into the tumor tissue thereby enhancing the accumulation of drugs within the
tumor.[104]
Imaging agents encapsulated with the chemotherapeutic agents will provide real
time visualization of target as well as off target site accumulation of chemotherapeutic agents
helping immediate assessment of over/under treatment conditions.[105]
The concept of nanoparticle transport through gaps between endothelial cells (inter-
endothelial gaps) in the tumour blood vessel is a central paradigm in cancer nanomedicine.
The size of these gaps was found to be up to 2,000 nm. This justified the development of
nanoparticles to treat solid tumours as their size is small enough to extravasate and access the
tumour microenvironment. From various data it is found that these inter-endothelial gaps are
not responsible for the transport of nanoparticles into solid tumours. Instead, found that up to
97% of nanoparticles enter tumours using an active process through endothelial cells106
. This
result is derived from analysis of four different mouse models, three different types of human
tumours, mathematical simulation and modelling, and two different types of imaging
techniques. These results challenge our current rationale for developing cancer nanomedicine
and suggest that understanding these active pathways will unlock strategies to enhance
tumour accumulation.
4.4. Hematological cancers
Hematologic malignancies are the most common type of cancer among children and young
adults, comprising leukemia, lymphoma, and myeloma, which affect the bone marrow,
lymphatic system, and blood cells. Leukemia is a clonal disorder originated in the bone
marrow during hematopoiesis and is characterized by the unregulated proliferation of poorly
differentiated white blood cells.
Classification of the disease is based on the type of cell affected (myeloid or lymphoid) and
the degree of cell proliferation (acute or chronic).[107]
Acute myeloid leukemia (AML) is the
most common type in adults and acute lymphocytic leukemia (ALL) that is more prevalent
among pediatric patients.[108]
Chronic myeloid leukemia (CML) is a myeloproliferative
disorder with an annual incidence of 1.8 cases per 100,000 adults, accounting for 15–20% of
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newly diagnosed cases of leukemia in adults, and an annual mortality rate of 0.4 cases per
100,000 adults.[109]
Lymphoma originates in lymph nodes where the lymphoid lineage of
hematopoiesis differentiates into B-cells, T-cells, or natural killer cells.
Abnormal events include extensive cell proliferation, somatic mutations, and antibody class
switching, that ultimately impair the immune system as a whole and the adaptive immune
response in particular.[110]
As compared to solid tumors, these cancers inflict greatest
challenge for therapy. The tumor microenvironment of these cancers is extremely diverse
than with solid tumors. Current treatment for leukemia and lymphoma involve chemotherapy
and radiation, which often induce long-term side effects and multidrug resistance.
Nanotechnology provides the possibility to selectively deliver a high payload of anticancer
agents to malignant cells without damaging healthy cells or systemic toxicity, allowing them
to reach critical tissue compartments, such as the lymph nodes and the bone marrow,
otherwise inaccessible to drugs. In liquid cancers, tumor cells are free in circulation, requiring
specific active targeting. However, confined tumor sites are also present, such as the bone
marrow and/or lymphoid tissues, nanosystems profiting from the enhanced permeability and
retention effect. EPR effect may be of extreme relevance in tackling these niches. This way,
therapeutic nanoconjugates may accumulate at tumor locations, where subsequent active
targeting to cancer cells may be achieved.[111]
A few preclinical studies on lymphoma
nanotheranostics using metal NPs, diatomite NPs (DNPs), and nanoantibodies (nanobodies)
have already been reported. Diatomite NPs, silica-based NPs of irregular shape and mean size
of approximately 200 nm, were also applied in the management of B-cell lymphoma.[112]
Another example of nanotheranostics using a nano-antibody composed of rituximab
conjugated to an NP albumin-bound paclitaxel [ambraxane (ABX)] has been developed
toward decimate B-cell lymphoma.[113]
4.5 Cancer stem cells (CSCs)
The first modern evidence for a role of stem cells in cancer came in 1994 with a study of
human acute myeloid Leukemia[114]
in which an AML-initiating cell population was
identified from AML patients by transplantation into severe combined immune-deficient
(SCID) mice. In 2003, human CSCs were identified in solid tumors, including breast[115]
and
brain cancer.[116]
The subsequent reports identified CSCs in a variety of tumors, including
colon, pancreas, lung, prostate, melanoma, and glioblastoma. Expression of cell surface
markers such as CD44, CD24, CD29, CD90, CD133, epithelial-specific antigen (ESA), and
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aldehyde dehydrogenase1 (ALDH1) have been used to isolate and enrich CSCs from
different tumors[117]
Notably, the expression of CSC surface markers is tissue type-specific,
even tumor subtype-specific.
CSCs are defined by their ability to generate more SCs (self-renewal) and to produce cells
that differentiate. Initially, CSCs were believed to represent a small fraction of the total cell
population in a solid tumor, however, it has been claimed that as many as 25% of cancer cells
may have the properties of CSCs.[118]
There are several different theories regarding the origin
of CSCs. One theory believes that CSCs arise from normal stem/progenitor cells which
obtain the ability to generate tumors when encountering a special genetic mutation or
environmental alteration. An alternative theory for the origin of CSCs suggests that they arise
from normal somatic cells which acquire stem-like characteristics and malignant behavior
through genetic and/or heterotypic alterations.
The identification of markers that allow the prospective isolation of CSCs from whole tumor
tissues helps to develop an understanding of several important biological properties of CSCs
such as cell origin for a given tumor, signaling pathways for self-renewal and/or
differentiation of CSCs, the molecules uniquely expressed on CSCs, and the mechanisms by
which CSCs escape conventional therapies. Studies on these biological properties should lead
to the development of therapies that target the CSC population and eliminate the „engine‟
that drives tumors to grow, invade, and seed metastatic lesions.[119]
Along with the tremendous advance in the discovery of various cell surface markers
distinguishing CSCs from non-CSCs, nanoparticles are expected to direct theranostics to
CSCs and improve the CSC-specific therapies. Taking the stem cell marker CD133, for
example, it was found to be expressed on the surfaces of stem cells of brain cancer, breast
cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, ovarian cancer, and
liver cancer.[120]
5. Challenges for the translation of nanotheranostics in to clinics
The challenge of an effective treatment relies on the existence of high heterogeneity among
tumors and patients and within tumor subpopulations. There is a need for clinically relevant
nanotheranostics in early stage diagnosis and treatments for patients with cancer. The
advantage of multifunctional hybrid nanosystems over single core-shell particles are real-time
monitoring of drug release, biodistribution and accumulation at the target site, increased
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therapeutic efficacy, and prediction of therapeutic response (including to disease progression
and treatment outcome in real-time).Furthermore, nanotheranostics might then assist in
treatment planning, the anticipation of therapeutic response, and monitoring, aiming at
personalized medicine . To the best of my knowledge, no current nanotheranostic formulation
has been approved for translation into clinical practice.
5.1. Biological challenges
Theranostic nanomedicine have potential to improve human health by giving insights into the
prevention, diagnosis and treatment of diseases. One of the major challenges associated with
the translation of theranostic nanomedicine to clinics is the nano-bio interaction. The
nanomedicine upon interaction with biological material can generate disorders like
immunoreaction, inflammation or related disease.[121]
When nanoparticles enter a biological
system they interact with proteins, which leads to the formation of „corona‟ on its surface.
This adsorption of protein onto the surface of nanoparticles alters their size, stability,
dispersibility, pharmacokinetics, biodistribution and toxicity profile.[122,123]
In addition, complement activation-related pseudo allergy is an acute adverse immune
reaction caused by many nanoplatforms.[124,125]
Therefore,it is essential to study the
physicochemical characteristics of nanomedicines with respect to pathophysiology and
heterogeneity of human diseases. Moreover, the concept of a one-size-fits-all approach in the
case of theranostic nanomedicine can make it difficult to get clinical approval, as the
treatment varies from person to person.[126]
Therefore, the safety profile of nanotheranostics
in humans remains a major concern for which long term close monitoring of patients in both
early and advanced phases of clinical trials is needed.
5.2. Commercialization challenges
Large-scale synthesis of nanoparticles suffers from insufficient batch-to-batch
reproducibility, varied physical and chemical characteristics and low yield. It has been
noticed that nanoplatforms with laborious and complex manufacturing processes rarely find
their way into the clinic due to inconvenience caused to pharmaceutical companies.[127]
Since
theranostic nanoparticles comprise of a multifunctional unit, more precise chemistry,
manufacturing and control along with good manufacturing practice are needed while
translating from laboratory to clinics, this is difficult on a large scale.
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A third major issue that needs to be addressed is the wide gap between the scientific
community and regulatory authorities. Timely and effective translation of theranostics to
market is highly affected due to the deficiency of clear regulatory and safety
guidelines.[128,129]
Nanomedicines currently available on the market have passed the general
regulatory standards, but these standards may not be sufficient to ensure the quality, safety
and efficacy of other nanotheranostics for human use.
Strategies to overcome these challenges
To overcome the biological barriers of nanotheranostics, much research effort needs to be
dedicated to understanding the correlation of patient biology and disease heterogeneity with
nanomedicine, which is the major reason for the failures observed in translation of promising
nanoformulations in clinical trials. Preclinical studies in animal models often provide useful
information toward the suitability of theranostic nanomedicine for treating and imaging
human patient groups.[130]
Rigorous evaluation of nanoformulations in multiple preclinical
animal models is necessary before the onset of clinical trials During the early stages of
clinical development, nanotoxicology profiles comprising of standardized assay protocols for
cytotoxicity, immunotoxicity and genotoxicity need to be implemented and followed for the
evaluation of the potential risk in patients.[131]
Establish a strong collaboration between laboratory groups and pharmaceutical companies.
Modified rules under good manufacturing practice that are suitable for large-scale synthesis
of theranostic nanoparticles must be developed. The use of software such as Aspen
(AspenTech, MA, USA) in industrial setting can be of great help to identify the key
parameters to optimize manufacturing at the early stages of development and handle batch-to-
batch variation. This may be beneficial for tightly controlled and robust manufacturing of the
product[132]
At last, the success of manufacturing is also highly dependent on the training of
personnel regarding the specificities, hurdles and challenges related to the products.
CONCLUSION
Actually theranostics is representative of the evolution of multidisciplinary nanoscience, as a
routine meeting of multiple disciplines including chemistry, material science,
Electromagnetics, biology, medical physics, and oncology. Nanotheranostics will be
developed in a broader sense so that therapy and diagnostics can work hand in hand. It is
possible to predict high-impact advances in this field as researchers‟ pioneer approaches to
develop nanoscale platforms with multiple functionalities. It is likely that in the coming
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years, theranostics nanoparticles will emerge and enter clinical trials. Nanoparticles that can
simultaneously detect, image, and treat disease may one day become the norm rather than the
exception. Oncology is one of the disciplines that have benefited the most from
nanotechnology. A wide acceptance of cancer nanotechnology will come from a better
understanding of how nanoparticles interact with biological systems; how multiple functions,
including imaging and therapy, can be incorporated in a single nanoplatform; and how to
harness the unique physicochemical properties of nanoparticles that do not otherwise exist in
small-molecular-weight molecules for the detection and destruction of cancer cells with high
selectivity and efficiency. The major challenges in successful clinical translation of targeted
delivery of nanoparticles include overcoming various biological barriers and demonstrating
better therapeutic efficacy than that of the current standard of care in the clinic.
Understanding these challenges is imperative for effectively moving the field of cancer
nanotheranostics forward. As we discussed herein, the role of nanotheranostics can be
appreciated with respect to cancer therapy. Formulations of polymeric and metallic
nanoparticles and liposomes play a very important role in improving the quality of clinical
care and treatments. Nanotheranostics may offer the right drug with the right dose to the right
patient at the right time. In a very near future, it will certainly attract an increasing amount of
interest from pharmaceutical companies for the development of successful theranostic
nanoplatforms with the subsequent introduction of those novel nanotheranostics into the
market.
Funding: No funding.
CONFLICT OF INTEREST: None declared
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