CANCER NANOTHERANOSTICS: AN ADVANCED APPROACH FOR …

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Khadeeja et al. World Journal of Pharmaceutical Research

1357

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



1358

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]



1369

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]



1370

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



1371

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



1372

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



1373

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.



1374

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



1375

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



1376

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



1377

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



1378

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.



1379

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



1380

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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