Nanotheranostics, a future remedy of neurological disorders

Abstract

Introduction:
Effective therapy of various neurological disorders is hindered on account of the failure of various therapeutics crossing blood-brain-barrier (BBB). Nanotheranostics has emerged as a cutting-edge unconventional theranostic nanomedicine, capable of realizing accurate diagnosis together with effective and targeted delivery of therapeutics across BBB to the unhealthy regions of the brain for potential clinical success. Areas covered: We have tried to review the current status of nanotheranostic based approaches followed to manage neurological disorders. The focus has been majorly laid on to explore various theranostic nanoparticles and their application potential towards image-guided neurotherapies. Additionally, the usefulness of exceptional diagnostic, imaging techniques including magnetic resonance imaging and fluorescence imaging are being discussed by highlighting their promising opportunities in the detection, diagnosis, and treatment of the neurological disorders. Expert opinion: Inimitable diagnostic and therapeutic potential of nanotheranostics have accomplished the aim of personalized therapies by governing the therapeutic efficacy of the system along with facilitating patient pre-selection grounded on non-invasive imaging, thereby predicting the responses of patients to nanomedicine treatments. While these accomplishments are encouraging, they are still the minority and demands for a continuous effort to improve sensitivity and precision in screening/diagnosis along with improving therapeutic efficacy in various neural disorders.

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Expert Opinion on Drug Delivery
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Nanotheranostics, a future remedy of neurological
disorders
Manju Sharma, Taru Dube, Sonika Chibh, Avneet Kour, Jibanananda Mishra
& Jiban Jyoti Panda
To cite this article: Manju Sharma, Taru Dube, Sonika Chibh, Avneet Kour, Jibanananda Mishra
& Jiban Jyoti Panda (2019) Nanotheranostics, a future remedy of neurological disorders, Expert
Opinion on Drug Delivery, 16:2, 113-128, DOI: 10.1080/17425247.2019.1562443
To link to this article: https://doi.org/10.1080/17425247.2019.1562443
Accepted author version posted online: 20
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Published online: 07 Jan 2019.
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REVIEW
Nanotheranostics, a future remedy of neurological disorders
Manju Sharma
a
, Taru Dube
a
, Sonika Chibh
a
, Avneet Kour
a
, Jibanananda Mishra
b
and Jiban Jyoti Panda
a
a
Institute of Nano Science and Technology, Mohali, India;
b
School of Bioengineering and Biosciences, Lovely Professional University, Phagwara,
India
ABSTRACT
Introduction: Effective therapy of various neurological disorders is hindered on account of the failure of
various therapeutics crossing blood-brain-barrier (BBB). Nanotheranostics has emerged as a cutting-
edge unconventional theranostic nanomedicine, capable of realizing accurate diagnosis together with
effective and targeted delivery of therapeutics across BBB to the unhealthy regions of the brain for
potential clinical success.
Areas covered: We have tried to review the current status of nanotheranostic based approaches
followed to manage neurological disorders. The focus has been majorly laid on to explore various
theranostic nanoparticles and their application potential towards image-guided neurotherapies.
Additionally, the usefulness of exceptional diagnostic, imaging techniques including magnetic reso-
nance imaging and fluorescence imaging are being discussed by highlighting their promising oppor-
tunities in the detection, diagnosis, and treatment of the neurological disorders.
Expert opinion: Inimitable diagnostic and therapeutic potential of nanotheranostics have accom-
plished the aim of personalized therapies by governing the therapeutic efficacy of the system along
with facilitating patient pre-selection grounded on non-invasive imaging, thereby predicting the
responses of patients to nanomedicine treatments. While these accomplishments are encouraging,
they are still the minority and demands for a continuous effort to improve sensitivity and precision in
screening/diagnosis along with improving therapeutic efficacy in various neural disorders.
ARTICLE HISTORY
Received 15 October 2018
Accepted 19 December 2018
KEYWORDS
BBB; contrast agent; image-
guided therapy;
nanotheranostics;
nanoparticles; neurological
disorders; targeted drug
delivery
1. Introduction
1.1. Nanotheranostics and neurological disorders
1.1.1. Nanotheranostics
The term ‘theranostics’is defined as the combination of diag-
nosis and therapy, an emerging and promising field of medi-
cine believed to hold great potential to cure many difficult to
treat diseases [1]. The motive behind its development has
hailed from the fact that all existing treatment modalities for
fatal diseases are only capable of treating limited patient
subpopulations and only at selective stages of disease devel-
opment. Therefore, an integration of diagnosis and therapeu-
tic approach could offer a superior therapeutic regimen which
is not only specific to the subjects but at the same time offer
improved prognosis [2]. Nanotheranostics is an advanced form
of theranostic system which involves ‘nanotechnology’for
diagnosis and therapy of different diseases with gloomy prog-
noses. This includes a new generation of various types of
nanocarriers such as polymer conjugates, dendrimers,
micelles, liposomes, metal and inorganic nanoparticles (NPs),
carbon nanotubes (CNTs) to develop souped-up nanomedi-
cine. The purpose of nanotheranostics is to diagnose and cure
diseases at their possible earliest stage of development. It will
not be wrong to mention here that nanotheranostic is a new-
angled and advanced class of nanomedicine which can
diagnose, treat and prevent diseases at the cellular and mole-
cular level by the application of nanotechnology [3].
Over the last few years, nanotheranostics has also emerged
as a promising tool in the area of nanomedicine for the
detection and remedy of fatal neurological disorders. This
review presents a comprehensive overview of the recent
breakthroughs in the nanotheranostics arena in combating
such neurological disorders (Figure 1).
1.1.2. Neurological disorders
Neurological disorder is defined as any type of abnormal
physical condition of the nervous system. Over the last few
years, increasing incidences of neurological disorders have
been witnessed to be the most common cause of disability
and death worldwide. Neurological disorders such as
dementia, Alzheimer’s disease (AD), Parkinson’sdisease
(PD), epilepsy and cerebrovascular diseases including stroke,
multiple sclerosis, migraine, neuroinfections, brain tumors
and traumatic disorders of the nervous system such as
brain trauma and autism are the leading causes of death
worldwide. These disorders affect the central nervous sys-
tem (CNS) or peripheral nervous system (PNS). Common
symptoms include structural, biochemical or electrical
abnormalities in the brain, spinal cord or other nerves of
the body. It is very much known that the CNS is a very
complex system, and infection of CNS causes many severe
CONTACT Jiban Jyoti Panda jyoti@inst.ac.in Institute of Nano Science and Technology, Punjab, India; Jibanananda Mishra mjiban@gmail.com
School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab 144411, India
EXPERT OPINION ON DRUG DELIVERY
2019, VOL. 16, NO. 2, 113–128
https://doi.org/10.1080/17425247.2019.1562443
© 2019 Informa UK Limited, trading as Taylor & Francis Group

neurological diseases due to its limited self-repairing prop-
erty in addition to ineffective delivery of CNS drugs across
a very selective blood-brain barrier (BBB).
The World Health Organization (WHO) reports that more
than 50 million people suffer from epilepsy [4]. It has been
reported that 47 million people have dementia, among which
36 million are suffering from AD [5]. In recent studies, it has
been found that stroke is one of the major causes of death
and disability in the world. According to a report by the
American Heart Association, the global prevalence of stroke
was 42.4 million in 2015, with the prevalence of ischemic
stroke of around 24.9 million and hemorrhagic stroke of
18.7 million globally [6]. It has been also noted that among
different types of cancer, brain cancer is evaluated as the most
fatal and intrusive type of CNS disorders [7,8]. Gliomas are
heterogeneous with multiple subtypes and the most prevalent
primary intracranial tumors that comprise 27% of all brain
tumor types, and 80% of malignant tumors. The most recur-
rent type of glioma is glioblastoma (consists of 56% of the
cases), with very poor consequences. Lower grade gliomas are
reported to be the second most prevailing glioma, especially
in adults (~30%) [9].
These disorders not only jeopardise patients’lives but also
greatly affect their families. Socio-economic burden due to
these disorders are also huge, affecting both individuals and
society multifariously. Currently, there is a dire need for rapid,
early and timely diagnosis of these neurological diseases to
rescue and improve the quality of patients’lives which will not
be attainable by conventional treatment regimen. Therefore,
‘nanotheranostics’a modern treatment approach indulging
the applicability of nanotechnology for realizing solutions for
diagnosis as well as therapy can be a great boon for the
patients suffering from various neurological disorders.
1.2. Nanotheranostics as both therapeutic and
diagnostic entity
Treatment of different dreaded diseases can be effective if
diagnosed at a very early stage. Whereas, as a matter of
concern, existing diagnosis approaches are usually incompe-
tent in diagnosing neural disorders at their primary stages.
Therefore, nanotheranostics comprising of nanocarriers,
carrying both therapeutic and/or diagnostic moieties can be
game changing in revolutionizing and personalizing neurome-
dicine. The diagnostic agents, which are often used in
nanotheranostics, are quantum dots or fluorescent dyes for
optical imaging, iron oxides for magnetic resonance imaging
(MRI), radionuclides for nuclear imaging and heavy metals for
computed tomography (CT). In addition to diagnostic agents,
therapeutic agents can be hydrophobic organic drugs, pro-
teins, peptides and genetic materials [2,3,10].
Besides, the imaging or diagnostic agents, nanocarriers are
the major components of a nanotheranostic system.
Nanocarriers foster pharmacokinetics, enhance biodistribution
of the loaded therapeutic and diagnostic moieties at the
target tissues [11], and increase drug efficacy along with les-
sening toxicity due to reduced non-specific biodistribution
[12,13]. These nanocarriers have been discerned to be functio-
nalized with biomarkers or other targeting ligands for achiev-
ing target-specific treatments and also to achieve diagnostic
ability in real time. Further, therapeutic entities such as small-
sized hydrophobic molecules, peptide drugs as well as oligo-
nucleotides have been shown to exhibit enhanced stability
when being loaded into nanocarriers [14].
1.3. Current approaches vs. nanotheranostics
Current treatment methods to treat neurological disorders
include surgery, radiotherapy, chemotherapy, and immu-
notherapy. In recent years, some other modern treatment
methods such as gene therapy, hyperthermia therapy, and
stem cell therapy [15–18] have also been probed for the
treatment of neurological disorders. However, for attaining
effective therapy, early diagnosis is a primary requisite.
Therefore, arming the surgeon with the magic wand of suita-
ble imaging techniques such as positron emission tomogra-
phy (PET), single-photon emission computed tomography
(SPECT), MRI and X-ray CT will possibly assist their timely
decisions, which in turn can reduce the risk of disease recur-
rence and repeated therapies [19–22]. PET and SPECT both are
nuclear medicine based imaging techniques and use radio
probes as the contrast agents. These radio probes emit
gamma rays which are collected to localize or quantify specific
receptors in the living brain that help to find out the neuro-
logical changes occurring during the progression of diseases
[23]. Interestingly, PET is more efficient imaging tool as com-
pared to SPECT due to its higher sensitivity and better resolu-
tion [24]. MRI and CT, both are noninvasive imaging
techniques which can detect morphological changes in dis-
eased tissues. CT uses specialized X-ray equipment to examine
different parts of the human body such as; brain, sinus, facial
bones, dental, spines, cervical, hands, wrist, elbow, shoulder,
hip, knee, ankle foot, renal tract. CT helps in diagnosing the
disease, detecting an abnormality, and planning treatment
accordingly. However, CT has limitations of low tissue contrast,
inability to visualize small groups of tumor cells those are
separated from the gross tumor, and lack of providing func-
tional information. While MRI is a new and powerful diagnostic
tool, widely used in the examination of different abnormalities
of various parts of the body, such as brain tumors, inflamma-
tion in the spine, injuries of joints, assessing blood flow and
Article highlights
●Nanotheranostics, defined as a multifunctional nanosystem with dual
capability of working as both diagnostics and therapeutic modality
has gained significant interest in the recent past.
●The article highlights the role of different nanocarrier systems as
theranostic agents for neurological disorders.
●Exemplifies various types of nanoparticle systems explored in the
arena of neurological ailments.
●Summarizes the research undertaken in the field of nanotheranostics
for achieving diagnosis and therapy of neurological disorders in the
last decade or so.
●Current challenges and future perspectives for advanced nanother-
anostic systems for neurological ailments diagnosis and treatment
are also being discussed.
This box summarizes key points contained in the article
114 M. SHARMA ET AL.

imaging of cardiac function, etc.. When compared to CT, MRI
uses radiofrequency waves for signal generation and offers
high-quality images with greater intrinsic soft-tissue contrast
and resolution [19,25]. As depending on the number of pro-
tons, few atomic nuclei, for example, hydrogen nucleus,
1
H,
possesses a ‘“spin”’ property. In MRI, spin possessing nuclei
present within the static magnetic field is excited by applying
a second radiofrequency magnetic field at an appropriate
resonant frequency and perpendicular to the static magnetic
field. Absorption of energy by the nuclei causes a transition
from higher to lower energy levels. The absorption and emis-
sion of energy by different nuclei (e.g. free water and water
bound to tissue) generates a voltage, which is detected, ampli-
fied and transformed into an image. Each tissue’s nuclei relax
at different rates, which give contrast between different tis-
sues. Now-a-days, a variety of paramagnetic and superpara-
magnetic metal nanoparticles are commonly used contrast
agents for MRI [26,27]. Similarly, fluorescence imaging is an
Figure 1. Graphical representation of different nanotheranostic systems having the potential for the treatment and diagnosis of neurological disorders. It
demonstrates the mechanism of how various targeted theranostic nanoparticles can across the blood-brain barrier and deliver requisite amount of treatment
modalities in the brain along with facilitating real-time diagnosis via imaging.
EXPERT OPINION ON DRUG DELIVERY 115

extremely beneficial tool for real-time assessment of diseased
tissues with complementary advantages such as low-cost, high
contrast/signal generation, high sensitivity, safety, and can be
designed to be activated at the target site through certain-
specific markers those are overexpressed in the affected area
while otherwise, they remain inactive. Furthermore, the use of
fluorescent probes in the infra-red region leads to an
increased penetration depth and reduced signal scattering,
thus allowing visualization of diseased tissues up to greater
depth [28].
Despite much progress in the current diagnostic modalities,
successful treatment of neurological disorders are limited
owing to many drawbacks of the currently available methods,
which include: 1) higher time consumption and low sensitivity
in MRI [29], 2) poor penetration and more scattering in the
brain tissues in fluorescence-based imaging [30], 3) inability to
monitor disease progression along with the administered
drug, and 4) exertion of toxic effects on the surrounding
healthy brain tissues due to lack of specific/targeted function
in case of radioactive tracer-based imaging in PET and SPECT
[31]. Likewise, conventional therapies such as chemotherapy,
photodynamic therapy, surgery, radiotherapy, immunotherapy
those are generally being followed for managing neurological
disorders especially CNS disorders, also experience various
challenges such as: 1) inability to cross BBB, 2) inadequate
drug uptake in the neural tissues, 3) inferior biocompatibility
4) non targeted delivery and distribution, 5) poor solubility, 6)
lower half-lives and retention time, and 7) undesirable effects
on rapidly dividing healthy cells.
To overcome all these issues and to achieve effective ther-
apy, there is a pressing need for the development of advanced
methods which possess high sensitivity, high resolution, deep
penetration power and ability to facilitate real-time monitor-
ing of disease progression along with biosafety. In this con-
text, ultrasmall multimodal nanotheranostics can show great
potential for biomedical imaging and disease therapy [32,33].
In this review, we have tried to provide a glimpse of nanother-
anostics based studies and related outcomes pertaining to
various neurological disorders. We hope that this review will
be instrumental in enriching the repertoire of knowledge of
researchers and clinicians on various nanotheranostic systems
under investigation as potential therapeutics towards neuro-
logical disorders.
2. Blood Brain Barrier (BBB): a major hindrance in
the path of drug delivery system
The greatest hindrance in delivering drugs to the brain is
attributed to the BBB. BBB acts as an insurmountable obstacle
for routing a large number of drugs such as antibiotics, cyto-
statics, and CNS-active drugs, etc., due to the presence of tight
endothelial junctions between the microvasculature and brain
parenchyma. BBB is composed of an endothelial monolayer,
pericytes enclosed within the endothelial basal lamina, and
astrocytes touching their end-feet to the abluminal side of the
brain vessels. Endothelial cells of the CNS are hold together by
tight junctions giving rise to a highly resistant paracellular
seal, which impedes the transport of various molecules and
ions into the neural tissues [34]. In addition to endothelial
cells, the astrocytic end-feet surrounding BBB regulate barrier
permeability and dictate the localization of transporters. There
are various transport mechanisms like passive diffusion, endo-
cytosis, receptor-mediated transcytosis, active transport and
carrier-mediated transport, which facilitate the transfer of var-
ious molecules, nutrients, and drugs across the BBB. These
transport mechanisms implicate various transport proteins
which mediate the uptake and expulsion of different metabo-
lites and compounds across the BBB [35]. Interestingly, BBB is
not a barrier in the true sense; it is dynamic in nature and
allows the entry of various essential nutrients, such as amino
acids, hexoses, proteins, peptides, and ions to assist normal
functioning of the brain and concurrently restrict entry of
noxious substances. Moreover, the presence of efflux pumps
such as P-glycoprotein quickly removes any foreign substance
that bypasses the BBB. As a result, only small, lipophilic com-
pounds, such as O
2
or steroid hormones readily diffuse across
the BBB facilitated by their concentration gradient. It has been
observed that more than 99.9% of macromolecules and
almost more than 98% of small molecules having a size
greater than 500 Da cannot penetrate the BBB [36].
Therefore, these unique attributes of the BBB microvasculature
govern molecular trafficking across the barrier and signifi-
cantly influence drug delivery to the brain [37], posing
a challenge to the effectiveness of neural therapeutics.
3. Different types of theranostic NPs used in
neurology
Recently, theranostic NPs are emerging as very promising and
efficient tools for achieving targeted drug delivery due to their
unique physiochemical properties such as nanoscale size, encap-
sulation of drug and adsorption or conjunction of contrast
agents on their surface. Moreover, to enhance the specificity of
theranostic NPs at their acting/target site of action, NPs surface
can be modified by various active and passive targeting agents.
Active targeting of these NPs can be achieved by functionalizing
with various ligands such as peptides, antibodies, aptamers, and
others, which specifically bind to the expressed receptors on the
brain endothelial cell surface and enable these NPs to cross the
BBB [38]. Likewise, for passive targeting, the surface of NPs can be
coated with hydrophilic polymers such as polyethylene glycol
(PEG), poly(acryloylmorpholine), poly-N-vinylpyrrolidones, poly-
vinyl alcohol and poly[N-(2-hydroxypropyl) methacrylamide].
Interestingly, these polymers coating not only enhance blood
circulation time but concurrently avert recognition by macro-
phages and monocytes. Thus, reducing the risk of opsonisation
and rapid clearance of NPs from the blood [39]. These multi-
functional nanosystems coated with targeting agents, hold the
potential of diagnosis, imaging, and treatment of disease
enacted by a single formulation of biocompatible and biode-
gradable NPs. Currently, there are various types of theranostic
nanoplatforms such as, lipid NPs, polymeric NPs (PNPs), inorganic
NPs and some others being explored for diagnosis and treatment
of neurological disorders [40].
Applications of these theranostic NPs for the treatment of
neurological disorders are compiled and discussed in Table 1
(Table 1). Lipid NPs are the most popular and extensively
116 M. SHARMA ET AL.

Table 1. List of nanoparticles explored as theranostic agents towards the treatment of various neurological disorders.
S.No. Theranostic NPs
Ligand/Transport
Method
Animal Model/Cell
lines
Imaging/
Diagnostic agent Therapeutic agent Neurological disorders Results Ref.
1 Liposome Endocytosis Female nude mice QDs
a
Apomorphine Parkinson’s disease ●First liposome drug QD hybrid.
●Enhances brain targeting
●Greater fluorescence intensity
●2.4 fold increases in drug accumulation
[42]
2 TPGS
b
liposomes Transferrin Charles Foster (CF) rats QDs Docetaxel Brain tumor ●Targeted therapy
●Higher drug delivery
●2 fold more efficient than non targeted
liposome
[43]
3 CMD
c
-Magnetoliposome Passive transport Human
neuroblastomaSH-
SY5Ycells s
SPIONs
d
Doxorubicin Brain tumor ●Higher stability and drug loading capacity
●Efficient T
2
weighted contrast agent
●Less toxic than free DOX
[44]
4 M40401 Liposomes Mnporphyrins Mice Mn(11) cation SOD
e
Cerebral Ischemia ●Efficient Mn-SOD mimetic
●T
1
contrast agent for MRI imaging
●Neuroprotective effect of mimetic SOD
[45]
5 Stealth
Immunoliposome
Anti-HSP72 Ischemic rats Rhodamine/Gadolinium Citicoline Cerebral ischemia ●A noval theranostic nanoplatform
●Targeted treatment
[46]
6 RGD-TPGS Liposome RGD/receptor mediated
endocytosis
Rats QDs DTX
f
and QDs Brain cancer ●Biocompatible liposome for targeted co
delivery of DTX and QDs
●Enhances 70% efficiency of Drug
encapsulation.
●Sustained the release of drug.
●6.47 fold more efficient than DocelTM
[47]
7 pyE- lipid nanoparticle Apo E3/transcytosis Orthotopic U87-GFP
tumor bearing mice
Porphyrin Porphyrin Glioblastoma
tumor
●Intrinsic theranostic properties
●Act as both glioma drug and contrast
agent
●In vitro uptake by LDLR
g
- mediated endo-
cytosis .
[48]
8 Liposome Anti-CD20 Athymic nude mice SPIONs Rituximab Primary central
nervous system
lymphoma (PCNSL)
●Novel theranostic NP developed for PCNSL
●Potent anti lymphoma activity
●Prolonged storage capacity of NPs
●Targeted drug delivery
[49]
9 Polymeric nanoparticle Endocytosis Rat Supermagetic iron oxide Temozolomide (TMZ) Malignant glioma ●Convection- enhanced drug delivery (CED)
●Tracked by iron oxide used as MRI contrast
agent
●Effectively reduced the growth of glioma
●Enhances the survival rate
[50]
10. Chitosan-coated iron
oxide cores
Chlorotoxin GBM6-Bearing mice SPION O6 –Benzylguanine (+oral
temozolomide)
Brain tumor ●Significant biodistribution in tumor region
●Real time monitoring of drug by MRI
h
●Amplify 3 fold survival rate
[51]
11 Polyfluorene−chitosan Adsorptive transcytosis Endothelial cells (EAhy
926.1)
Polyfluorene Polyfluorene Alzheimer’s and
presenile dementia
●Novel polymer conjugate
●Inhibits or modulates amyloid aggregates
●Sense by their unique optical properties
[52]
12 PEG
i
-PLA
j
-NPs TGN and QSH peptides AD model mice DIR
k
Coumarin-6 Alzheimer’s Disease ●Higher uptake and distribution in brain.
●Improved targeted delivery to amyloid
plaque in mice brain
[92]
13 Alginate coated Iron
oxide core
G23 Peptide/receptor
mediated endocytosis
U87-luc2- bearing
mice
Iron oxide Doxorubicin Brain tumor ●Safe nanocarrier for brain tumor therapy
●MRI contrast agent for in vitro and in-vivo
diagnosis
●Significant shrinkage of tumor in treated
mice after 7 days
[53]
(Continued )
EXPERT OPINION ON DRUG DELIVERY 117

Table 1. (Continued).
S.No. Theranostic NPs
Ligand/Transport
Method
Animal Model/Cell
lines
Imaging/
Diagnostic agent Therapeutic agent Neurological disorders Results Ref.
14 Polymeric nanoparticle F3 peptide Glioma bearing rats Iron oxide Photofrin Brain tumor ●Targeted drug delivery
●Improved therapeutic efficiency
●Significant increases in survival rate
[13]
15 PHEMA-RA-PCB-CPP
l
polymeric
nanoparticle
CPP/endocytosis 2×Tg
m
-AD mice SPIONs siSOX9 Alzheimer’s disease ●Efficiently controlled the differentiation of
normal stem cells to neuron
●Enhances cellular uptake
●Ameliorates neurological changes
●Real time monitoring and migration of
NSCs
n
by SPIONs
[54]
16 PCB polymer Endocytosis 2×Tg-AD mice SPIONs let-7b antisense
oligonucleotide and
simvastatin
Alzheimer’s disease ●Self-assembled traceable NPs
●Traceable NPs with higher drug loading
capacity
●Effective Control release of drug
●Rescued memory deficits
[55]
17 SPIONs Anti-Aβmonoclonal
antibodies
(aAβmAbs)
NI
o
SPIONs NI Alzheimer’s Disease ●Temperature responsive magnetic drug
delivery system
●Targeted drug delivery system
[56]
18 SPIONs Anti-Aβmonoclonal
antibodies
(aAβmAbs)
Transgenic mice model
of AD
p
Fluorescent SPIONs BAM10 Alzheimer’s Disease ●Inhibition of Aβ
q
40 fibrillation by 5 fold
●Detected Aβ40 fibrils by MRI and fluores-
cence imaging
[57]
19 Iron oxide magnetic
nanoparticles
Penetration APPswe/PS1dE9
transgenic mouse
Iron oxide MNPs
r
Rutin Alzheimer’s disease ●Congo red labelled MNPs
●Aβaggregates detected by MRI
●Controlled release of drug in a H
2
O
2
-
responsive manner
●Prevent oxidative stress for AD therapy
[83]
20 Den-RGD-Reg peptide
nanoparticle
c(RGDyK) Orthotopic U87-GFP
tumor bearing mice
NIR
s
fluorophore IR640B Paclitaxel Brain tumor ●Glioma targeted specificity
●Enhanced survival rate
●Image-guided chemotherapy.
[58]
a
QDs = Quantum dots.
b
TPGS = D-alpha-tocopheryl polyethylene glycol 1000 succinate mono-ester.
c
CMD = Carboxymethyl dextran.
d
SPIONs = Superparamagnetic iron oxide nanoparticles.
e
SODs = Superoxide dismutase.
f
DTX = Docetaxel.
g
LDLR = Low-Density Lipoprotein Receptor.
h
MRI = Magnetic Resonance Imaging.
i
PEG = Polyethylene glycol.
j
PLA = Poly (lactic acid).
k
DIR = 1,1 -dioctadecyl-3,3,3,3 -tetramethylindotricarbocyanine Iodide.
l
PHEMA-RA-PCB-CPP = Poly(2-hydroxyethyl methacrylate)-RA-poly(carboxybetaine) cellpenetrating peptide.
m
Tg = Transgenic.
n
NSCs = Neural stem cells.
o
NI = Not informed.
p
AD = Alzheimer’s disease.
q
Aβ= Amyloid beta.
r
MNPs = Magnetic nanoparticles.
s
NIR = Near-infrared region.
118 M. SHARMA ET AL.

studied NPs. These are the first nanomedicine delivery systems
having clinical acceptance. Based on the types of lipids and
their physiochemical properties, different types of lipid NPs
such as a liposome, solid-lipid NPs, porphysomes, lipid coated
calcium phosphate, etc., are available [41]. These NPs have the
ability to deliver both hydrophobic and hydrophilic substance.
Moreover, their surface can be functionalized or modified with
multiple molecules for various applications, such as an ima-
ging agent for diagnosis or non-invasive biodistribution mon-
itoring, ligands for specific targeting and PEGylation for
prolonged circulation in blood.
PNPs are colloidal solid NPs of size <1000 nm, derived from
both synthetic polymers, such as poly (lactic acid) (PLA) and
poly(lactide-coglycolide) (PLGA), and natural polymers, such as
chitosan and collagen which are mostly investigated for bio-
medical applications [59]. PNPs are the most versatile and
widely accepted nanocarrier systems for delivering drugs to
CNS due to their ability to entrap drugs inside and can be
functionalized with suitable cell-penetrating peptides and/or
targeting ligands for drugs delivery successfully across the BBB
[60]. Currently, these are used as robust nanotheranostic
agents for the treatment and diagnosis of neurological disor-
ders considering their unique ability of conjugation, entrap-
ment or encapsulation of both drugs and diagnostic agents on
their matrix [61].
Chitosan has been found to be the most common natural
polymer used as theranostic agents for neurodegenerative
diseases due to its nontoxic, biocompatible and biodegrad-
able nature [62]. Like natural polymers, synthetic polymers
such as PLA and PLGA are also commonly employed to con-
struct theranostic agents for neurological disorders owing to
their biocompatible, biodegradable and low immunogenic
nature [63].
Furthermore, inorganic NPs such as iron oxide, ceria, gold,
and quantum dots are most robustly used theranostic nanos-
tructures owing to their controllable size, great biocompatibil-
ity, easy surface modification and multifunctional nature [64].
Although inorganic NPs have gained tremendous attention as
theranostic systems for neurological disorders, their instability
and potential toxicity to human systems limit their clinical
applications.
Moreover, in recent years nanosystems like upconversion
NPs (UCNPs), dendrimers, and CNTs have evoked notable
interest among various researchers. UCNPs have a unique
property of generating high energy visible radiations from
low energy near-infrared (NIR) radiations due to nonlinear
optical process. Interestingly, UCNPs get excited within
a narrow absorption band at around 975 nm, which fall within
the NIR range considered to be the ‘optical transparency
window’(700–1100 nm) of tissues. It has been noted that
biological tissues have relatively small scattering and absorp-
tion at 975 nm and also less autofluorescence while collecting
the NIR UC emission. Therefore, excitation of UCNPs at this
wavelength does not cause any photodamage to the sur-
rounding biological tissues [65–67].
Thus, UCNPs with low toxicity profiles, remarkable optical
properties such as large Stokes shifts, narrow emission peaks,
and good chemical and physical stabilities, can act as powerful
smart nanoprobes for potential nanotheranostic applications
[68]. In addition to the UCNPs, dendrimers are also drawing
significant attention as theranostic nanocarrier systems.
A well-organized 3D structure and easy surface modification
ability of dendrimers with different functional groups endow
them with high drug loading capacities side by side making
them suitable diagnostic and imaging agents. Moreover, sur-
face modified dendrimers exhibit less cytotoxicity and greater
biocompatibility for in vivo applications [69]. Likewise, CNTs
demonstrate special electronic and mechanical qualities suita-
ble for use in biomedical applications. Surface functionaliza-
tion and modification of CNTs with hydrophilic or
biocompatible molecules improve their target-specific cell/tis-
sue delivery, water dispersibility and minimize toxicity.
Interestingly, intrinsic NIR photoluminescence optical and
thermal properties of CNTs have shown high potential for
brain-targeted theranostic applications as compared to other
theranostic NPs [70].
4. Specific examples of theranostic applications of
nanosystems in neurological disorders
Various features of nanotheranostic systems can be tremen-
dously helpful in formulating the next generation nano-neuro-
therapeutics those can serve as both diagnostic and therapeutic
modalities to treat dreaded neurological disorders as exemplified
in different diseases mentioned below.
4.1. Glioma (brain tumors)
During the last few years, the number of deaths due to cancer has
been increasing at a striking rate. Now-a-days, radiotherapy and
chemotherapy are being used in various cancer treatments.
However, these methods are non-specific and render annihilation
of normal tissues along with the cancer tissues. Majority of antic-
ancer drugs fail to reach brain due to the presence of BBB. Thus,
theranostic nanomedicines are being developed to improve cur-
rent cancer therapeutics to overcome the existing limitations [71].
Ruan et. al. developed a tumor microenvironment sensitive size-
shrinkable theranostic system in order to improve targeted deliv-
ery to glioma tissues as well as to monitor drug delivery and
treatment outcomes. This system integrates small-sized gold NPs
(AuNPs) onto gelatin NPs, which is a substrate for enzyme matrix
metalloproteinase-2 (MMP-2), doxorubicin (DOX) (therapeutic
moiety) and Cyanine-5.5 (Cy5.5, a fluorescent probe) decorated
onto AuNPs through a hydrazone bond, making the system pH
sensitive and arginine-arginine-glycine-aspartic acid (RRGD,
a tandem peptide of RGD) and octarginine showing both tumor
targeting and tumor penetration ability. The system was surface-
modified with glioma targeting sequence (G-AuNPs-DC-RRGD) to
enable active targeting. In vitro, the size of G-AuNPs-DC-RRGD
could effectively shrink from 188.2 nm to 55.9 nm after 24-hour
incubation with MMP-2, while DOX and Cy5.5 were observed to be
released in a pH-dependent manner. G-AuNPs-DC-RRGD could
enter inside cells and displayed high glioma targeting and accu-
mulation efficiency, capable of delivering DOX to tumors. By virtue
of fluorescence imaging, these systems further facilitated the
simultaneous tracking of drug delivery potential and therapeutic
outcomes in vivo [72]. In another study, Ching et. al.usedsuper-
EXPERT OPINION ON DRUG DELIVERY 119

paramagnetic iron oxide (SPIO)-conjugated with doxorubicin-
loaded microbubbles (DOXSPIO-MBs) for the diagnosis and treat-
ment of a brain tumor. They used focused ultrasound technique to
noninvasively and locally open the BBB. The microbubbles with
sensitiveness towards focused ultrasound (FUS) acted as stable
nanosystems which were designed to induce BBB-opening and
successful delivery of therapeutic drugs upon FUS exposure in rat
C6 glioma model was achieved and can be magnificent tools for
future image-guided diagnosis and treatment of brain tumors
[73]. Sun et. al. fabricated a novel formulation of mixed gold and
SPIO loaded micelles (GSMs) coated with polyethylene glycol-
polycaprolactone (PEG-PCL) copolymer (hydrodynamic diameter
approximately 100 nm) as both therapeutic and diagnostic tool in
the management of glioblastoma multiforme (GBM). To deter-
mine the potential theranostic applications of novel GSMs, they
investigated the radiosensitizing efficacy of GSMs by quantifying
gH2AX (gamma H2AX, a marker of early dsDNA breaks) DNA
damage foci in glioblastoma cell lines (U251 and U373), and
found that GSMs administration in conjunction with radiation
therapy led to ~2-fold increase in density of dsDNA breaks. As
a diagnostic tool for GBM, GSMs were used as contrast agents for
both CT and MRI of GBM tumors implanted in a mouse model [74].
Zhou et. al. have prepared iNGR-modified doxorubicin loaded
sterically stabilized liposomes (iNGR-SSL/DOX) to overcome the
tumor vascular barrier and tumor-stroma barrier by surface mod-
ification of liposome with iNGR, a tumor-penetrating peptide. In
vitro study of iNGR-SSL/DOX on uppsala 87 malignant glioma
(U87MG) cells and human umbilical vein, endothelial cells
(HUVEC) showed higher uptake with greater cytotoxicity of dox-
orubicin-loaded iNGR-SSL as compared to the unmodified lipo-
some. Additionally, they encapsulated Fluorescein amidite (FAM)
or DiR as a fluorescent tracer in the nanostructures for aiding
in vivo imaging and demonstrated a significant increase in lipo-
some amount in orthotopic tumor tissues of the animal model
due to iNGR modification (Figure 2)[75]. Ramachandran et. al.
reported a simple and innovative method for making custom
designed theranostic implants by creating a library of drug-
loaded polyester nanofibers of PLGA-PLA-PCL blends. Nanofibers
with different release kinetics (from hours to months) were suita-
bly mixed at appropriate weight fractions and electrospun
together to form a single three-dimensional (3D) composite nano-
fiber implant containing a separate set of nanofibers capable of
releasing the anti-glioma drug temozolomide for a specific period
and then shifted to next set for another period, thus continuously
releasing the drug upto one month into the orthotopic brain
tumor at a constant rate. Additionally, they loaded nanofiber
implant with Fe
2+
doped calcium phosphate NPs (nCP: Fe) as
contrast agents for MRI-guided non–invasive imaging of the nano-
device in vivo (Figure 3)[76]. Gamage et. al. have reported a novel
Curcumin-conjugated generation-3 (G3-Cur) dendrimer to ame-
liorate in vivo systemic bioavailability and drug delivery into brain
tumors. These nanoconjugates exhibited enhanced diagnostic
imaging potential with minimized drug-related systemic toxicity
in an orthotopic preclinical glioma model. G3-Curc can be promis-
ing new formulation for clinical translationofCurcumintocancer
patients due to superior bioavailability and protracted therapeutic
efficacy [69]. Jing and group demonstrated efficient NIR mediated
photoimmunotherapy (PIT) in human tumor xenografts devel-
oped from cancer stem cells (CSCs), using target-specific AC133
monoclonal antibody (mAb) and NIR photosensitizer dye phtha-
locyanine IR700 conjugates (AC133-IR700 conjugate). Theranostic
AC133-IR700 conjugates permitted precise image-guided and
spatiotemporally controlled eradication of tumor cells. This study
highlighted non-invasive NIR fluorescence imaging of orthotopic
gliomas and PIT in glioblastoma stem cells (GBM-SCs). Results
indicated rapid shrinkage of both invasively and subcutaneously
growing brain tumors in a single treatment. Target binding effi-
ciency and uptake of the AC133-IR700 conjugate was evaluated in
nude mice bearing U251 glioma cells over-expressing CD133 by
harnessing NIR-fluorescence molecular tomography (FMT). Such
designed theranostic systems might be used well for intra-
operative imaging and histopathological evaluation of tumor bor-
ders in patients towards fluorescence-guided tumor resection [77].
Sun and group worked on highly specific and biocompatible
nanoprobes generated from PEG-coated iron oxide nanoparticles
via functionalizing the surface of the nanoparticles with glioma
targeting peptide, chlorotoxin (NP-PEG-CTX nanoprobe). This arti-
cle highlights preferential accumulation of NP-PEG-CTX nanop-
robes inside glioma tissues, followed by their in vitro
demonstration of contrast enhancement in MRI both in 9L cells
(Rat malignant glioma) and in xenografts. TEM imaging further
revealed the internalization of NP-PEG-CTX nanoprobes into the
cytoplasm of 9L cells. Developed nanoprobe with specific target-
ing and biocompatibility offers a potential platform to assist
simultaneous diagnosis and treatment of deadly gliomas and
other neurological disorders [78].
4.2. Alzheimer’s disease (AD)
AD is one of the most common neurodegenerative disorders and
the main hallmark of AD is the accumulation of plaques formed
due to the aggregation of β-amyloid and intracellular neurofibril-
lary tangles formed because of phosphorylated tau protein [79].
Despite a multidisciplinary team of researchers involved, till date,
no effective therapy has been developed towards this disease.
Anti-AD drugs in clinical studies majorly target the CNS as a site
of action. However, the presence of BBB as a protective, as well as
a very selective barrier in CNS, impedes the drugs to cross through
it in significant concentrations [80]. Zhi Du et. al. developed
a‘sense and treat system’to target amyloid aggregates related
to AD, which is one of the best examples to illustrate ‘image-
guided therapy’of Alzheimer’s by simultaneous diagnosis and
treatment. They used magnetic NPs (MNPs) whose surface was
modified with two moieties, firstly, by napthalimide based fluor-
escent probe (NFP) which was an oligomer-specific fluorescent
probe designed against the exposed hydrophobic regions on Aβ
oligomer surface and secondly, by Aβ-targetpeptide,KLVFF.The
complex (MNP@NFP-pep) monitored the changes in Aβmorphol-
ogy results due to the disaggregation of Aβaggregates by the local
heat generated by MNPs that could be sensed by the fluorescence
probe (Figure 4(a)).Therefore,itcanbeusedasareal-time,‘sense
and treat’system for the treatment of AD [81]. In another report,
researchers have developed a novel tau targeted multifunctional
nanocomposite, ceria nanocrystals (CeNC) and iron oxide nano-
crystals (IONCs) onto the surface of mesoporous silica nanoparti-
cles (MSNs) functionalized with amino-T807 (PET tau tracer), an
amino substituent of T807 and methylene blue (CeNC/IONC/MSN-
T807-MB) for AD theranostics. They focused on alternative tau
120 M. SHARMA ET AL.

targeting approach for treating AD instead of amyloid-β(Aβ)
targeted therapy. The CeNC/IONC/MSN-T807-MB nanocomposite
was formed by the controlled assembly of ultrasmall ceria nano-
crystals (CeNCs), as tau hyperphosphorylation inhibitor and iron
oxide nanocrystals (IONCs), as MRI agent, on the surface of uniform
mesoporous silica NPs (MSNPs). Further, the surface of MSN was
functionalized with amino-T807, via 1,4,7-triazacyclononane-
1,4,7-triacetic acid (NOTA), for active targeting of tau protein.
Methyleneblue(MB),asmallinhibitor for tau aggregation was
further loaded into the pores of MSNs (Figure 4(b,c)). In vitro and
in vivo studies of CeNC/IONC/MSN-T807-MB nanocomposite for-
mulations using SH-SY5Y cells and AD rat models demonstrated
significant suppression of tau hyperphosphorylation and protec-
tion of neural death [82]. Zhang and group reported
a nanotheranostics system (Congo red/Rutin-MNPs) based on
magnetic iron oxide NPs (MNPs) with ultrasmall size to realize
in vivo imaging of amyloid plaques along with targeted delivery
and H
2
O
2
controlled release of therapeutic agent rutin. Congo red/
Rutin-MNPs theranostic system when co-administered with man-
nitol was able to breach and cross BBB of the APPswe/PS1dE9
transgenic mouse and specifically bind to amyloid plaques, allow-
ing the recognition of amyloid plaques by MRI along with targeted,
and stimuli-responsive delivery of Rutin via the Aβ-induced pro-
duction of H
2
O
2
. Rutin is a powerful antioxidant which prevents
oxidative stress, interferes with Aβaggregation, and reduces amy-
loid plaques and neuronal loss [83].
Similarly, Li et. al. have reported novel multifunctional peptide
conjugated gold (Au) nanorods for diagnosis and treatment of AD.
They combined unique high NIR absorption property of AuNRs
with two Aβinhibitors, Aβ15–20 (Aβ-targeted peptide inhibitor)
and polyoxometalates (POMs) for effective inhibition of Aβaggre-
gation and also dissociation of amyloid deposits by NIR irradiation.
Additionally, shape and size-dependent optical properties of gold
nanorods were used as effective diagnostic probes for detection of
Aβaggregates. Thus, this study exemplifies a multifunctional ther-
anostic nanosystem containing various components such as
a targeting ligand, a reporter, and inhibitors in one system for
treating AD [84]. Cui et. al.havereportedanovelsmartUCNP-
based nanoprobe that can simultaneously serve the purpose for
accurate diagnosis and effective therapy of AD. UCNPs nanoprobe
is comprised of two major components: UCNPs for detection and
imaging, the chelator 8-hydroxyquinoline-2-carboxylic acid (HQC)
for capturing of Cu
2+
,andtherapyofAD.Thesemultifunctional
UCNPs were capable of detecting and capturing Cu
2+
both in vitro
Figure 2. The figure shows increased accumulation of liposomes in tumor tissues after modification with iNGR. In vivo fluorescence images of glioblastoma bearing
nude mice after i.v. injection of SSL/DiR (left), NGR-SSL/DiR(middle), and iNGR-SSL/DiR (right). Reprinted with permission from [75].
EXPERT OPINION ON DRUG DELIVERY 121

and in vivo.Fascinatingly,thissystem has also shown the unique
ability to inhibit as well as transforming toxic Aβintermediates into
nontoxic fibers [85]. Recently, Pedro et. al. reported the synthesis of
functionalized CNTs (f-CNTs) and used them as theranostic carriers
for brain delivery of amyloid-targeting drugs/compounds that effi-
ciently cross the BBB. Importantly, attractive intrinsic optical, ther-
mal properties, and the ability to cross biological barriers by both
energy-dependent and independent mechanisms of functionalized
CNTs (f-CNTs), bestows them as useful tools towards brain targeting
theranostic applications [86]. Functionalized multi-walled carbon
nanotubes (f-MWNTs) capable of crossing an intact BBB have
already been demonstrated by Kafa and group [87–89]. They
functionalized MWNTs with two PiB derivative Gd
3+
complexes-
Gd (L2) and Gd(L3). PiB is an Aβ-binding molecule and used as a PET
imaging agent. In vivo biodistribution results demonstrated con-
siderable uptake and accumula
tion of f-MWNTs in the brain as compared to free metal complexes.
Thus,thisreportclaimsthatf-MWNTs could be used as carriers in
theranostic applications involving brain delivery of BBB imperme-
able compounds [90]. Li and group showed the theranostic effect
of (E)-4-(4-(dibutylamino)styryl)-1-(2-hydroxyethyl) quinolin-1-ium
chloride (DBA-SLOH) NIR dye which accomplished AD diagnostics
via NIR based in vivo imaging of Aβplaques in APP/PS1 transgenic
(Tg) mouse over-expressing Aβ. Concomitantly therapeutics was
Figure 3. In vitro, drug release profile of TMZ loaded nano wafers (W1 to W6) in artificial CSF at different time intervals (a). Comparative in vivo drug release
behavior of implanted nano wafer 6 in normal brain versus tumor model (b). Post-mortem analysis of implanted tumor (W6, 20wt% TMZ) after one week showing
almost complete degradation of the implant in the tumor microenvironment (c). In vivo NMR chemical shift imaging of intracranial C6 glioma and normal brain. In
tumor brain, prominent lactate and lipid peak (red mark) can be seen which is absent in normal brain (blue mark) (d). In vivo drug release profile of wafers (W6-
W11) in C6 glioma model (e). Reprinted with permission from [76].
Figure 4. Detection and magneto-thermal disassembly of Aβaggregates by MNP@NFP-pep under an AMF. Fluorescence intensity represents the respective states of
Aβmonomers, oligomers, and fibrils after binding of MNP@NFP-pep (a). Reprinted with permission from [81]. Schematic representation of the synthetic procedure of
CeNC/IONC/MSN-T807- MB and its tau-targeted treatment strategy. Fabrication of mesoporous silica nanoparticles surface via small iron oxide, ceria nanocrystals,
NOTA-T807 targeting ligands and methylene blue (b). Bimodal imaging of CeNC/IONC/MSN-T807-MB to target hyperphosphorylated tau, the combinational
therapeutic strategy of ROS scavenging and methylene blue release (c). Reprinted with permission from [82].
122 M. SHARMA ET AL.

achieved by inhibiting Aβmonomers to self-aggregate. This group
developed three cationic NIR dyes and confirmed their activity to
inhibit Aβpeptide aggregation by ThT fluorescence assays, CD
spectroscopy, in vitro fluorescence staining of Aβplaques in brain
slices, and in vivo NIR imaging in animal model. Among them, DBA-
SLOH showed highest BBB permeability, excellent selectivity and
binding affinity to Aβpeptides, and intense enhancement of fluor-
escence signal in the NIR window upon binding with Aβaggre-
gates. The developed theranostic design with excellent BBB
permeability integrating both NIR imaging of Aβspecies and inhi-
bition of Aβaggregation in vivo for the diagnosis and therapy of AD
may open up new avenue in AD treatment [91]. In another study,
Zhang and group developed dual functional pegylated poly (lactic
acid) NPs (PEG-PLA NPs) based targeted delivery system for the
early diagnosis and treatment of AD. To achieve dual targeting,
a 12-amino acid peptide, TGN (targeting ligand for BBB),
D-enantiomeric peptide, QSH (targeting ligand for Aβ42 deposits
in the brain), were surface functionalized over the NPs. Dual-
targeting of the designed system was confirmed via brain distribu-
tion studies of NPs using a near-infrared dye, DiR, as a probe and ex
vivo imaging studies. T3Q3-NP showed precise and improved tar-
geted delivery towards amyloid plaque in the brains of AD mice
model pointing towards a valuable theranostic system for AD diag-
nosis and therapy [92].
4.3. Parkinson’s disease (PD)
After AD, PD is the most common age-related neurodegen-
erative disease [93]. Neuropathologically, PD is gradual loss of
dopaminergic neurons in the substantianigra pars compacta
(SNC) which leads to depletion of dopamine content, causing
severe cognitive and motor deficits [94,95]. Recently,
Dopamine is replaced with L-3,4-dihydroxyphenylalanine
(levodopa) precursor of dopamine which can easily cross the
BBB via large neutral amino acid transporter (LAT1) transporter
[96]. Now-a-days, L-DOPA is used as an effective medicine for
PD patients [97]. In this context, Birgitte et. al .designed
a novel nanosystem of manganese oxide NPs (MONPs) func-
tionalized with L-DOPA capable of releasing Mn
2+
ions and
L-DOPA concurrently in water after the disintegration of
MONPs. They have used MONPs as an MRI agent for imaging
and diagnosis via a time-dependent switch in MR contrast and
L-DOPA as a stabilizer as well as an active drug for PD [98]. Niu
et. al. developed a nano-gene delivery technique using mag-
netic Fe
3
O
4
NPs coated with oleic acid and decorated with
short hairpin RNA (shRNA) plasmid to interfere with α-
synuclein expression in neurons. To render the system to be
temperature and pH-responsive for effective release of gene,
N-isopropylacrylamide derivative (NIPAm-AA) was photo-
immobilized onto the oleic acid molecules. Similarly, to pro-
mote enhanced neuronal uptake through receptor-mediated
endocytosis, nerve growth factor (NGF) was absorbed onto
NIPAm-AA. In vitro and in vivo results demonstrated that this
system is effective in inhibiting apoptosis and repairing a PD
model [99]. Wen et. al. have developed a novel OL-PEG-PLGA
(Odorranalectin conjugated poly (ethylene glycol)-poly(lactic-
co-glycolic acid) nanoconjugate system which was used to
increase the delivery of drugs from nose to the brain for
effective treatment of PD. Odorranalectin (OL) is low
immunogenic and is the smallest member of lectin family.
Further, they have functionalized the OL-NP nanoconjugates
with a neuroprotective drug, urocortin peptide and
a fluorescent tracer, DiR, for in vivo fluorescence imaging. In
vitro studies have shown a significant increase in the uptake of
modified NPs and in vivo studies in hemiparkinsonian rats
demonstrated a proper distribution of OL-NP/UCN nanosys-
tems in brain region along with enhanced therapeutic effects.
Therefore, OL conjugated nanosystems could be used as
potential non-invasive brain drug delivery systems for the
treatment of CNS disorders [100]. Hu and group constructed
an innovative biodegradable system for efficient brain drug
delivery from lactoferrin (Lf) conjugated PEG-PLGA nanoparti-
cles (Lf-NPs). The group focused on utilizing the iron-binding
cationic glycoprotein, Lf as brain targeting ligand. Lf-NPs were
loaded with the cytoprotectant peptide urocortin (UCN),
a corticotrophin-releasing hormone related peptide to arrest
the development of Parkinsonian-like features. In vitro and
in vivo theranostic and targeting properties of Lf-NPs were
evaluated by incorporating coumarin-6 as a fluorescent
probe. Qualitative and quantitative uptake studies of Lf-NPs
showed prominent accumulation of Lf-NPs via clathrin-
mediated endocytosis in bEnd.3 cells. UCN-loaded Lf-NPs sig-
nificantly mitigated the striatum lesion caused due to 6-OHDA.
All these results demonstrated UCN loaded Lf-NPs as promis-
ing brain drug delivery systems in treating PD [101].
4.4. Neurovascular diseases
Neurovascular diseases are one of the topmost leading causes
of death and disability worldwide. According to the statistics
obtained from the American Heart Association (2016), major
vascular diseases include atherosclerosis, stroke, thrombosis,
coronary artery, and peripheral artery diseases. Current inter-
ventions/treatments for vascular diseases have exhibited lim-
ited long-term success and suffer from drawbacks like an
insignificant accumulation of drugs at a target site, rapid
clearance of drugs, and toxicity to normal cells, etc.. Thus,
nanotherapeutic systems can be made to target specific vas-
cular regions by surface modification of NPs with specific
ligands or peptides [102]. Mc Carthy et. al. developed macro-
phage targeting fluorescence NPs for the treatment of athero-
sclerosis. They prepared magnetic fluorescent NPs (MFNPs) by
conjugating dextran-coated magnetic NPs with NIR dye, which
was then analyzed towards photodynamic therapy. It was
observed that upon excitation (at 646 nm) the MFNPs gener-
ated singlet oxygen species those killed the macrophages
without affecting neighboring normal cells [103]. Another
study carried out by Myerson et. al. harnessed the concept
of nanotheronaostics to treat thrombosis. In this study, they
developed bivalirudin-functionalized perfluorocarbon NPs to
target thrombin as a theranostic platform. The NPs bound at
the site of active clotting, and then quenched local thrombin
activity by inhibiting platelet deposition [104]. Sun et. al. car-
ried out a study in the mice hind limb model by developing
VEGF-loaded and IR800-conjugated, graphene oxide NPs as
a theranostic platform to image therapeutic angiogen-
esis [105].
EXPERT OPINION ON DRUG DELIVERY 123

In another report, Agyare et. al. designed theranostic nano
vehicles (TNVs) for targeting, diagnosis, and treatment of cere-
brovascular amyloid deposits which causes recurrent hemorrha-
gic strokes due to the deposition of these amyloid proteins
within the walls of the cerebral vasculature. TNVs were com-
posed of a polymeric nanocore formed of chitosan conjugated
with gadopentetate dimeglumine (Magnevist®), an MRI contrast
agent and cyclophosphamide, an immunosuppressant
entrapped inside for the treatment of cerebrovascular inflamma-
tion. Additionally, they also functionalized TNVs, nanocore sur-
face by the F(ab′)2 fragment (F(ab′)24.1) of a novel anti-amyloid
antibody, IgG4.1 to target cerebrovascular amyloid. Further,
in vitro studies in polarized human microvascular endothelial
cell monolayers (hCMEC/D3) and in vivo studies in mice clearly
demonstrated the capability of TNVs to target as well as image
cerebrovascular amyloid by MRI and single photon emission
computed tomography techniques [106]. Therefore, TNVs served
as new generation advanced theranostic nanocarriers with the
capability to simultaneously detect amyloid accumulation and
inhibit cytokines produced by Aβ40 in the bovine brain micro
vascular endothelial (BBMVE) cells. Similarly, Liu et. al. have
developed a label-free, CDPC-liponanoformulation by the encap-
sulation of citicoline in liposome for the treatment of ischemic
stroke. Citicoline is a well-known neutral neuroprotective used to
treat neurodegenerative diseases. This group has discovered its
inherent chemical exchange saturation transfer (CEST) MRI sig-
nal, which is an interesting property of citicoline for its applica-
tion as a theranostic agent. In vitro results demonstrated clearly
two inherent CEST signals of citicoline at +1 and +2 ppm.
Moreover, in vivo results of CDPC-lipo in rat brain model demon-
strated enhanced accumulation of the nanoformulation in the
ischemic area that could be also monitored by CEST MRI.
Therefore, liposomal citicoline may be a potential label-free ther-
anostic system for the treatment of ischemic stroke [107].
Recently, Wang et. al. have also developed an anti-PirB immuno-
liposome nanoprobe labeled with NIR probe, as a novel thera-
nostic system to target ischemic stroke. PirB is basically a paired
immunoglobulin-like receptor B which is expressed by neurons
and can inhibit neurite outgrowth. They have used soluble PirB
ectodomain (sPirB) protein as a therapeutic reagent for ischemic
stroke. Their results demonstrated that sPirB immunoliposome
could significantly accumulate in the ischemic region and
improved motor abilities of the cerebral ischemic model of
mice [108].
5. Conclusion
In spite of continuous developments in the scientific field,
brain-related maladies remain a serious problem with a high
risk of mortality. Nanotheranostics is a promising area which
has integrated real-time diagnostic, imaging, targeting and
drug delivery features on a single nanoplatform. Copious ther-
apeutic drugs and contrast agents are actually in existence for
achieving therapy and diagnosis of neurological disorders.
However, a lot of factors limit their applications. Importantly,
contrast agents and drugs are not capable of entering the
brain due to BBB, which pose a major challenge in the path
of development of an efficacious and safe theranostic system.
NPs which exhibit low toxicity profile hold great opportunities
to be developed as nanotheranostic systems. In this review,
we have highlighted the description of some nanotheranostic
systems which are currently under investigation for diagnosis
as well as treatment of brain tumor and other neurodegen-
erative conditions. These NPs including lipid NPs, PNPs, inor-
ganic NPs and some others like dendrimers, UCNPs, and CNTs.
We have also analyzed various diagnosis techniques for neu-
rological disorders that include optical imaging, MRI and
SPECT and concurrently different therapeutic modalities for
these ailments are being presented. However, despite these
promising results, the field of nanothernostics is still in its
infancy and yet there are no nanotheranostic systems that
can meet clinical standards for successful clinical translation.
So, undoubtedly there is a need for more efforts to overcome
multiple snags, only then we can transfer the technology from
the laboratory to patient’s bedside for effective and persona-
lized therapy.
6. Future prospects
Undoubtedly nanotheranostic is unique and uncoventional,
carries immense potentional to influence our health-care sys-
tem and society in the near future. From the last few years,
various theranostic systems have been widely used for ima-
ging, therapy, and development of targeted drug delivery
systems toward various CNS disorders. Besides imaging and
therapy, nanotheranostic systems are being used to monitor
pharmacokinetics, distribution of the particles in the tissue,
and accumulation of drug at the target site. Thus, comprehen-
sive knowledge of the pathophysiology of neurological dis-
eases has been obtained by using this innovative technology.
In the current scenario, we have noticed remarkable in vitro
studies mostly focused on preparation and physiochemical
characterization of the nanotheranostics. However, we may
encounter more challenges towards their in vivo applications
while validating their safety and efficacy prior to clinical appli-
cations. To overcome these challenges, progress is being
made for constructing highly advanced biomaterials, which
are able to interact with biological systems at sub-cellular
levels that may be of both basic and clinical significance in
various pathological conditions including neurological disor-
ders. Nanotheranostics can also be applied to discover and
image targeting biomarkers for tracking the progression of
disease non-invasively, judge success of therapy and predict-
ing their outcomes. Further, application of novel nanothera-
nostics based delivery systems of various drugs, growth
factors, and stem cells have been shown to promote the
regeneration of damaged tissues that might bring in better
remedial for the neurological disorders.
7. Expert opinion
In the past few years, a surge in the application of nanotheranostics
as therapeutic or diagnostic/imaging entity has been witnessed in
the treatment/diagnosis of various neural ailments. Major compo-
nents of a nanotheranostic system include imaging/diagnostic
agents and nanocarriers. Diagnostic nano-agents such as quantum
dots (QDs), fluorescent dyes, iron oxides, radionuclides, heavy
metals, etc., have been combined with various brain imaging
124 M. SHARMA ET AL.

techniques such as PET, MRI, X-ray CT, SPECT, etc., for the in-depth
investigation of the pathology of neural diseases. However, PET
and SPECT are disadvantageous over other imaging methods, as
they employ radioactive probes that emit ionizing radiation, which
may affect the surrounding healthy tissues. In this context, fluor-
escence imaging is encouraging with the benefits of being cost-
effective, superior contrast/signal generation, elevated sensitivity
and safety, and real-time assessment of unhealthy tissues. This tool
can be strategically designed for specific markers overexpressed at
the affected region and subsequent activation at the target sites.
Additionally, employment of fluorescent probes in the infrared
region can engender an augmented pervasion with diminished
signal scattering; hence in-depth visualization of diseased tissues
would be feasible.
There are several challenging issues, from nanotoxicity to
efficacy and precision therapies to efficient biomarkers, which
require focused research and attention. In nanotheranostic
systems, the major challenge of fluorescence-guided imaging
is the designing of probes with greater photostability, superior
target selectivity, enhanced accumulation, limited toxicity, and
clear visualization through an improved signal-to-noise ratio.
Clinical use of QDs as fluorescent agents poses an important
safety issue due to slow degradation, metabolism, and excre-
tion. Modification of their surface via biocompatible polymers
would be helpful, however, there is an immense need of
understanding their toxicity mechanism before they are con-
sidered for human use. The efficiency of drug delivery to the
brain is also an important aspect, which depends on effective
targeting strategies to enhance the therapeutic efficacy of
nanosystems by intravenous or intranasal routes and demands
an utmost attention. Likewise, the existence of complex phy-
siopathological conditions along with our inadequate under-
standing of the diverse molecular and cellular mechanisms of
neurological disorders estranges identifying effective tissue
biomarkers for diagnosis and successful therapy of neurologi-
cal disorders. Furthermore, the relationship between in vitro
and in vivo models is an area of imperative concern for the
fruitful translation of preclinical studies of nanotheranostics
into clinical trials. Moreover, the existence of inefficient meth-
odologies, inappropriate use of animal models and conduct-
ing clinical trials in the advanced disease stage contribute to
the failure. Besides, high-cost of these theranostic nanomedi-
cines due to their complexity is often a pragmatic issue.
To deal with these problems, innovative solutions are
desired to construct cost-effective and affordable nanothera-
nostics for facilitating inexpensive diagnostic tests and increas-
ing therapeutic efficacy for the treatment of the dreaded
neural diseases. For example, European regulatory approved
NanoTherm® therapy (MagForce AG, Germany), a magnetic
hyperthermia therapy indicated for malignant gliomas seems
promising. However, there is a need to adjudge how to max-
imize our approach to benefit a number of patients suffering
from difficult-to-treat neuro-diseases. In order to achieve clin-
ical outcomes, much more efforts are being solicited towards
developing these nanotheranostics in the coming generations
by the collaborative efforts between nanomaterial engineers,
basic scientists, and clinicians.
In the treatment of brain diseases, the primary challenge
is to deliver the relevant therapeutics across the BBB.
Passive targeting has numerous snags like poor distribution
and availability of the insignificant quantity of therapeutics
in the target tissues/cells. Though there is a considerable
progress in therapeutic and diagnostic modalities, however,
present methods are time-consuming and imprecise with
meagre BBB permeability. Their incompetence to achieve
real-time imaging of living tissues as well as the execution
of lethal effects on the surrounding healthy brain tissues
due to the dearth of specific/targeted function in fruitful
management of the neurological disorders have been
limited.
The promise of nanotheranostics for successful neural
therapy is real and ligand –modified nanocarriers can be
the foremost choice in this arena. Efficient amalgam of
imaging and therapeutic agents in the same system is
expected to advance the nanomedicine turf towards perso-
nalized medicine. In the continuous effort to improve sensi-
tivity and precision in screening/diagnosis as well as the
effectiveness of treatment strategies for neurodegenerative
diseases, the combination of imaging and therapeutic func-
tion within a single nanomedicine platform as in the case of
nanotheranostics, holds a great potential in future neu-
rotherapeutics. To envisage positive treatment responses it
is also essential to bridge the target site information with
various noninvasive imaging modalities to understand bio-
distribution profile of the therapeutics and/or nano-carriers
at the target site. While nanotheranostics accomplishments
are encouraging, they are still the minority.
Acknowledgments
The authors acknowledge the Institute of Nano Science and Technology,
an autonomous institute supported by Department of Science and
Technology (DST), Government of India, for all the essential facilities to
complete this work.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Jibanananda Mishra http://orcid.org/0000-0003-4011-3539
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