Perspective

Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX pubs.acs.org/chemneuro

Drug-Abuse Nanotechnology: Opportunities and Challenges

Morteza Mahmoudi,*,† Sepideh Pakpour,‡,§ and George Perry∥
†
Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United
States
‡
Infectious Disease & Microbiome, Broad Institute, Cambridge, Massachusetts 02142, United States
§
School of Engineering, University of British Columbia, Kelowna, BC V1V 1V7, Canada
∥
Neurosciences Institute and Department of Biology, College of Sciences, University of Texas, San Antonio, Texas 78249, United
States

ABSTRACT: Opioid drug abuse and dependence/addiction

are complex disorders regulated by a wide range of interacting
networks of genes and pathways that control a variety of
phenotypes. Although the field has been extensively
progressed since the birth of the National Institute on Drug
Abuse in 1974, the fundamental knowledge and involved
mechanisms that lead to drug dependence/addiction are
poorly understood, and thus, there has been limited success in
the prevention of drug addiction and development of
therapeutics for definitive treatment and cure of addiction
disease. The lack of success in both identification of addiction
in at-risk populations and the development of efficient drugs
has resulted in a serious social and economic burden from
opioid drug abuse with global increasing rate of mortality from drug overdoses. This perspective aims to draw the attention of
scientists to the potential role of nanotechnologies, which might pave the way for the development of more practical platforms
for either drug development or identification and screening of patients who may be vulnerable to addiction after using opioid
drugs.
KEYWORDS: Opioid drug abuse, dependence/addiction, nanoparticle, nanotechnology, early detection, therapeutics

■ INTRODUCTION
Opioid abuse remains a serious social and economic burden
with an estimated 64 000 deaths from drug overdoses
(including both illicit drugs and prescription opioids) in the
United States in 2016, which has nearly doubled in a decade,
according to the National Center for Health Statistics.1 Drug
abuse and dependence/addiction are complex disorders that are
regulated by a wide range of interacting networks of genes and
pathways that control a variety of phenotypes.2−6 Therefore,
both identification of the at-risk population and treatment of
the addiction disorders are strongly reliant on the development
of new and innovative approaches for understanding the
mechanisms underlying drug dependency and addiction. For
example, many of the current approaches to identify at-risk and
addiction disorder populations are focused on screening
questionnaires and urine drug monitoring.7,8 However, both
sensitivity and specificity of these approaches together with the
required time of detection in urine are below the clinical needs
(e.g., typical cutoff for opioid drugs is ∼300−2000 mg/mL and
the timing is 2−4 days).9,10 In other words, the conventional
approaches have their own limitations which are mainly focused
on long detection time (2−4 days), low sensitivity and
specificity (∼300−2000 mg/mL), and false outcomes (detailed
information on pros and cons of screening tools and resource
materials are available online11). For example, urine drug
monitoring using immunoassay and/or chemotherapy has a
range of shortcomings, including the possibility of false result
readouts based on detection limitation (e.g., inability of
immunoassay to sensitively detect oxycodone, methadone,
and fentanyl; inability of chemotherapy to detect morphine
before codeine metabolism) and concealment (e.g., by taking
poppy seeds).7−10,12,13 Although there were several attempts to
enhance the sensitivity and specificity of these assays (to μg/
mL level) (e.g., development of surface plasmon resonance
based immunosensors14), the field urgently needs alternative
platforms for fast and accurate identification of drugs with
robust specificity and sensitivity.
Apart from identification of the at-risk population, treatment
of the addiction disorders is another major issue in the field of
drug abuse. One of the central reasons that the current
approaches have not been successful is the numerous and
extremely complicated strategies and alterations that host
systems use to cope with drugs. These strategies/alterations
Special Issue: DARK Classics in Chemical Neuroscience
Received: March 18, 2018
Accepted: May 7, 2018

© XXXX American Chemical Society A DOI: 10.1021/acschemneuro.8b00127

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Figure 1. (A) Gold nanorods substantially facilitate transmigration of siRNA across the blood brain barrier model (upper and lower chambers are
representative of blood and brain ends, respectively), compared to the siRNA alone. (B) Substantially higher gene silencing efficiency of gold
nanorod-DARPP-32 siRNA complexes in dopaminergic neuronal cells, compared to siRNA alone and conventional gene transfection approach
(positive control). Reprinted with permission from ref 32 Copyright (2009) National Academy of Sciences.
take place in different biosystems and organs, including brain
anatomical15 and physiological16 functions, gut microbiota
dysbiosis,17 immune system,18,19 and biological barriers20 (e.g.,
blood brain barrier). Therefore, it is obvious that a wide range
of expertise (e.g., medicine, microbiology, physiology, genetics,
bioengineering, nanomedicine, bioinformatics, mathematics,
proteomics, and biochemistry) should be combined and
interconnected to define and connect the involved mechanisms
of drug dependency and addiction. Many experts already exist
in all of those fields, but it is crucial to bridge the gap between
these experts. The outcome may pave the way for the
development of platforms which allows us to overcome the
serious social and economic burden of opioid drug abuse safely,
effectively, and at a lower cost.
The main aim of this perspective is to introduce possible
potential capacities of nanotechnology and shine more light by
providing knowledge to the field of drug dependency and
addiction. Due to their unique properties (e.g., physical,
chemical, electrical, optical, and mechanical), nanotechnologies
offer enormous opportunities in various fields of science,
including medicine.21 For example, nanotechnologies are being
widely used for targeted delivery of therapeutic biomolecules,22
contrast agents to monitor cancer cells and tumor binderies,23
hyperthermia,24 immunotherapies,25 and tissue engineering
applications.26 Although nanotechnologies are now being used
in identification and treatment of several diseases, including
cancers,27 cardiovascular,28 and neurodegenerative disorders,29
their potential application in drug abuse is poorly investigated.
For example, nanotechnologies have been widely used for drug
delivery applications;22,30,31 however, their potential role in
drug screening purposes, in various types of biological fluids
including blood and urine, and also in drug-abuse applications
is poorly investigated. In other words, there are fewer than
expected reports on developing nanotechnologies for the
treatment of drug abuse,32−35 detecting drugs (e.g., meth-
amphetamine) in human urine36−38 and saliva,1,39,40 reducing
the toxic concentrations of drugs in blood,41 and also for
probing the effect of drug abuse on biochemical or structural
variations of brain tissue.42
Developing new and innovative approaches for under-
standing the mechanisms underlying addiction is of crucial
importance in the field of opioid drug abuse, as it may lead to
B DOI: 10.1021/acschemneuro.8b00127
Perspective
(i) identification of at-risk individuals in the population
(presently, it is impossible to predict which patients will be
affected by opioids), (ii) new therapeutic targets, and (iii)
personalized selection of appropriate treatments. Although
probing the differences in genes of interest between addicted
patients and healthy subjects can provide useful information on
possible involved mechanism, dissecting out the roles of specific
genes in addiction is a very difficult task that requires parsing
the contributions of individual genes and complex gene−gene
interactions. This aspect is further complicated by the
differences between opioid dependency (physical dependence
in which the body adapts to the drug) and addiction (i.e., an
inability to stop using a drug; failure to meet work, social, or
family obligations).
■ NANOTECHNOLOGIES FOR DRUG ADDICTION
THERAPY
Nanotechnologies can be designed and engineered to regulate
brain signaling pathways that are associated with drug
addiction. This particular approach needs development of
multifunctional nanoparticles that have a unique capacity to
transmigrate across blood brain barrier and target the desired
site of the brain.43 One of the well-recognized opioid-
dependent triggering biomolecules is adenosine 3′,5′-mono-
phosphate-regulated phosphoprotein (DARPP-32).44,45 This
biomolecule has crucial effects on extracellular signal-regulated
kinase activity, which controls transcriptional and behavioral
effects of substance abuse.32,46 For suppression of DARPP-32
gene expression, Bonoiu et al.32 developed gold nanorod-
DARPP-32 siRNA complexes with unique capacity to pass the
blood brain barrier, target the dopaminergic neuronal cells, and
suppress the target gene DARPP-32 (Figure 1). These
surprising outcomes demonstrate the capacity of the gold
nanorods for treatment of drug addiction. Law and coworkers47
used PEGylated quantum rod for the delivery of the same
siRNAs to the dopaminergic neuronal cells, and their outcomes
were in agreement with the previous report.
Another developed approach was to conjugate glial cell line-
derived neurotrophic factor to the surface of nanoparticles to
make drug-conjugated nanoparticles for treatment of cocaine
addiction.33 The therapeutic efficacy of the conjugated
nanoparticles was probed in cocaine addicted rat model, and
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the results revealed that the nanoparticles could not only block
the acquisition of cocaine self-administration but also decreased
lever cocaine dose response compared to the control groups.
Few other nanotechnologies were also developed to reduce the
adverse effects of substance abuse on other organs; for example,
hydrophilic C60(OH)10/2-hydroxypropyl-β-cyclodextrin nano-
particles were developed to minimize adverse effects of
acetaminophen’s overdose on a liver injury.48
Due to their high surface to volume ratio, nanoparticles have a
unique capacity in concentrating small biomolecules at their
surfaces (i.e., the biomolecular corona). This unique feature of
nanoparticles can be empowered by the use of targeting
moieties at the surface of nanoparticles that have a great affinity
to the desired drugs in urine. Using plasmonic nanoparticles,
colorimetric assays could be developed for a fast, cheap, and
reliable assessment of drugs or their related biomolecules (e.g.,

■
substance drugs and neurotransmitters) in urine. For example,
NANOTECHNOLOGIES FOR BETTER nanoparticle-based paper devices were developed to detect
UNDERSTANDING OF BRAIN ANATOMICAL traces of cocaine in human saliva samples (Figure 2).59 This
CHANGES
Opioid drugs demonstrated a great capacity in altering
important brain areas, including the cerebral cortex and limbic
system.49−51 These anatomic functional variations can alter
biochemistry balance of the brain (e.g., substantial changes in
release of neurotransmitters such as dopamine, serotonin,
gamma-aminobutyric acid, and norepinephrine) and affect
many of the brain’s critical functions, including problem
solving, decision making, and rewarding circuit system.15,52,53
Real time monitoring of particular neurotransmitters and brain
anatomical changes using highly sensitive approaches is of great
importance to shed more light on the mechanistic role of drug
abuse on brain functions.
Magnetic nanoparticles, as sensitive contrast agents, have
been used for substantial enhancement of diagnostic capacity of Figure 2. Cartoon showing the mechanism for detection of cocaine
magnetic resonance imaging (MRI) in animal and human using a nanoparticle-based paper device. The presence of cocaine can
reassemble anticocaine aptamer fragments (i.e., ACA-1 and ACA-2)
models.24 Among various types of nanoparticles, super-
and quench the UCNPs luminescence by gold nanoparticles, which
paramagnetic iron oxide nanoparticles showed great potential can be identified and roughly quantified by a smart phone camera.
in safe and efficient molecular imaging of different sites of the Reprinted with permission from ref 59 He et al. Copyright 2016
human body, including brain tissue.54,55 These nanoparticles American Chemical Society.
demonstrated promising outcomes for a wide range of
theragnosis purposes in a wide range of neurodegenerative
device contains an anticocaine aptamer (ACA), which
diseases, including multiple sclerosis, stroke, Alzheimer’s
demonstrated high affinity to cocaine, upconversion nano-
disease, meningitis, epilepsy, and brain tumors (see ref 56 for
particles (UCNPs), and gold nanoparticles; the aptamer was
a comprehensive review on in vivo molecular imaging capacity
cut into two flexible pieces (ACA-1 and ACA-2). To attach
of disease particles). Magnetic nanoparticles have been also
nanoparticles and aptamers to the cellulose filter of the device,
used for substance abuse.57,58 For example, Sagar and
the UCNPs were functionalized with poly(ethylenimine)
coworkers developed iron oxide nanoformulation of a highly
(PEI), and ACA-1 was directly modified with amine. ACA-2
selective and potent morphine antagonist, which could protect
was modified with sulfhydryl and attached to the gold
modulation of neuronal dendrite and spine morphology during
nanoparticles. In the absence of cocaine, there are no
both morphine exposure and morphine-treated HIV infec-
interactions between ACA-1 and ACA-2 and the luminescence
tion.58
of UCNPs; by contrast, the existence of cocaine can reassemble
The use of engineered superparamagnetic iron oxide
ACA-1 and ACA-2 and quench the UCNPs luminescence by
nanoparticles for imaging of anatomic functional and
gold nanoparticles, which can be identified and roughly
biochemistry variations in addicted patients may open a new
quantified. A similar strategy can be used for other types of
opportunity to provide better information regarding the nature
substance abuse.
of brain structural and biochemical changes and site of changes
The use of engineered nanoparticles can substantially
after drug addiction. Despite the critical potential of nano-
enhance identification and discrimination capacity of healthy,
technologies, their usage in the field of drug abuse has been
at-risk populations and addiction patients in a short period of
poorly evaluated.

■
NANOTECHNOLOGIES ENHANCE SENSITIVITY OF
DRUG DETECTION APPROACHES
Many of the current approaches to identify at-risk populations
and addiction patients are focused on screening questionnaires
and urine drug monitoring.7,8 Although promising, the urine
drug monitoring conventional approaches are time-consuming
and faced a wide range of issues including, but not limited to,
low sensitivity (∼300−2000 mg/mL) and unacceptable risk of
false outcomes.9,10 The central reason for the low sensitivity of
these approaches is the low concentration of drugs in the urine.
C DOI: 10.1021/acschemneuro.8b00127
time with reliable and reproducible outcomes. Although
nanotechnologies showed great potential in overcoming the
issues of conventional drug monitoring approaches, their usage
for this purpose is poorly investigated.
■ MICROBIOME-GUT-BRAIN AXIS
Human gut is colonized with a plethora of microorganisms,
playing crucial roles in physiology and immunity and impacting
human health and disease.60−63 Although a high interindividual
variability exists in the gut microbiome, an individual’s gut
microbiota can remain stable over time.64 Many factors such as
antibiotic treatments can change the gut microbial structure
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and distance it from a stable and healthy ecosystem. The
unbalanced gut microbiota may be associated with several
diseases65 such as neurodegenerative disorders.66−68 The gut
microbiome can influence monoamine-containing enterochro-
maffin cells (residing in the mucosal and submucosa of the
stomach and small intestine) and their ability to produce
serotonin, dopamine, and norepinephrine, which can affect host
behavior.69 Many reports have revealed this bidirectional
communication between gut microbiota and neural signaling,
which is referred to as the microbiome-gut-brain axis.49,54,61−65
Inflammatory gut microbial species have a direct connection
with the brain via the neurotransmitters they produce and the
vagus nerve receptors in the gut.70 The vagus nerve seems to be
capable of differentiating between harmless and potentially
harmful bacteria, even when there is no inflammation, and vagal
pathways can send signals to the brain that can induce either
anxiety-producing or calming effects. The gut-brain axis with
serotonin functioning has been found to be a key signaling
molecule in the enteric nervous system (ENS) and the central
nervous system (CNS).71 The gut microbiota can directly or
indirectly recruit tryptophan metabolism and serotonergic
signaling and profoundly influence the CNS.72 Chronic opioid
usage can lead to gut microbiome dysbiosis. Morphine, for
example, can disrupt the gut epithelial barrier and lead to a
leaky gut and bacterial translocation. Changes in the gut
microbiota can also affect opioid tolerance in the cell bodies of
extrinsic sensory neurons.73 The microbiome can also play a
role in the development of opioid tolerance73 and alter
important synaptic transcripts in the brain’s reward circuitry.17
Gut microbiota depletion can increase sensitivity to the
rewarding and sensitizing properties of cocaine,17 which may
be through the reduction of short chain fatty acids (SCFAs)
production.17 The relationship between gut bacteria and drug
addiction is still in its infancy, and in-depth studies are required
to better understand and define the mechanisms involved in
opioid addiction and dependency.
■
POTENTIAL APPLICATION OF
NANOTECHNOLOGIES IN MONITORING BLOOD
PLASMA VARIATIONS
Gut-Brain Axis and Its Impact on Blood Plasma. Opiate
addiction and dependency is involved in the activation of
several signaling pathways [e.g., cAMP-dependent pathway (i.e.,
adenylyl cyclase pathway) and extracellular signal-regulated
kinase (ERK) mitogen-activated protein (MAP) kinase
cascades],46,74,75 transcription factors, and proteins (FBJ
murine osteosarcoma viral oncogene homologue B (FosB), c-
Fos, activator protein 1 complexes, and cAMP-response-
element binding protein). These pathways are present and
vary in different parts of brain tissue, spinal cord, and gut. For
instance, cAMP pathways are upregulated in locus coeruleus,
ventral tegmental area, periaqueductal gray, dorsal horn of the
spinal cord, and myenteric plexus of the gut.74,76
Both the gut and brain may induce substantial variations to
plasma composition due to substance abuse, which at least in
theory can be detected by advanced proteomic approaches. For
example, the link between gut microbiome and brain disorders
can change immune functions and immune-related proteins/
paracrine-factors and cells.77,78 It is noteworthy that some of
the immune related cells (e.g., B cells, T cells, and
macrophages) express opioid receptors.79 Gut microbiota
have displayed a great capacity in dynamic alteration of several
circulating biomolecules of their host. Opioid substance abuse
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Perspective
is shown to induce multiple gastrointestinal symptoms (e.g.,
impairing epithelial integrity) which cause release of several gut
microbiota biomolecules into circulation [it may even cause
bacterial translocation, which may induce immune reaction80
and in some cases induce sepsis81,82 (e.g., chronic admin-
istration of morphine activated Pseudomonas aeruginosa
virulence expression which led to lethal gut-derived sepsis in
mice model83)].84−86
While proteomic characterization of blood plasma is of
central importance to possible biomarker discovery studies, the
vast dynamic range and high complexity of the plasma
proteome presents serious challenges, which have so far led
to unacceptable trade-offs between depth of coverage and
sample throughput.87 Therefore, advances in the fields of
proteomics and genomics have not yet translated into a
workable platform for either the development of suitable drugs
to identify at-risk populations or diminishing the risk of
addictive relapse. This is largely due to the fact that no
individual plasma protein is specific and sensitive enough to
identify the source of its corresponding genetic variation and
gene−gene interactions, and appropriate technology platforms
for accurate and sensitive multivariate plasma analysis relevant
to opioid drug addiction have remained elusive.
How Can Nanotechnologies Be of Help? Nano-
technologies have a unique capacity to be used as a probe for
gathering useful information on dissimilarities between the
plasma composition of healthy and addicted patient groups.
Once in contact with human plasma or serum, the surface of
nanoparticles is covered by a layer composed of different type
of biomolecules (i.e., biomolecular corona).88−90 The bio-
molecular corona contains wide range of proteins, enzymes,
and other biomolecules such as metabolites. During the
formation of biomolecular corona, proteins with high
concentrations first come to the surface of nanoparticles.
However, these proteins will be replaced by other proteins with
a higher binding affinity to the surface of nanoparticles, which is
known as the Vroman effect.91,92 This means that the
biomolecular corona provides more information about proteins
that are at very low concentrations in human plasma and other
complex biological fluids; without biomolecular corona, such
low concentration proteins cannot be easily detected and
analyzed in the entire plasma using current available proteomics
approaches.93,94
The composition of biomolecular corona is strongly
dependent on the physicochemical properties of nano-
particles,95 environmental factors (e.g., incubating temper-
ature96), and biological factors (e.g., type of biological fluids97
and plasma/cell sex98).99 Recently, it was found that various
diseases and medical interventions may change the concen-
tration/conformation of human plasma proteins and metab-
olomes; these include various types of cancers, hemodialysis,
neurodegenerative diseases, and diabetes.100−105 Changes in
plasma protein profiles/biomarkers are already widely used for
diagnosis of several diseases.106−110 On the basis of these
variations, we introduced the concept of disease-specific protein
corona and personalized protein corona, demonstrating that
variation in plasma proteins caused by disease type can
significantly change the composition of the biomolecular
corona formed around NPs.111−114 The concept is now being
increasingly accepted by the scientific community, and many
other groups have applied this strategy to define the exact
biological identity of NPs for safe design of nanotechnolo-
gies.115−120 In addition, very recently, we demonstrated that the
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metabolomes can also significantly affect the composition of
biomolecular corona and even can interfere with the Vorman
effect.121 As drugs can substantially affect the metabolomics
composition of blood plasma122,123 and can also interact with
plasma proteins,124−126 we can expect these metabolomic and
protein variations to alter the biomolecular corona profile of
nanoparticles, which may be used for identification and
discrimination of not only people with addiction disorder, but
also drug-specific addictions. This is driven by previous reports
on the use of nanotechnologies for detection of substance abuse
using the specific metabolites of drugs in human sweat.127,128
For example, anticotinine antibody functionalized gold nano-
particles were developed to provide fast and accurate chemical
information on specific metabolites of sweat.127
We believe that the changes in metabolites and plasma
protein compositions that reflect the spectrum of healthy, at-
risk population for drug dependency and drug addiction
disorder can drastically change biomolecular corona composi-
tion (Figure 3). The central reason for the proposed substantial
Figure 3. Scheme showing differences in the biomolecular corona
structures after interaction of nanoparticles with plasma of healthy
individuals and people with a risk of drug dependency and patients
with drug addiction disorders. The changes in the biomolecular corona
structures can be driven by variations of plasma protein and
metabolomic compositions of healthy, at-risk, and drug addiction
disorder individuals.
changes in the biomolecular corona, beside the interaction of
drugs with metabolomes and proteins, is that it is increasingly
being accepted that gut microbiota can generate numerous
biomolecules that can enter the bloodstream and thus have a
crucial capacity to directly alter the compositions of plasma
metabolomes and also indirectly regulate protein conforma-
tions and hormones.129−131 In addition, the gut microbiota can
signal to the brain via a number of pathways, including
regulating metabolomic profiles of host plasma, immune
activity, and the production of a wide range of proinflammatory
cytokines, paracrine factors, and neurotransmitters which can
directly and indirectly affect the activity of the host’s central
nervous systems.132 Many of these produced biomolecules can
cross the blood brain barrier and affect brain function, which
may further induce inflammatory and metabolomic changes to
E DOI: 10.1021/acschemneuro.8b00127
Perspective
the blood.133 As mentioned earlier, these variations in the
metabolomes and biomolecular composition of plasma can
make detectable substantial changes in biomolecular corona at
the surface of nanoparticles. By combination of advanced
mathematical approaches with the biomolecular corona, this
approach may provide a unique capacity to (i) identify and
discriminate vulnerable populations to addiction disorders after
using opioid drugs, (ii) to identify patients vulnerable to
addiction after recreational use of opioid drugs, (iii) to identify
novel protein and metabolomic markers related to addictive
behavior, and (iv) to investigate genes possibly helpful in
identifying at-risk individuals.
After more information is obtained on the important proteins
which may have critical roles in drug dependency addiction,
much easier, cheaper, and faster colorimetric nanotechnologies
can be developed for diagnostic purposes (Figure 4). For
Figure 4. Scheme showing possible role of substance abuse
biomolecular corona in changing the color of colloidal nanoparticles
which may be used for development of cheap, fast, and reliable
biosensors for identification of substance abuse disorder.
example, plasmonic nanoparticles (e.g., gold) can be engineered
in a way that the existence of particular protein, specific to drug
dependency/addiction, can induce aggregation of the particles
and cause visible substantial changes in the colloidal color of
nanoparticle-plasma solutions. This approach has been
successfully used for a wide range of biomolecular sensing134
and diseases such as cancer135 and infectious diseases.136
Another type of colorimetric approach has been employed
for detection of cocaine. For instance, Du and coworkers137
combined cocaine aptamer fragments (i.e., SH-C2) labeled
magnetic nanoparticles and DNAzyme-based colorimetric
sensor (using hemin-G-quadruplex complex) for fast and
sensitive (i.e., 50 nM) detection of cocaine in a 3,3,5,5-
tetramethylbenzidine sulfate (TMB)−H2O2 reaction system.
The functionalized magnetic nanoparticles can concentrate and
separate cocaine and, in combination with the catalytic activity
of the DNAzyme in the reaction system, can change the
solution color at the very low cocaine concentration (Figure 5).
Importance of Multianalyte Strategies. The majority of
the conducted studies in the field of drug abuse have been
focused on monitoring the differences of selected genes
between at-risk populations, addicted patients, and healthy
individuals; however, due to parsing the contributions of
individual genes and complexity of gene−gene interactions,
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Figure 5. Scheme showing the color change strategy of the biosensor
in the presence of cocaine. Reprinted with permission from ref 137,
Du et al. Copyright 2011, Royal Society of Chemistry.
dissecting out the roles of specific genes in at-risk population
and addiction has proved to be very difficult. By combination of
biomolecular corona and proteomics approaches, one promis-
ing possibility for achieving more in-depth understanding on
the underlying mechanisms of drug dependency addiction may
be the use of multianalyte (e.g., combination of proteomics,
genetics, and metabolomics) approaches. Although the central
disadvantage of multianalyte approaches is to deal with a large
data source and multivariant analysis, these issues are now
being solved by recent advances in data science approaches and
advanced statistics and clustering approaches such as machine
learning approach and deep learning techniques.138−141 For
example, Cohen et al.142 developed a multianalyte blood test
(by combination of protein biomarkers with genetic
biomarkers) followed by machine learning evaluation of the
outcomes for successful robust identification and discrimination
of eight types of cancers (i.e., breast, colorectum, ovary, liver,
lung, stomach, pancreas, and esophagus).
Figure 6. Engineering the gut microbiota to treat drug abuse: (A) conventional probiotic approach and (B) novel microbiome therapeutic approach
using nano- and microtechnologies.
F DOI: 10.1021/acschemneuro.8b00127
Perspective
The multianalyte evaluations may be used for minimizing the
complication in finding differences between opioid dependency
and addiction. In other words, this approach may be able to
robustly probe subtle dissimilarities in genetics, proteomics, and
metabolomics between the plasma composition of healthy and
addicted patient groups. Such a multianalyte analysis may
define the role of proteins, genes, and metabolomes relevant to
the identification of individuals who are addicted and
distinguish variations among them according to the drug they
are abusing. This may help in the discovery of novel genes and
their interactions that can be easily affected by proteomic
variations induced by drug abuse. It may also contribute to the
discovery of new drugs that can act against important protein
modifications in human plasma and thus inhibit drug addiction.
■ NANOTECHNOLOGIES FOR ALTERATION OF GUT
MICROBIOTA PATTERN
As stated earlier, it is increasingly being accepted that the gut
microbiota plays multiple critical roles in health spectrum
maintenance of their host, including controlling gastrointestinal
physiology, communication with central nervous system
through microbiota-gut-brain axis, and alteration of plasma
metabolomes and hormones.133,143 Therefore, it is legitimate to
hypothesize that manipulation of gut microbiota profiles may
have a capacity to minimize adverse effects of drug abuse. To
develop such an approach for this purpose, we need a deep
understanding of the role of drug abuse on the gut-brain axis; as
our understanding of the effects of opioid drugs on the gut-
brain axis is extremely limited, a huge amount of effort should
be conducted to achieve the required information on the
potential roles of bacterial pattern alteration on minimizing
prevalence of drug addiction disorders. Initial efforts are now
being conducted to change the gut microbiota pattern for
therapeutic applications.144−149 As interest in manipulating the
gut microbiota to treat diseases increases, nano- and micro-
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technologies148−150 can innovatively be employed for target
delivery of pre- and probiotics to specific sites of the gut and its
mucous layer. Persistent establishment of these organisms can
eventually drive the host gut microbiota to a healthy state and
eventually impact the host’s health (Figure 6). So far, almost all
of the reports in the field are focused on monitoring the toxic
effects of antibacterial nanoparticles (e.g., silver nanoparticles)
on gut microbiota and inducing dysbiosis.150−153 However, the
use of nanotechnologies for controlling/altering gut microbiota
pattern for therapeutic purposes is not being investigated.
■
CONCLUSIONS AND FUTURE PERSPECTIVE
This perspective offers an outline of key potential applications
of nanotechnology in achieving not only more knowledge on
drug dependency/addiction mechanisms but also efficient
predictive and therapeutic approaches for opioid dependency
and addiction diseases. Nanotechnologies are comprehensively
being used/developed for diagnosis and treatment of a wide
range of diseases; however, the field of drug-abuse nano-
technology has been poorly investigated. More specifically,
although some efforts to use nanotechnologies were developed
for diagnostic, drug detoxification, and therapeutic application
in drug addiction here and there,32−34,41,47,48,57−59,137,154,155 no
systematic trends can be drawn from the current literature. One
of the central reason for the limited use of nanotechnologies in
drug-abuse applications is the lack of investment from
government and foundations in the field of drug-abuse
nanotechnology. Therefore, we believe that specific funding
for drug-abuse nanotechnology should be established and
substantially increased to empower the use of nanotechnologies
in the field, which may pave a way for emerging of
breakthrough discoveries for diagnosis and therapeutic
applications in drug abuse. With the help of funding agencies
together with establishment of collaborations between nano-
medicine and drug-abuse experts, we believe that nano-
technologies will provide a unique capacity for both predictive
and therapeutic approaches in opioid dependency and
addiction in the foreseeable future.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: mmahmoudi@bwh.harvard.edu or morteza.
mahmoudi@gmail.com.
ORCID
Morteza Mahmoudi: 0000-0002-2575-9684
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
M.M. thanks Jonathan D. Pollock for his helpful comments and
feedback. S.P. thanks the contribution provided by Ms. Negin
Kazemian.
■
REFERENCES
(1) Andreou, C., Hoonejani, M. R., Barmi, M. R., Moskovits, M., and
Meinhart, C. D. (2013) Rapid detection of drugs of abuse in saliva
using surface enhanced Raman spectroscopy and microfluidics. ACS
Nano 7, 7157−7164.
(2) Oslin, D. W., Berrettini, W., Kranzler, H. R., Pettinati, H.,
Gelernter, J., Volpicelli, J. R., and O’Brien, C. P. (2003) A functional
polymorphism of the μ-opioid receptor gene is associated with
naltrexone response in alcohol-dependent patients. Neuropsychophar-
macology 28, 1546.
G DOI: 10.1021/acschemneuro.8b00127
Perspective
(3) Hoehe, M. R., Köpke, K., Wendel, B., Rohde, K., Flachmeier, C.,
Kidd, K. K., Berrettini, W. H., and Church, G. M. (2000) Sequence
variability and candidate gene analysis in complex disease: association
of μ opioid receptor gene variation with substance dependence.
Human molecular genetics 9, 2895−2908.
(4) Crowley, J. J., Oslin, D. W., Patkar, A. A., Gottheil, E., DeMaria,
P. A., Jr, O’brien, C. P., Berrettini, W. H., and Grice, D. E. (2003) A
genetic association study of the mu opioid receptor and severe opioid
dependence. Psychiatr. Genet. 13, 169−173.
(5) Jin, J., Kittanakom, S., Wong, V., Reyes, B. A., Van Bockstaele, E.
J., Stagljar, I., Berrettini, W., and Levenson, R. (2010) Interaction of
the mu-opioid receptor with GPR177 (Wntless) inhibits Wnt
secretion: potential implications for opioid dependence. BMC
Neurosci. 11, 33.
(6) Crist, R. C., Clarke, T.-K., Ang, A., Ambrose-Lanci, L. M., Lohoff,
F. W., Saxon, A. J., Ling, W., Hillhouse, M. P., Bruce, R. D., Woody, G.,
and Berrettini, W. H. (2013) An intronic variant in OPRD1 predicts
treatment outcome for opioid dependence in African-Americans.
Neuropsychopharmacology 38, 2003.
(7) Kahan, M., Srivastava, A., Wilson, L., Gourlay, D., and Midmer,
D. (2006) Misuse of and dependence on opioids: study of chronic
pain patients. Canadian Family Physician 52, 1081−1087.
(8) Carmichael, A.-N., Morgan, L., and Del Fabbro, E. (2016)
Identifying and assessing the risk of opioid abuse in patients with
cancer: an integrative review. Substance abuse and rehabilitation 7, 71.
(9) Gourlay, D. L., Heit, H. A., and Caplan, Y. H. (2010) Urine drug
testing in clinical practice: the art and science of patient care; PharmaCom
Group.
(10) Christo, P. J., Manchikanti, L., Ruan, X., Bottros, M., Hansen,
H., Solanki, D. R., Jordan, A. E., and Colson, J. (2011) Urine drug
testing in chronic pain. Pain Physician 14, 123−143.
(11) National Institute on Drug Abuse. Chart of Evidence-Based
Screening Tools for Adults and Adolescents. https://www.drugabuse.
gov/nidamed-medical-health-professionals/tool-resources-your-
practice/screening-assessment-drug-testing-resources/chart-evidence-
based-screening-tools-adults.
(12) Vaglienti, R. M., Huber, S. J., Noel, K. R., and Johnstone, R. E.
(2003) Misuse of prescribed controlled substances defined by
urinalysis. West Virginia medical journal 99, 67−70.
(13) Katz, N. P., Sherburne, S., Beach, M., Rose, R. J., Vielguth, J.,
Bradley, J., and Fanciullo, G. J. (2003) Behavioral monitoring and
urine toxicology testing in patients receiving long-term opioid therapy.
Anesth. Analg. 97, 1097−1102.
(14) Shankaran, D. R., Gobi, K. V., and Miura, N. (2007) Recent
advancements in surface plasmon resonance immunosensors for
detection of small molecules of biomedical, food and environmental
interest. Sens. Actuators, B 121, 158−177.
(15) Koob, G. F. (1992) Drugs of abuse: anatomy, pharmacology and
function of reward pathways. Trends Pharmacol. Sci. 13, 177−184.
(16) Robinson, T. E., and Berridge, K. C. (1993) The neural basis of
drug craving: an incentive-sensitization theory of addiction. Brain Res.
Rev. 18, 247−291.
(17) Kiraly, D. D., Walker, D. M., Calipari, E. S., Labonte, B., Issler,
O., Pena, C. J., Ribeiro, E. A., Russo, S. J., and Nestler, E. J. (2016)
Alterations of the host microbiome affect behavioral responses to
cocaine. Sci. Rep. 6, 35455.
(18) Sacerdote, P. (2006) Opioids and the immune system. Palliative
medicine 20, 9−15.
(19) Postler, T. S., and Ghosh, S. (2017) Understanding the
holobiont: how microbial metabolites affect human health and shape
the immune system. Cell Metab. 26, 110−130.
(20) Fiala, M., Gan, X.-H., Zhang, L., House, S., Newton, T., Graves,
M., Shapshak, P., Stins, M., Kim, K.-S., and Witte, M. (1998) Cocaine
enhances monocyte migration across the blood-brain barrier. In Drugs
of Abuse, Immunomodulation, and Aids, pp 199−205, Springer.
(21) Kim, B. Y., Rutka, J. T., and Chan, W. C. (2010) Nanomedicine.
N. Engl. J. Med. 363, 2434−2443.
(22) Farokhzad, O. C., and Langer, R. (2009) Impact of
nanotechnology on drug delivery. ACS Nano 3, 16−20.
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience
(23) Brigger, I., Dubernet, C., and Couvreur, P. (2012) Nanoparticles
in cancer therapy and diagnosis. Adv. Drug Delivery Rev. 64, 24−36.
(24) Laurent, S., Dutz, S., Häfeli, U. O., and Mahmoudi, M. (2011)
Magnetic fluid hyperthermia: focus on superparamagnetic iron oxide
nanoparticles. Adv. Colloid Interface Sci. 166, 8−23.
(25) Zanganeh, S., Hutter, G., Spitler, R., Lenkov, O., Mahmoudi, M.,
Shaw, A., Pajarinen, J. S., Nejadnik, H., Goodman, S., and Moseley, M.
(2016) Iron oxide nanoparticles inhibit tumour growth by inducing
pro-inflammatory macrophage polarization in tumour tissues. Nat.
Nanotechnol. 11, 986.
(26) Shi, J., Votruba, A. R., Farokhzad, O. C., and Langer, R. (2010)
Nanotechnology in drug delivery and tissue engineering: from
discovery to applications. Nano Lett. 10, 3223−3230.
(27) Shi, J., Kantoff, P. W., Wooster, R., and Farokhzad, O. C. (2017)
Cancer nanomedicine: progress, challenges and opportunities. Nat.
Rev. Cancer 17, 20.
(28) Mahmoudi, M., Yu, M., Serpooshan, V., Wu, J. C., Langer, R.,
Lee, R. T., Karp, J. M., and Farokhzad, O. C. (2017) Multiscale
technologies for treatment of ischemic cardiomyopathy. Nat. Nano-
technol. 12, 845.
(29) Hajipour, M. J., Santoso, M. R., Rezaee, F., Aghaverdi, H.,
Mahmoudi, M., and Perry, G. (2017) Advances in alzheimer’s
diagnosis and therapy: The implications of nanotechnology. Trends
Biotechnol. 35, 937−953.
(30) Lavan, D. A., McGuire, T., and Langer, R. (2003) Small-scale
systems for in vivo drug delivery. Nat. Biotechnol. 21, 1184.
(31) Mahmoudi, M., Sant, S., Wang, B., Laurent, S., and Sen, T.
(2011) Superparamagnetic iron oxide nanoparticles (SPIONs):
development, surface modification and applications in chemotherapy.
Adv. Drug Delivery Rev. 63, 24−46.
(32) Bonoiu, A. C., Mahajan, S. D., Ding, H., Roy, I., Yong, K.-T.,
Kumar, R., Hu, R., Bergey, E. J., Schwartz, S. A., and Prasad, P. N.
(2009) Nanotechnology approach for drug addiction therapy: gene
silencing using delivery of gold nanorod-siRNA nanoplex in
dopaminergic neurons. Proc. Natl. Acad. Sci. U. S. A. 106, 5546−5550.
(33) Green-Sadan, T., Kuttner, Y., Lublin-Tennenbaum, T., Kinor,
N., Boguslavsky, Y., Margel, S., and Yadid, G. (2005) Glial cell line-
derived neurotrophic factor-conjugated nanoparticles suppress acquis-
ition of cocaine self-administration in rats. Exp. Neurol. 194, 97−105.
(34) Rao, P., Yallapu, M. M., Sari, Y., Fisher, P. B., and Kumar, S.
(2015) Designing novel nanoformulations targeting glutamate trans-
porter excitatory amino acid transporter 2: Implications in treating
drug addiction. Journal of personalized nanomedicine 1, 3.
(35) Ignatowski, T., Aalinkeel, R., Reynolds, J., Nair, B., Sykes, D.,
Gleason, C., Law, W., Mammen, M., Prasad, P., Schwartz, S., and
Mahajan, S. D. (2015) Nanotherapeutic Approach for Opiate
Addiction Using DARPP-32 Gene Silencing in an Animal Model of
Opiate Addiction. Journal of Neuroimmune Pharmacology 10, 136−152.
(36) Chen, W., Peng, C., Jin, Z., Qiao, R., Wang, W., Zhu, S., Wang,
L., Jin, Q., and Xu, C. (2009) Ultrasensitive immunoassay of 7-
aminoclonazepam in human urine based on CdTe nanoparticle
bioconjugations by fabricated microfluidic chip. Biosens. Bioelectron. 24,
2051−2056.
(37) Han, Z., Liu, H., Wang, B., Weng, S., Yang, L., and Liu, J. (2015)
Three-dimensional surface-enhanced Raman scattering hotspots in
spherical colloidal superstructure for identification and detection of
drugs in human urine. Anal. Chem. 87, 4821−4828.
(38) Dong, R., Weng, S., Yang, L., and Liu, J. (2015) Detection and
direct readout of drugs in human urine using dynamic surface-
enhanced Raman spectroscopy and support vector machines. Anal.
Chem. 87, 2937−2944.
(39) Inscore, F., Shende, C., Sengupta, A., Huang, H., and
Farquharson, S. (2011) Detection of drugs of abuse in saliva by
surface-enhanced Raman spectroscopy (SERS). Appl. Spectrosc. 65,
1004−1008.
(40) Farquharson, S., Shende, C., Sengupta, A., Huang, H., and
Inscore, F. (2011) Rapid detection and identification of overdose
drugs in saliva by surface-enhanced Raman scattering using fused gold
colloids. Pharmaceutics 3, 425−439.
H DOI: 10.1021/acschemneuro.8b00127
Perspective
(41) Kaminsky, Y. G., Kosenko, E., Alexandrovich, Y. G., and
Ataullakhanov, F. (2012) Experiments on alcocytes containing enzyme
nanoparticles for reducing toxic blood concentration of ethanol. Bull.
Exp. Biol. Med. 153, 170−172.
(42) Ribeiro, J. A., Fernandes, P. M., Pereira, C. M., and Silva, F.
(2016) Electrochemical sensors and biosensors for determination of
catecholamine neurotransmitters: A review. Talanta 160, 653−679.
(43) Krol, S., Macrez, R., Docagne, F., Defer, G., Laurent, S.,
Rahman, M., Hajipour, M. J., Kehoe, P. G., and Mahmoudi, M. (2013)
Therapeutic benefits from nanoparticles: the potential significance of
nanoscience in diseases with compromise to the blood brain barrier.
Chem. Rev. 113, 1877−1903.
(44) Gould, T. D., and Manji, H. K. (2005) DARPP-32: A molecular
switch at the nexus of reward pathway plasticity. Proc. Natl. Acad. Sci.
U. S. A. 102, 253−254.
(45) Calabresi, P., Gubellini, P., Centonze, D., Picconi, B., Bernardi,
G., Chergui, K., Svenningsson, P., Fienberg, A. A., and Greengard, P.
(2000) Dopamine and cAMP-regulated phosphoprotein 32 kDa
controls both striatal long-term depression and long-term potentiation,
opposing forms of synaptic plasticity. J. Neurosci. 20, 8443−8451.
(46) Valjent, E., Hervé, D., and Girault, J.-A. (2005) Drugs of abuse,
protein phosphatases, and ERK pathway. Med Sci 21, 453.
(47) Law, W.-C., Mahajan, S. D., Kopwitthaya, A., Reynolds, J. L.,
Liu, M., Liu, X., Chen, G., Erogbogbo, F., Vathy, L., and Aalinkeel, R.
(2012) Gene silencing of human neuronal cells for drug addiction
therapy using anisotropic nanocrystals. Theranostics 2, 695.
(48) Umezaki, Y., Iohara, D., Anraku, M., Ishitsuka, Y., Irie, T.,
Uekama, K., and Hirayama, F. (2015) Preparation of hydrophilic C60
(OH) 10/2-hydroxypropyl-β-cyclodextrin nanoparticles for the treat-
ment of a liver injury induced by an overdose of acetaminophen.
Biomaterials 45, 115−123.
(49) Daglish, M. R., Weinstein, A., Malizia, A. L., Wilson, S.,
Melichar, J. K., Britten, S., Brewer, C., Lingford-Hughes, A., Myles, J.
S., Grasby, P., and Nutt, D. J. (2001) Changes in regional cerebral
blood flow elicited by craving memories in abstinent opiate-dependent
subjects. Am. J. Psychiatry 158, 1680−1686.
(50) Lapchak, P., Araujo, D., and Collier, B. (1989) Regulation of
endogenous acetylcholine release from mammalian brain slices by
opiate receptors: hippocampus, striatum and cerebral cortex of guinea-
pig and rat. Neuroscience 31, 313−325.
(51) Ellgren, M., Spano, S. M., and Hurd, Y. L. (2007) Adolescent
cannabis exposure alters opiate intake and opioid limbic neuronal
populations in adult rats. Neuropsychopharmacology 32, 607.
(52) Le Merrer, J., Becker, J. A., Befort, K., and Kieffer, B. L. (2009)
Reward processing by the opioid system in the brain. Physiol. Rev. 89,
1379−1412.
(53) Koob, G. F. (2011) Neurobiology of addiction. Focus 9, 55−65.
(54) Mahmoudi, M., Hofmann, H., Rothen-Rutishauser, B., and
Petri-Fink, A. (2012) Assessing the in vitro and in vivo toxicity of
superparamagnetic iron oxide nanoparticles. Chem. Rev. 112, 2323−
2338.
(55) Mahmoudi, M., Hosseinkhani, H., Hosseinkhani, M., Boutry, S.,
Simchi, A., Journeay, W. S., Subramani, K., and Laurent, S. (2011)
Magnetic resonance imaging tracking of stem cells in vivo using iron
oxide nanoparticles as a tool for the advancement of clinical
regenerative medicine. Chem. Rev. 111, 253−280.
(56) Sharifi, S., Seyednejad, H., Laurent, S., Atyabi, F., Saei, A. A., and
Mahmoudi, M. (2015) Superparamagnetic iron oxide nanoparticles for
in vivo molecular and cellular imaging. Contrast Media Mol. Imaging 10,
329−355.
(57) Sagar, V., Atluri, V. S. R., Pilakka-Kanthikeel, S., and Nair, M.
(2016) Magnetic nanotherapeutics for dysregulated synaptic plasticity
during neuroAIDS and drug abuse. Mol. Brain 9, 57.
(58) Sagar, V., Pilakka-Kanthikeel, S., Atluri, V. S., Ding, H., Arias, A.
Y., Jayant, R. D., Kaushik, A., and Nair, M. (2015) Therapeutical
neurotargeting via magnetic nanocarrier: implications to opiate-
induced neuropathogenesis and neuroAIDS. J. Biomed. Nanotechnol.
11, 1722−1733.
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience
(59) He, M., Li, Z., Ge, Y., and Liu, Z. (2016) Portable upconversion
nanoparticles-based paper device for field testing of drug abuse. Anal.
Chem. 88, 1530−1534.
(60) Krishnan, S., Alden, N., and Lee, K. (2015) Pathways and
functions of gut microbiota metabolism impacting host physiology.
Curr. Opin. Biotechnol. 36, 137−145.
(61) Fukuda, S., and Ohno, H. (2014) Gut microbiome and
metabolic diseases. Semin. Immunopathol. 36, 103−114.
(62) Kinross, J. M., Darzi, A. W., and Nicholson, J. K. (2011) Gut
microbiome-host interactions in health and disease. Genome Med. 3,
14.
(63) Gérard, P. (2014) Metabolism of cholesterol and bile acids by
the gut microbiota. Pathogens 3, 14−24.
(64) David, L. A., Materna, A. C., Friedman, J., Campos-Baptista, M.
I., Blackburn, M. C., Perrotta, A., Erdman, S. E., and Alm, E. J. (2014)
Host lifestyle affects human microbiota on daily timescales. Genome
Biology 15, R89.
(65) Temko, J. E., Bouhlal, S., Farokhnia, M., Lee, M. R., Cryan, J. F.,
and Leggio, L. (2017) The Microbiota, the Gut and the Brain in Eating
and Alcohol Use Disorders: A ‘Ménage à Trois’? Alcohol Alcohol. 52,
403−413.
(66) Jangi, S., Gandhi, R., Cox, L. M., Li, N., Von Glehn, F., Yan, R.,
Patel, B., Mazzola, M. A., Liu, S., and Glanz, B. L. (2016) Alterations of
the human gut microbiome in multiple sclerosis. Nat. Commun. 7,
12015.
(67) Scheperjans, F., Aho, V., Pereira, P. A., Koskinen, K., Paulin, L.,
Pekkonen, E., Haapaniemi, E., Kaakkola, S., Eerola-Rautio, J., and
Pohja, M. (2015) Gut microbiota are related to Parkinson’s disease
and clinical phenotype. Mov. Disord. 30, 350−358.
(68) Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri,
G. G., Ilhan, Z. E., Challis, C., Schretter, C. E., Rocha, S., and
Gradinaru, V. (2016) Gut microbiota regulate motor deficits and
neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469−
1480 e1412.
(69) Jose, P. A., and Raj, D. (2015) Gut microbiota in hypertension.
Curr. Opin. Nephrol. Hypertens. 24, 403−409.
(70) Forsythe, P., Bienenstock, J., and Kunze, W. A. (2014) Vagal
Pathways for Microbiome-Brain-Gut Axis Communication. In Micro-
bial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease
(Lyte, M., and Cryan, J. F., Eds.), pp 115−133, Springer.
(71) O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., and
Cryan, J. F. (2015) Serotonin, tryptophan metabolism and the brain-
gut-microbiome axis. Behav. Brain Res. 277, 32−48.
(72) Clarke, G., Grenham, S., Scully, P., Fitzgerald, P., Moloney, R.
D., Shanahan, F., Dinan, T. G., and Cryan, J. F. (2013) The
microbiome-gut-brain axis during early life regulates the hippocampal
serotonergic system in a sex-dependent manner. Mol. Psychiatry 18,
666−673.
(73) Akbarali, H. I., and Dewey, W. L. (2017) The gut-brain
interaction in opioid tolerance. Curr. Opin. Pharmacol. 37, 126−130.
(74) Nestler, E. J. (2004) Historical review: molecular and cellular
mechanisms of opiate and cocaine addiction. Trends Pharmacol. Sci. 25,
210−218.
(75) Valjent, E., Pascoli, V., Svenningsson, P., Paul, S., Enslen, H.,
Corvol, J.-C., Stipanovich, A., Caboche, J., Lombroso, P. J., and Nairn,
A. C. (2005) Regulation of a protein phosphatase cascade allows
convergent dopamine and glutamate signals to activate ERK in the
striatum. Proc. Natl. Acad. Sci. U. S. A. 102, 491−496.
(76) Nestler, E. J. (2001) Molecular basis of long-term plasticity
underlying addiction. Nat. Rev. Neurosci. 2, 119.
(77) Leclercq, S., De Saeger, C., Delzenne, N., de Timary, P., and
Stärkel, P. (2014) Role of inflammatory pathways, blood mononuclear
cells, and gut-derived bacterial products in alcohol dependence. Biol.
Psychiatry 76, 725−733.
(78) Taylor, A. (2018) Revealing a Brain-Gut Microbiome
Connection Following Chronic Opioid Treatment. J. Pain 19, S1.
(79) Eisenstein, T. K. (2011) Opioids and the immune system: what
is their mechanism of action? British journal of pharmacology 164,
1826−1828.
I DOI: 10.1021/acschemneuro.8b00127
Perspective
(80) Schulzke, J. D., Ploeger, S., Amasheh, M., Fromm, A., Zeissig, S.,
Troeger, H., Richter, J., Bojarski, C., Schumann, M., and Fromm, M.
(2009) Epithelial tight junctions in intestinal inflammation. Ann. N. Y.
Acad. Sci. 1165, 294−300.
(81) Hilburger, M. E., Adler, M. W., Truant, A. L., Meissler, J. J., Jr.,
Satishchandran, V., Rogers, T. J., and Eisenstein, T. K. (1997)
Morphine induces sepsis in mice. J. Infect. Dis. 176, 183−188.
(82) MacFarlane, A. S., Peng, X., Meissler, J. J., Jr., Rogers, T. J.,
Geller, E. B., Adler, M. W., and Eisenstein, T. K. (2000) Morphine
increases susceptibility to oral Salmonella typhimurium infection. J.
Infect. Dis. 181, 1350−1358.
(83) Babrowski, T., Holbrook, C., Moss, J., Gottlieb, L., Valuckaite,
V., Zaborin, A., Poroyko, V., Liu, D. C., Zaborina, O., and Alverdy, J.
C. (2012) Pseudomonas aeruginosa virulence expression is directly
activated by morphine and is capable of causing lethal gut derived
sepsis in mice during chronic morphine administration. Ann. Surg. 255,
386.
(84) Harari, Y., Weisbrodt, N. W., and Moody, F. G. (2006) The
effect of morphine on mast cell−mediated mucosal permeability.
Surgery 139, 54−60.
(85) Brosnahan, A. J., Jones, B. J., Dvorak, C. M., and Brown, D. R.
(2014) Morphine attenuates apically-directed cytokine secretion from
intestinal epithelial cells in response to enteric pathogens. Pathogens 3,
249−257.
(86) Wang, F., and Roy, S. (2017) Gut Homeostasis, Microbial
Dysbiosis, and Opioids. Toxicol. Pathol. 45, 150−156.
(87) Keshishian, H., Burgess, M. W., Specht, H., Wallace, L., Clauser,
K. R., Gillette, M. A., and Carr, S. A. (2017) Quantitative, multiplexed
workflow for deep analysis of human blood plasma and biomarker
discovery by mass spectrometry. Nat. Protoc. 12, 1683.
(88) Monopoli, M. P., Åberg, C., Salvati, A., and Dawson, K. A.
(2012) Biomolecular coronas provide the biological identity of
nanosized materials. Nat. Nanotechnol. 7, 779.
(89) Nel, A. E., Mädler, L., Velegol, D., Xia, T., Hoek, E. M.,
Somasundaran, P., Klaessig, F., Castranova, V., and Thompson, M.
(2009) Understanding biophysicochemical interactions at the nano−
bio interface. Nat. Mater. 8, 543.
(90) Mahmoudi, M., Lynch, I., Ejtehadi, M. R., Monopoli, M. P.,
Bombelli, F. B., and Laurent, S. (2011) Protein− nanoparticle
interactions: opportunities and challenges. Chem. Rev. 111, 5610−
5637.
(91) Vilaseca, P., Dawson, K. A., and Franzese, G. (2013)
Understanding and modulating the competitive surface-adsorption of
proteins through coarse-grained molecular dynamics simulations. Soft
Matter 9, 6978.
(92) Kharazian, B., Hadipour, N. L., and Ejtehadi, M. R. (2016)
Understanding the nanoparticle-protein corona complexes using
computational and experimental methods. Int. J. Biochem. Cell Biol.
75, 162−174.
(93) Distler, U., and Tenzer, S. (2017) Tools for Pathogen
Proteomics: Fishing with Biomimetic Nanosponges. ACS Nano 11,
11768−11772.
(94) Wang, W., Sedykh, A., Sun, H., Zhao, L., Russo, D. P., Zhou, H.,
Yan, B., and Zhu, H. (2017) Predicting Nano−Bio Interactions by
Integrating Nanoparticle Libraries and Quantitative Nanostructure
Activity Relationship Modeling. ACS Nano 11, 12641−12649.
(95) Lundqvist, M., Stigler, J., Elia, G., Lynch, I., Cedervall, T., and
Dawson, K. A. (2008) Nanoparticle size and surface properties
determine the protein corona with possible implications for biological
impacts. Proc. Natl. Acad. Sci. U. S. A. 105, 14265−14270.
(96) Mahmoudi, M., Abdelmonem, A. M., Behzadi, S., Clement, J. H.,
Dutz, S., Ejtehadi, M. R., Hartmann, R., Kantner, K., Linne, U., and
Maffre, P. (2013) Temperature: the “ignored” factor at the nanobio
interface. ACS Nano 7, 6555−6562.
(97) Mueller, L. K., Simon, J., Rosenauer, C., Mailänder, V.,
Morsbach, S., and Landfester, K. (2018) The transferability from
animal models to humans: challenges regarding aggregation and
protein corona formation of nanoparticles. Biomacromolecules 19, 374.
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience
(98) Serpooshan, V., Sheibani, S., Pushparaj, P., Wojcik, M., Jang, A.
Y., Santoso, M. R., Jang, J. H., Huang, H., Safavi-Sohi, R., Haghjoo, N.,
Nejadnik, H., Aghaverdi, H., Vali, H., Kinsella, J. M., Presley, J., Xu, K.,
Yang, P. C.-M., and Mahmoudi, M. (2018) Effect of Cell Sex on
Uptake of Nanoparticles: The Overlooked Factor at the Nanobio
Interface. ACS Nano 12, 2253−2266.
(99) Mahmoudi, M. (2018) Debugging Nano−Bio Interfaces:
Systematic Strategies to Accelerate Clinical Translation of Nano-
technologies. Trends Biotechnol., 1 DOI: 10.1016/j.tibtech.2018.02.014.
(100) Kennedy, L., Mehl, T. D., Elder, E., Varghese, M., and
Merimee, T. J. (1982) Nonenzymatic glycosylation of serum and
plasma proteins. Diabetes 31, 52−56.
(101) Engström, G., Lind, P., Hedblad, B., Stavenow, L., Janzon, L.,
and Lindgärde, F. (2002) Effects of cholesterol and inflammation-
sensitive plasma proteins on incidence of myocardial infarction and
stroke in men. Circulation 105, 2632−2637.
(102) Lin, Y.-P., Yang, C.-Y., Liao, C.-C., Yu, W.-C., Chi, C.-W., and
Lin, C.-H. (2012) Plasma protein characteristics of long-term
hemodialysis survivors. PLoS One 7, e40232.
(103) Acharya, S., and Dimichele, D. (2008) Rare inherited disorders
of fibrinogen. Haemophilia 14, 1151−1158.
(104) Kelly-Spratt, K. S., Pitteri, S. J., Gurley, K. E., Liggitt, D., Chin,
A., Kennedy, J., Wong, C.-H., Zhang, Q., Buson, T. B., and Wang, H.
(2011) Plasma proteome profiles associated with inflammation,
angiogenesis, and cancer. PLoS One 6, e19721.
(105) Bowen, D. J. (2002) Haemophilia A and haemophilia B:
molecular insights. Mol. Pathol. 55, 1.
(106) Blennow, K., Hampel, H., Weiner, M., and Zetterberg, H.
(2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer
disease. Nat. Rev. Neurol. 6, 131−144.
(107) Ridker, P. M., Brown, N. J., Vaughan, D. E., Harrison, D. G.,
and Mehta, J. L. (2004) Established and emerging plasma biomarkers
in the prediction of first atherothrombotic events. Circulation 109, IV-
6−IV-19.
(108) El-Agnaf, O. M., Salem, S. A., Paleologou, K. E., Curran, M. D.,
Gibson, M. J., Schlossmacher, M. G., and Allsop, D. (2006) Detection
of oligomeric forms of α-synuclein protein in human plasma as a
potential biomarker for Parkinson’s disease. FASEB J. 20, 419−425.
(109) Hanash, S. M., Pitteri, S. J., and Faca, V. M. (2008) Mining the
plasma proteome for cancer biomarkers. Nature 452, 571−579.
(110) Wei, J., Gao, W., Zhu, C.-J., Liu, Y.-Q., Mei, Z., Cheng, T., and
Shu, Y.-Q. (2011) Identification of plasma microRNA-21 as a
biomarker for early detection and chemosensitivity of non−small
cell lung cancer. Aizheng 30, 407.
(111) Hajipour, M. J., Laurent, S., Aghaie, A., Rezaee, F., and
Mahmoudi, M. (2014) Personalized protein coronas: a “key” factor at
the nanobiointerface. Biomater. Sci. 2, 1210−1221.
(112) Caracciolo, G., Farokhzad, O. C., and Mahmoudi, M. (2017)
Biological Identity of Nanoparticles In Vivo: Clinical Implications of
the Protein Corona. Trends Biotechnol. 35, 257−264.
(113) Hajipour, M. J., Raheb, J., Akhavan, O., Arjmand, S.,
Mashinchian, O., Rahman, M., Abdolahad, M., Serpooshan, V.,
Laurent, S., and Mahmoudi, M. (2015) Personalized disease-specific
protein corona influences the therapeutic impact of graphene oxide.
Nanoscale 7, 8978−8994.
(114) Corbo, C., Molinaro, R., Tabatabaei, M., Farokhzad, O. C., and
Mahmoudi, M. (2017) Personalized protein corona on nanoparticles
and its clinical implications. Biomater. Sci. 5, 378−387.
(115) Caputo, D., Papi, M., Coppola, R., Palchetti, S., Digiacomo, L.,
Caracciolo, G., and Pozzi, D. (2017) A protein corona-enabled blood
test for early cancer detection. Nanoscale 9, 349−354.
(116) Strojan, K., Leonardi, A., Bregar, V. B., Križaj, I., Svete, J., and
Pavlin, M. (2017) Dispersion of nanoparticles in different media
importantly determines the composition of their protein corona. PLoS
One 12, e0169552.
(117) Vlasova, M., and Smirin, B. V. (2017) Personalized Approach
in Nanomedicine: Understanding Adverse Effects and Their Risk
Assessment. Recent Advances in Drug Delivery Technology, 1−21.
J DOI: 10.1021/acschemneuro.8b00127
Perspective
(118) Park, S.-M., Aalipour, A., Vermesh, O., Yu, J. H., and Gambhir,
S. S. (2017) Towards clinically translatable in vivo nanodiagnostics.
Nature Reviews Materials 2, 17014.
(119) Colapicchioni, V., Tilio, M., Digiacomo, L., Gambini, V.,
Palchetti, S., Marchini, C., Pozzi, D., Occhipinti, S., Amici, A., and
Caracciolo, G. (2016) Personalized liposome−protein corona in the
blood of breast, gastric and pancreatic cancer patients. Int. J. Biochem.
Cell Biol. 75, 180−187.
(120) Choi, H., Lee, Y.-S., Hwang, D. W., and Lee, D. S. (2016)
Translational radionanomedicine: a clinical perspective. Eur. J.
Nanomed. 8, 71−84.
(121) Tavakol, M., Montazeri, A., Naghdabadi, R., Hajipour, M.,
Zanganeh, S., Caracciolo, G., and Mahmoudi, M. (2018) Disease-
related metabolites affect protein-nanoparticle interactions. Nanoscale
10, 7108.
(122) Salomon, F., Cuneo, R. C., Hesp, R., and Sönksen, P. H.
(1989) The effects of treatment with recombinant human growth
hormone on body composition and metabolism in adults with growth
hormone deficiency. N. Engl. J. Med. 321, 1797−1803.
(123) Beger, R. D., Sun, J., and Schnackenberg, L. K. (2010)
Metabolomics approaches for discovering biomarkers of drug-induced
hepatotoxicity and nephrotoxicity. Toxicol. Appl. Pharmacol. 243, 154−
166.
(124) Goldstein, A. (1949) The interactions of drugs and plasma
proteins. Pharmacol. Rev. 1, 102−165.
(125) Martin, B. (1965) Potential effect of the plasma proteins on
drug distribution. Nature 207, 274.
(126) Davis, B. D. (1943) The binding of sulfonamide drugs by
plasma proteins. A factor in determining the distribution of drugs in
the body. J. Clin. Invest. 22, 753−762.
(127) Leggett, R., Lee-Smith, E. E., Jickells, S. M., and Russell, D. A.
(2007) Intelligent” fingerprinting: simultaneous identification of drug
metabolites and individuals by using antibody-functionalized nano-
particles. Angew. Chem. 119, 4178−4181.
(128) Hazarika, P., Jickells, S. M., Wolff, K., and Russell, D. A. (2008)
Imaging of latent fingerprints through the detection of drugs and
metabolites. Angew. Chem., Int. Ed. 47, 10167−10170.
(129) Matsumoto, M., Kibe, R., Ooga, T., Aiba, Y., Kurihara, S.,
Sawaki, E., Koga, Y., and Benno, Y. (2012) Impact of intestinal
microbiota on intestinal luminal metabolome. Sci. Rep. 2, 233.
(130) Wikoff, W. R., Anfora, A. T., Liu, J., Schultz, P. G., Lesley, S. A.,
Peters, E. C., and Siuzdak, G. (2009) Metabolomics analysis reveals
large effects of gut microflora on mammalian blood metabolites. Proc.
Natl. Acad. Sci. U. S. A. 106, 3698−3703.
(131) Clarke, G., Stilling, R. M., Kennedy, P. J., Stanton, C., Cryan, J.
F., and Dinan, T. G. (2014) Minireview: Gut microbiota: the neglected
endocrine organ. Mol. Endocrinol. 28, 1221−1238.
(132) Kennedy, P. J., Cryan, J. F., Dinan, T. G., and Clarke, G.
(2017) Kynurenine pathway metabolism and the microbiota-gut-brain
axis. Neuropharmacology 112, 399−412.
(133) de la Fuente-Nunez, C., Meneguetti, B. T., Franco, O. L., and
Lu, T. K. (2018) Neuromicrobiology: How Microbes Influence the
Brain. ACS Chem. Neurosci. 9, 141−150.
(134) Saha, K., Agasti, S. S., Kim, C., Li, X., and Rotello, V. M. (2012)
Gold nanoparticles in chemical and biological sensing. Chem. Rev. 112,
2739−2779.
(135) Zheng, T., Pierre-Pierre, N., Yan, X., Huo, Q., Almodovar, A. J.
O., Valerio, F., Rivera-Ramirez, I., Griffith, E., Decker, D. D., Chen, S.,
and Zhu, N. (2015) Gold Nanoparticle-Enabled Blood Test for Early
Stage Cancer Detection and Risk Assessment. ACS Appl. Mater.
Interfaces 7, 6819−6827.
(136) Zheng, T., Finn, C., Parrett, C. J., Dhume, K., Hwang, J. H.,
Sidhom, D., Strutt, T. M., Li Sip, Y. Y., McKinstry, K. K., and Huo, Q.
(2017) A Rapid Blood Test To Determine the Active Status and
Duration of Acute Viral Infection. ACS Infect. Dis. 3, 866−873.
(137) Du, Y., Li, B., Guo, S., Zhou, Z., Zhou, M., Wang, E., and
Dong, S. (2011) G-Quadruplex-based DNAzyme for colorimetric
detection of cocaine: Using magnetic nanoparticles as the separation
and amplification element. Analyst 136, 493−497.
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience Perspective

(138) Goldberg, D. E., and Holland, J. H. (1988) Genetic algorithms (155) Wolfbeis, O. S. (2009) Nanoparticle-Enhanced Fluorescence
and machine learning. Machine learning 3, 95−99. Imaging of Latent Fingerprints Reveals Drug Abuse. Angew. Chem., Int.
(139) Deo, R. C. (2015) Machine learning in medicine. Circulation Ed. 48, 2268−2269.
132, 1920−1930.
(140) Murdoch, T. B., and Detsky, A. S. (2013) The inevitable
application of big data to health care. Jama 309, 1351−1352.
(141) McAfee, A., Brynjolfsson, E., Davenport, T. H., Patil, D., and
Barton, D. (2012) Big data: the management revolution. Harvard
business review 90, 60−68.
(142) Cohen, J. D., Li, L., Wang, Y., Thoburn, C., Afsari, B., Danilova,
L., Douville, C., Javed, A. A., Wong, F., Mattox, A., Hruban, R. H.,
Wolfgang, C. L., Goggins, M. G., Dal Molin, M., Wang, T.-L., Roden,
R., Klein, A. P., Ptak, J., Dobbyn, L., Schaefer, J., Silliman, N., Popoli,
M., Vogelstein, J. T., Browne, J. D., Schoen, R. E., Brand, R. E., Tie, J.,
Gibbs, P., Wong, H.-L., Mansfield, A. S., Jen, J., Hanash, S. M., Falconi,
M., Allen, P. J., Zhou, S., Bettegowda, C., Diaz, L., Tomasetti, C.,
Kinzler, K. W., Vogelstein, B., Lennon, A. M., and Papadopoulos, N.
(2018) Detection and localization of surgically resectable cancers with
a multi-analyte blood test. Science 359, 926−930.
(143) Yan, J., and Charles, J. F. (2018) Gut microbiota and IGF-1.
Calcif. Tissue Int. 102, 406−414.
(144) Hsiao, E. Y., McBride, S. W., Hsien, S., Sharon, G., Hyde, E. R.,
McCue, T., Codelli, J. A., Chow, J., Reisman, S. E., and Petrosino, J. F.
(2013) Microbiota modulate behavioral and physiological abnormal-
ities associated with neurodevelopmental disorders. Cell 155, 1451−
1463.
(145) Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat,
B., Guyonnet, D., Legrain-Raspaud, S., Trotin, B., Naliboff, B., and
Mayer, E. A. (2013) Consumption of fermented milk product with
probiotic modulates brain activity. Gastroenterology 144, 1394−1401.
(146) Bravo, J. A., Forsythe, P., Chew, M. V., Escaravage, E.,
Savignac, H. M., Dinan, T. G., Bienenstock, J., and Cryan, J. F. (2011)
Ingestion of Lactobacillus strain regulates emotional behavior and
central GABA receptor expression in a mouse via the vagus nerve. Proc.
Natl. Acad. Sci. U. S. A. 108, 16050−16055.
(147) Acosta-Martinez, V., Dowd, S., Sun, Y., and Allen, V. (2008)
Tag-encoded pyrosequencing analysis of bacterial diversity in a single
soil type as affected by management and land use. Soil Biol. Biochem.
40, 2762−2770.
(148) Partty, A., Kalliomaki, M., Wacklin, P., Salminen, S., and
Isolauri, E. (2015) A possible link between early probiotic intervention
and the risk of neuropsychiatric disorders later in childhood: a
randomized trial. Pediatr. Res. 77, 823−828.
(149) Desbonnet, L., Garrett, L., Clarke, G., Bienenstock, J., and
Dinan, T. G. (2008) The probiotic Bifidobacteria infantis: An
assessment of potential antidepressant properties in the rat. J.
Psychiatr. Res. 43, 164−174.
(150) Fröhlich, E. E., and Fröhlich, E. (2016) Cytotoxicity of
nanoparticles contained in food on intestinal cells and the gut
microbiota. Int. J. Mol. Sci. 17, 509.
(151) Van Den Brûle, S., Ambroise, J., Lecloux, H., Levard, C.,
Soulas, R., De Temmerman, P.-J., Palmai-Pallag, M., Marbaix, E., and
Lison, D. (2015) Dietary silver nanoparticles can disturb the gut
microbiota in mice. Part. Fibre Toxicol. 13, 38.
(152) Javurek, A. B., Suresh, D., Spollen, W. G., Hart, M. L., Hansen,
S. A., Ellersieck, M. R., Bivens, N. J., Givan, S. A., Upendran, A.,
Kannan, R., and Rosenfeld, C. S. (2017) Gut dysbiosis and
neurobehavioral alterations in rats exposed to silver nanoparticles.
Sci. Rep. 7, 2822.
(153) Williams, K., Milner, J., Boudreau, M. D., Gokulan, K.,
Cerniglia, C. E., and Khare, S. (2015) Effects of subchronic exposure
of silver nanoparticles on intestinal microbiota and gut-associated
immune responses in the ileum of Sprague-Dawley rats. Nanotoxicology
9, 279−289.
(154) Fallon, M. S., Varshney, M., Dennis, D. M., and Chauhan, A.
(2004) A physiologically-based pharmacokinetic model of drug
detoxification by nanoparticles. J. Pharmacokinet. Pharmacodyn. 31,
381−400.

K DOI: 10.1021/acschemneuro.8b00127
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