![A conceptual illustration of the design for drug-loaded nanoparticle targeting to the heart in vivo and in vitro, and the clinical application of nanoparticles in humans. Reprinted with permission from [100], K. T. Fitzgerald, et al., Standardization of models and methods used to assess nanoparticles in cardiovascular applications. Small 7, 705 (2011). © 2011, John Wiley and Sons.](https://www.researchgate.net/profile/Hai-Sheng-Peng/publication/265968880/figure/fig2/AS:392140078239746@1470504888145/A-conceptual-illustration-of-the-design-for-drug-loaded-nanoparticle-targeting-to-the_Q320.jpg)
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Review
Journal of
Biomedical Nanotechnology
Vol. 10, 2038–2062, 2014
www.aspbs.com/jbn
Heart-Targeted Nanoscale Drug Delivery Systems
Meifang Liu1, Minghui Li1, Guangtian Wang1, Xiaoying Liu1, Daming Liu1,
Haisheng Peng12∗, and Qun Wang23∗
1Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing, 163319, China
2Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA
3Department of Civil, Construction and Environmental Engineering, Iowa State University, Ames, IA 50011, USA
The efficacious delivery of drugs to the heart is an important treatment strategy for various heart diseases. Nanocarriers
have shown increasing promise in targeted drug delivery systems. The success of nanocarriers for delivering drugs to
therapeutic sites in the heart mainly depends on specific target sites, appropriate drug delivery carriers and effective
targeting ligands. Successful targeted drug delivery suggests the specific deposition of a drug in the heart with mini-
mal effects on other organs after administration. This review discusses the pathological manifestations, pathogenesis,
therapeutic limitations and new therapeutic advances in various heart diseases. In particular, we summarize the recent
advances in heart-targeted nanoscale drug delivery systems, including dendrimers, liposomes, polymer-drug conjugates,
microparticles, nanostents, nanoparticles, micelles and microbubbles. Current clinical trials, the commercial market and
future perspective are further discussed in the conclusions.
KEYWORDS: Heart-Targeted, Nanoscale, Materials, Drug Delivery Systems, Clinical Trials.
CONTENTS
Introduction ...................................2038
Cardiovascular Physiological Properties .................2040
Cardiac Physiology ............................2040
Cardiac Cells for Drug Targeting ...................2042
Cardiovascular Diseases ...........................2043
Ischemia and Infarction .........................2043
Heart Failure ................................2045
Myocardial Hypertrophy .........................2045
Restenosis ..................................2045
Heart-Targeted Drug Delivery Systems ..................2046
Dendrimers .................................2046
Liposomes ..................................2047
Polymeric Drug Conjugates .......................2048
Microparticles ...............................2049
Nanoparticles ................................2049
Micelles ...................................2052
Stents with Nano-Coating ........................2053
Microbubbles ................................2054
Clinical Trials and Commercial Market .................2054
Conclusions and Future Direction .....................2054
Acknowledgments .............................2054
References ..................................2055
∗Authors to whom correspondence should be addressed.
Emails: fisher1688@163.com, qunwang@iastate.edu
Received: 13 January 2014
Accepted: 26 January 2014
INTRODUCTION
Cardiovascular disease, particularly ischemic impairment,
is an important cause of morbidity and mortality world-
wide and will become most common cause of death after
10 years.1The heart is an organ of concern at the molec-
ular level and is easily affected by disease in both child
and adult populations.2–4 Human cardiac disease involves
abnormalities in morphogenesis, muscle repair and func-
tion and cardiac rhythm.5A promising solution to heart
disease involves directly delivering cardioprotective drugs
into the infarcted myocardium and cardiovascular system.
The need for improved therapies has led to the emergence
of targeted drug delivery to the heart.
In 1906, Erhlich et al. originally proposed the concept
of targeted delivery in the form of a magic bullet that
would attack affected cells but without any influence on
normal tissues.6The strategies of targeted drug delivery
refer to the direction of active agents and their carriers into
the affected tissue with minimal effects on surrounding
healthy tissues after systemic administration.7–11 In addi-
tion, the old therapeutics always require higher doses
to acquire enough effect-site concentration to achieve a
valid therapeutic effect due to the limited solubility of
the drugs.12 In addition, biomolecules, such as oligonu-
cleotides, proteins and peptides and small chemicals with
2038 J. Biomed. Nanotechnol. 2014, Vol. 10, No. 9 1550-7033/2014/10/2038/025 doi:10.1166/jbn.2014.1894
Liu et al. Heart-Targeted Nanoscale Drug Delivery Systems
a short half-life in the circulation require the adminis-
tration of repeated doses to maintain active levels in the
vessels. Under some circumstances, drug levels in the
body exceed the minimum toxic concentration and gen-
erate adverse effects for the patient. Overall, the conven-
tional application of drugs is limited by several hurdles,
such as weak effectiveness, poor biodistribution and low
selectivity.13–15
Meifang Liu is a graduate student in pharmaceutics at Harbin Medical University
(Daqing). She received her bachelor’s degree from WeiFang Medical University in 2011.
She has 7 publications in international journals. Currently she is working on exploring
the use of antibody-modified liposomes loaded with AMO-1 to deliver oligonucleotides
to ischemic myocardium for arrhythmia therapy; the corresponding research paper has
been accepted by the Journal of Biomaterials.
Minghui Li works as a lecturer and a vice director in the Department of Pharmaceutics
at Harbin Medical University (Daqing). She got her Master degree in Pharmaceutical
Engineering from Dalian University of Technology in 2010. She got Bachelor degree in
Harbin Medical University in 2007. Li Minghui’s research interests include controlled
release formulations and targeted drug delivery.
Guangtian Wang is a graduate student in Harbin Medical University (Daqing). He
received a B.S. degree in Harbin University of Science and Technology. Currently, he
is doing research in the laboratory of Dr. Haisheng Peng. His areas of interests include
biomaterials, nanotechnology and drug delivery.
Xiaoying Liu is a graduate student in Harbin Medical University (Daqing). She got
the bachelor degree in Harbin Medical University (Daqing) in 2013. Currently, she is
doing research in the laboratory of Dr. Haisheng Peng. Her areas of interests include
biomaterials, nanotechnology and ischemic myocardial delivery.
All of these drawbacks drive researchers forward to
further develop and optimize new drug carriers. Targeted
drug delivery enhances the specific deposition of drugs
in the abnormal foci after administration and simultane-
ously decreases the adverse effects in healthy organs.16–22
Drug carriers are vehicles for the protection of drugs dur-
ing transportation after administration and for the mainte-
nance of controlled-release in the body.2324 The promising
J. Biomed. Nanotechnol. 10, 2038–2062, 2014 2039
Heart-Targeted Nanoscale Drug Delivery Systems Liu et al.
Daming Liu is a graduate student in the 2nd Hospital Affiliated of Harbin Medical
University. He got his bachelor degree in Harbin Medical University in 2006. He had
been working as a neurosurgeon in Harbin Red Cross Hospital for 6 years. He will con-
tinue his study for M.D. majored in Neurology and Pharmacy. Daming Liu’s research
focuses on targeted drug delivery in the treatment of ischemia and tumor.
Haisheng Peng works as an Associate Professor in the Department of Pharmaceutics
at Harbin Medical University (Daqing) and is a Postdoctoral Fellow in the Department
of Chemical and Biological Engineering at Iowa State University. He finished his first
postdoctoral training in cardiovascular pharmacology at Harbin Medical University in
2011. He earned his Ph.D. in neural biology from Harbin Medical University in 2008.
Dr. Peng’s areas of interest include the design of drug delivery systems, the investigation
of distribution behavior and mechanisms, stem cell engineering and biomaterials.
Qun Wang works as an Assistant Professor with a joint appointment in the Department
of Chemical and Biological Engineering and the Department of Civil, Construction and
Environmental Engineering at Iowa State University. He is also an Associate Scientist
at the Ames National Laboratory of Department of Energy. He earned his Ph.D. in
chemical and petroleum engineering from the University of Kansas in 2010. He also
received another Ph.D. in environmental science and engineering from Wuhan Univer-
sity in 2007. Dr. Wang’s areas of interest include biomaterials, intestinal engineering,
nanotechnology and drug delivery. At Iowa State University, Dr. Wang BINDs his
research in these areas to provide innovative solutions and products for human health.
drug carriers include osmotic pumps, liposomes, hydro-
gels and polymeric microparticles.25–28 Successful targeted
drug delivery can decrease toxicity and improve the solu-
bility and stability of the loaded drug.2930 Classical target-
ing nanoscale carriers usually consist of several functional
elements, including drugs, targeting ligands and the bio-
compatible coating of nanoparticles.31–34 These elements
could avoid the quick clearance of nanocarriers by the
reticuloendothelial system. A conceptual illustration of the
design of drug-loaded nanoparticle targeting to the heart
is shown in Figure 1.
Recent therapeutic approaches to prevent heart fail-
ure after myocardial infarction (MI) mainly rely on the
systemic injection of proangiogenic peptides and stem
cell therapy.35–37 Unfortunately, some data have confirmed
the absence of effectiveness of these active biomacro-
molecules due to their short half-life and low stability.
Therefore, a heart-targeted nanoparticle drug delivery sys-
tem is emerging and looks promising. The major task for
fabricating heart-targeted nanoparticles is to choose the
appropriate drug delivery carriers and to select effective
targeting ligands that will ensure a specific interaction of
carriers with the complementary molecules on the targeted
cell membrane. The tissue-recognition ligands in the heart
have been widely studied and include PECAM-1, myosin,
P-selection, cTnI and cTnC. This review summarizes the
properties, symptoms and therapies of various heart dis-
eases and discusses the emerging developments of heart-
targeted nanoscale drug delivery systems.
CARDIOVASCULAR PHYSIOLOGICAL
PROPERTIES
Cardiac Physiology
Rhythmicity
The rhythm of the heart refers to the heart beating.
It should be very homogeneous in a healthy heart.
The cardiac pacemaker is the sinoatrial nodal cell,
which generates normal, homogeneous heart contractions
(Fig. 2). The electrical signals derived from the sinoatrial
2040 J. Biomed. Nanotechnol. 10, 2038–2062, 2014
Liu et al. Heart-Targeted Nanoscale Drug Delivery Systems
Figure 1. Heart-targeted nanoscale drug delivery systems (DDS).
node are distributed over the heart surface by a special-
ized conduction system; these signals can be recorded
as an electrocardiogram (ECG). Moreover, the sinoatrial
cells are highly resistant to cardiac failure and ischemia.38
However, when the heart pacemaker, resulting heart rate
and rhythm and impulse conduction exhibit pathological
changes, arrhythmias occur in the form of bradycardia,
tachycardia and other rhythm abnormalities. Standard lead
II electrocardiograms are used to record the rhythm of the
heart in vivo for diagnosing arrhythmias. In 1988, Curtis
and Walker defined the arrhythmia score to evaluate this
disease.39
Many ion channel diseases are diagnosed through
ECG recordings. The ECG abnormalities mainly include
Figure 2. Heart structures and associated cells for drug targeting. SAN: sinoatrial node, AVN: atrioventricular node, AMC: aor-
tomitral continuity, L&R BD: left and right bundle branches, PF: Purkinje fibers, EC: endothelial cells, SC: smooth cells, VM:
ventricular myocytes and NHA: normal human artery.
catecholaminergic polymorphous ventricular tachycardia,
long-QT or short-QT syndrome and Brugada syndrome.
However, there are ECG abnormalities with no explana-
tion, such as prolonged QT interval, ventricular extrasys-
tole on stress ECG, ST segment elevation in the precordial
leads and negative or abnormal Twaves.40 The clinical
symptoms of various arrhythmias have been described by
previous investigators.4142 The diagnosis and therapy of
arrhythmias are carried out in many ways.4344 In 2008,
Churchill et al. proposed that PKC isozymes may be the
therapeutic targets of chronic cardiac diseases.45 Moreover,
it has been reported that an irregular ventricular rhythm
causes an alteration in excitation-contraction coupling,
which contributes to the progression of heart failure.46
J. Biomed. Nanotechnol. 10, 2038–2062, 2014 2041
Heart-Targeted Nanoscale Drug Delivery Systems Liu et al.
Blood Pressure
Blood pressure refers to the lateral pressure from blood
flow per unit area in blood vessels. It can be divided into
diastolic blood pressure (DBP) and systolic blood pressure
(SBP). Clinical diagnostics have shown that abnormalities
in SBP and DBP are associated with some heart diseases,
such as stroke, myocardial infarction and heart failure.
Hypertension is a major risk factor that increases the inci-
dence of cardiovascular disease (CVD), which impairs
quality of life and usually leads to higher mortality.47–49
In addition, hypertension in the elderly contributes to
numerous structural and functional changes to the vascu-
lature during arterial aging. These changes usually lead to
isolated systolic hypertension, diastolic heart failure and
small vessel disease in the brain and other organs.50 Other
risk factors are involved in hypertension, such as dimin-
ished kidney function, increasing age, diabetes mellitus,
higher body mass index and genetic factors.51–54
In the 1960s, safe and effective antihypertensive drugs
were first developed and led to dramatic improvements in
the prognosis of patients with malignant hypertension.55
Over the next few decades, the use of an expanding arma-
mentarium of blood pressure-lowering drugs has effec-
tively eradicated the risk of malignant hypertension.56
However, the issues related to drug interactions and the
side effects of antihypertensive medications, such as ortho-
static hypotension in the setting of autonomic dysreg-
ulation, are of increasing concern. Recent studies have
indicated that renal denervation was a new interventional
approach that significantly reduced blood pressure with-
out causing major complications in patients with resistant
hypertension.5758 In addition, there is class I, level B evi-
dence that 150 minutes of weekly physical activity may
be used to complement antihypertensive medication.59
Blood Flow and Output
Blood flow is well known as a basis of the diagnosis of
cardiac disease states and can be influenced by numer-
ous factors.60 The evaluation of cardiac blood flow is use-
ful in the hemodynamic management of neonates. It is
an effective indicator of health or disease and a pathway
to assess the reaction to various stimuli and pharmaceuti-
cal interventions.6162 Although the measurement of flow
is more difficult than the measurement of pressure, most
organs require flow rather than pressure. Blood flow can
be estimated by functional echocardiography by measur-
ing upper body systemic blood flow.63 Estimating car-
diac blood flow offers a clearer understanding of the
pathophysiology underling the various clinical conditions
and guidance in the management of these conditions. For
example, thrombus resulting from pathological conditions
in blood vessel contributes to ischemia, myocardial infarc-
tion, atherosis, restenosis, etc. To treat these diseases,
the biodegradable polymer-coated stent and ultrasound-
mediated microbubble destruction have been developed
and have shown potential application value for restoring
blood flow.64–67
Cardiac Cells for Drug Targeting
Cardiac Muscle Cells
Cardiomyocytes are highly specialized cells that are
responsible for the bioelectric variations that generate
autorhythmicity, excitability and conductibility. Autorhyth-
micity is the property that cardiomyocytes acquire
spontaneous diastolic depolarization followed by an elec-
trical impulse in the absence of external electrical
stimuli.68 Under normal conditions, the sinoatrial node has
the highest autonomy and determines the heart rate in var-
ious mammalian species, followed by the atrioventricular
junction area and then the Purkinje fibers. Spontaneously
originated action potentials (APs) are propagated via car-
diomyocytes when the cardiac cells are exposed to a stim-
ulus with a generative AP, which refers to the excitability
of cardiac cells.69
Gap junctions are specialized membrane structures.
Intercellular ion channels in gap junctions form a path-
way of cell-to-cell communication. Gap junctions play an
important role in the propagation of cardiac impulses.70
In addition, the suppression or enhancement of pacemaker
activities and automaticity may cause clinical arrhythmias.
The individual ion channels, gap junctions and exchanger
activities determine cardiac excitability and electrical
activity. Previous reports have demonstrated that primary
heart disease, which has an increased arrhythmia risk, and
primary arrhythmia syndromes are caused by dysfunction
of the ion channels in the cardiac muscle.71–74 Many data
have supported that cardiovascular abnormalities, such as
coronary artery disease, stroke and heart failure, are asso-
ciated with changes in cardiac electrical excitability due to
transcriptional and post-translational modifications of ion
channels and gap junction proteins.7576 Typical nanoparti-
cle systems target thrombi in lining of artery are demon-
strated in Figure 3.
In addition, some previous studies have also indicated
that the interactions and fine balance between various
transmembrane ion currents regulate cardiac repolarization
and, consequently, the duration of the ventricular action
Figure 3. Nanoparticles target thrombi in the lining of an
artery.
2042 J. Biomed. Nanotechnol. 10, 2038–2062, 2014
Liu et al. Heart-Targeted Nanoscale Drug Delivery Systems
potential.7778 First, K+channels play an important role in
determining the morphology and repolarization of the car-
diac action potential. At least eleven K+currents have been
characterized pharmacologically by molecular cloning.79
For example, the cardiac delayed rectifier K+current (Ik)
mainly consists of two components, the rapidly activat-
ing (Ikr ), which is blocked by the class III antiarrhyth-
mic agent E4031, and the slowly activating (Iks), which is
inhibited by chromanol 293B.8081 In addition, the inward
rectifier K+current (Ik1) influences terminal repolarization
and stabilization of the resting membrane potential in car-
diac cells.82 Changes in Ik1currents density are relevant to
arrhythmogenesis.83
Second, high-voltage, L-type Ca2+channels and low-
voltage, T-type Ca2+channels have been identified in the
sarcolemma of cardiac cells.8485 The influx of Ca2+ions
through Ca2+channels contributes to cardiac excitability
and excitation-contraction coupling.12 Braz et al. proposed
that protein kinase C may affect cardiac excitation-
contraction coupling through a negative feedback of sar-
coplasmic reticulum Ca2+load in addition to its effects on
cardiomyocyte excitability, further affecting cardiac per-
formance during cardiac dysfunction and heart failure.86
It is implied that transient low-voltage, activated currents
(ICaT) could trigger Ca2+ion release from the sarcoplas-
mic reticulum and induce contraction of Purkinje cells.6287
Previous studies have reported that the levels of re-
expression of T-type Ca2+channels are increased in cer-
tain pathologic states, such as ventricular hypertrophy.6388
Third, voltage-gated Na+channels are the primary
channels that control the rising phase of the action
potential in excitable cells. Some researchers have dis-
covered that the down-regulation of Ca2+and Na+chan-
nel currents through the protein kinase isozyme (II, )
may lead to cardiac hypertrophy, heart failure and a
disruption in cardiac excitability.79 Voltage-gated sodium
channels (VGSCs) are a family of proteins with 9 iso-
forms that regulate the inward Na+current upon mem-
brane depolarization. Various inherited arrhythmias may
be caused by VGSC dysfunction, such as long QT syn-
drome and Brugada syndrome.89 Fibroblast growth factor
homologous factors (FGFHFs), which are comprised of
four genes (FGF11–14), are intracellular proteins that
modulate VGSCs and are potential regulators responsible
for cardiac conduction abnormalities.90 Additionally, gap
junctions also play an essential role in the electrical cell-to-
cell coupling and impulse propagation between cells. The
Na+/Ca2+exchanger is responsible for regulating intracel-
lular Ca2+homeostasis to maintain the normal electrical
and mechanical activities of the heart.
Endothelial Cells
As a dynamic component of the cardiovascular system,
the endothelium lines the luminal surface of blood ves-
sels and plays an important role in cardiac health and dis-
ease. It is a barrier between the blood vessels and vascular
smooth muscle cells (VSMC) and releases mediators that
regulating vascular tone and growth, blood fluidity, platelet
function and coagulation.91 Under pathological conditions,
endothelial damage or dysfunction generally leads to a loss
of anti-aggregative, anti-thrombotic, anti-inflammatory and
anti-VSMC activation/growth properties.92 Designed inter-
ference in these processes may yield optimistic therapeu-
tic benefit in the treatment of diseases that are associated
with endothelial damage and dysfunction. Therefore,
many diseases, including angiogenesis, atherosclerosis,
tumor growth, myocardial infarction and limb and car-
diac ischemia, can be treated by the regulation of
endothelium.93–95 Vascular endothelial cells (VECS) are
particular important targets for circulating drug delivery
systems because of their large population and contiguity
with the blood stream.96
Various therapeutic approaches have been developed
to fight against vascular diseases.97 Recently, some
researchers have proposed the targeted delivery of
endothelial cells by overexpressing interleukin-8 receptors
A and B (IL8-RA and -RB). This approach prevented
inflammatory responses and promoted the structural recov-
ery of arteries following endothelial injury by reducing
IL-8 in injured or infected tissues.96 However, only a small
fraction of injected therapeutic agents bind to endothelial
cells (EC) due to a lack of affinity for the endothelium
or removal by hemopsonin. Another challenge for deliv-
ering drugs to the endothelium is that many therapeutic
agents require precise delivery to specific subcellular com-
partments. The goal of endothelial targeting is to specially,
safely and effectively transport a drug to specific parts of
ECs to achieve local effects, thereby, improving pharma-
cological interventions, including those for metabolic and
oncological diseases.9899 The design determinant of tar-
geted drug delivery systems (DDS) is shown in Figure 4.100
A large number of molecules can serve as specific
ligands for EC targeting, such as vascular endothelial
growth factor (VEGF), cell adhesion molecule (CAM)
and immunoglobulin G (IgG)-type antibodies.101102 Drugs
loaded into liposomes or polymer vehicles or conjugated
with affinity moieties for targeting to ECs may also
improve the treatment of vascular diseases. Recent research
has attempted to explore efficient targeted drug delivery
vehicles to the endothelium, such as liposomes, polymeric
nanocarriers and ultrasound-mediated microbubbles.103–105
CARDIOVASCULAR DISEASES
Ischemia and Infarction
Cardiovascular diseases are usually characterized by lower
blood perfusion. Coronary arteriosclerosis due to coro-
nary artery stenosis or occlusion is the leading cause
of coronary heart disease. Coronary arteriosclerosis may
result in myocardial infarction with ischemic death of
cardiomyocytes.106107 To salvage the myocardium from
acute or chronic ischemia, reperfusion is the essential
J. Biomed. Nanotechnol. 10, 2038–2062, 2014 2043
Heart-Targeted Nanoscale Drug Delivery Systems Liu et al.
Figure 4. A conceptual illustration of the design for drug-loaded nanoparticle targeting to the heart in vivo and in vitro, and the
clinical application of nanoparticles in humans. Reprinted with permission from [100], K. T. Fitzgerald, et al., Standardization of
models and methods used to assess nanoparticles in cardiovascular applications. Small 7, 705 (2011). © 2011, John Wiley and
Sons.
strategy and is achieved through thrombolysis, percuta-
neous coronary angioplasty and/or coronary bypass.75108
Previous studies have shown that a pathological change
in the ischemic myocardium was expressed by cardiac
troponin I (cTnI). As a current gold-standard marker,
cTnI is uniquely expressed only when cardiac damage has
occurred.109 Therefore, the pathological overexpression of
cTnI can, as a target for the myocardium, be designed
as a drug delivery system for targeting ischemic arrhyth-
mias. However, injury to the endothelium and cardiomy-
ocytes occurs after reperfusion.110111 Ischemia-reperfusion
Figure 5. Signal pathways of microRNAs after myocardial ischemia-reperfusion (I/R). miR-92a is expressed in vascular endothe-
lia and inhibits the expression of proangiogenic proteins to block ischemic angiogenesis. In contrast, the levels of miR-499 and
miR-24 were decreased after I/R injury. MiR499 represses cells apoptosis via calcineurin, while miR-24 decreases apoptosis via
the down-regulation of BIM levels. Therefore, the down-regulation of miR-92a expression or the up-regulation of miR-499 or miR-
24 expression may be of benefit to myocardial ischemia and reperfusion. Calcineurin (CN); endothelial cell (EC). Reprinted with
permission from [114], H. K. Eltzschig and T. Eckle, Ischemia and reperfusion [mdash] from mechanism to translation. Nat. Med.
17, 1391 (2011). © 2011, Nature Publishing Group.
(I/R) injury is another important factor responsible for
infarct size and cardiac dysfunction. The negative effects
of I/R mainly included intracellular calcium overload and
oxidative stress, which eventually lead to cell death.112
In addition, myocardial I/R also leads to arrhythmias and
cardiac contractile dysfunction.113 The new mechanisms
and microRNA pathways of myocardial I/R injury are
shown in Figure 5.114 It has been reported that the pri-
mary determinant of the outcome of an I/R insult is
the pressure, and associated mechanical stress/load, on
the myocardium.115 The evaluation of I/R injury mainly
2044 J. Biomed. Nanotechnol. 10, 2038–2062, 2014
Liu et al. Heart-Targeted Nanoscale Drug Delivery Systems
depends on hemodynamic parameters, including heart rate,
aortic flow, coronary flow, perfusion pressure and cardiac
output.97 Recent studies have shown that cardioprotective
drugs, such as ginsenoside-Re, pioglitazone and follistatin-
like 1, significantly inhibited the cardiac injury caused
by I/R.116–118
Heart Failure
Heart failure (HF) is a complex pathophysiological syn-
drome. It arises from the debilitated function of the
heart to fill and/or eject blood sufficiently. The clini-
cal manifestations of HF are associated with myocardial
insult, including coronary artery disease, genetic factors
or hypertension, and their attendant sequelae. It is esti-
mated that HF is the primary cause of over 55,000 deaths
each year, and the incidence of symptomatic HF rises
with the increasing age.119120 Chronic HF (CHF) generally
occurs due to continued left ventricular (LV) remodeling
and the progressive loss of function, leading to abnormali-
ties in diastolic and/or systolic function.121 The myocardial
injury evokes an increased orchestrated cascade of remod-
eling stimuli within the heart and leads to alterations in
neurohormones, vascellum, the kidney and skeletal mus-
cle. Lymperopoulos et al. have articulated the idea that G
protein-coupled receptors (GPCRs) are the major neuro-
hormonal receptors that control cardiac function and phys-
iology. For example, the -adrenergic receptors (1- and
2-ARs) in the membranes of cardiomyocytes dominate
cardiac contractile function. Angiotensin II (AngII) type 1
receptors (AT1Rs), which are mainly present in the mem-
branes of endothelial cell and cardiac fibroblasts, regulate
the cardiac structure and morphology. Heart rate is regu-
lated by the balance between muscarinic cholinergic recep-
tors and -adrenergic receptors.122123
Given the weak potential of the available therapeutic
approaches, it is essential to design new drug delivery sys-
tems for the treatment of HF.124 Some studies have revealed
that CHF increases action potential duration (APD), which
leads to early after depolarizations (EAD) and lethal ven-
tricular tachyarrhythmias.2123 The molecular mechanism
may lie in that tumor necrosis factor-(TNF-) prolongs
APD. This mechanism is a potential reason for electro-
physiological abnormalities and sudden death in HF.125
Recently, many researchers have focused on strategies
based on regulatory RNA (related to heart diseases) or gene
transfer to the heart. For instance, in 2007 Yang et al. dis-
covered that microRNA-1 (miR-1) had important physio-
logical effects in relieving arrhythmias.83
Myocardial Hypertrophy
In adult mammalian heart, the cardiomyocytes possess
poor proliferative capacity. The heart increases in size
in response to increased workload or stress, such as
aortic stenosis, hypertension, vascular heart disease and
myocardial infarction. A hypertrophied heart is showed in
Figure 6. The increase in cardiomyocyte size is referred
Figure 6. Hypertrophied heart.
to as myocardial hypertrophy. The cellular responses of
cardiomyocytes to various signaling pathways are used to
maintain cardiac homeostasis and to prevent pathologi-
cal cardiac hypertrophy. In general, cardiomyocytes ini-
tiate a hypertrophic response to adapt to stress and to
improve cardiac function when the heart is suffering from
various stimuli, including mechanical, hemodynamic, hor-
monal and pathologic variations. The adaptive response is
triggered by a complex cascade of signaling pathways.126
Compared to the physiologically normal myocardium, the
hypertrophic myocardium needs more oxygen to main-
tain blood circulation. Under this condition, the coronary
arteries cannot provide enough blood supply, which even-
tually leads to heart failure.
Myocardial hypertrophy is usually accompanied by the
increased synthesis of proteins, assembly of sarcomeres,
perivascular and interstitial fibrosis and increased expres-
sion of embryonic genes. As a result, hypertrophy even-
tually leads to heart failure.127 Cardiac hypertrophy is an
important risk factor for the development of heart fail-
ure with increased mortality.128129 Recent studies have
revealed that the expression signatures of miRNAs have
been linked to pathological cardiac hypertrophy.130 The
data indicate that miRNAs are a new regulator in cardiac
development and disease.
Restenosis
Restenosis is a serious complication of the vascular inter-
ventional procedures that aim to restore blood flow across
obstructed arteries (Fig. 7).131 Although angioplasty and
stent implants remove the occlusion and expand the inner
diameter of the artery with improved hemodynamic flow
rate, restenosis remains a limitation to the overall effi-
cacy of vascular reconstruction and has a 30%–40%
incidence.132 Restenosis is characterized as an inflam-
matory process that occurs after injury caused by stent
replacement and balloon dilation during angioplasty.133134
In general, restenosis is associated with neointimal for-
mation from smooth muscle cell (SMC) proliferation
and migration. In addition, some new pathophysiologi-
cal mechanisms of restenosis have been well elucidated.
For example, some new signaling molecules (microRNAs)
have been deemed to control the formation of restenosis.
In the 1970s, the prevention of restenosis through
systemic drug therapy was first investigated. However,
J. Biomed. Nanotechnol. 10, 2038–2062, 2014 2045
Heart-Targeted Nanoscale Drug Delivery Systems Liu et al.
Figure 7. Therapeutic effects of miR-143/145 on in-stent
restenosis: vascular smooth muscle cell (VSMC) proliferative
capacity is reduced by miR-143/145, which may relieve in-
stent restenosis. Reprinted with permission from [131], J. F.
O’Sullivan, et al., Microribonucleic acids for prevention of
plaque rupture and in-stent restenosis “a finger in the dam.”
J. Am. Coll. Cardiol. 57, 383 (2011). © 2011, Elsevier Limited.
systemic administration has been plague by poorly tol-
erated dosages, narrow therapeutic ranges and dimin-
ished efficacy.135136 Given these disadvantages of systemic
drug delivery, local drug delivery systems were proposed
based on different approaches. For instance, higher doses
of a therapeutic agent were administered directly to a
treated artery or vein without causing adverse systemic
effects.137138 Other promising approaches have been inves-
tigated to prevent restenosis, such as drug-eluting balloons,
periadventitial drug delivery and targeted-nanoparticle sys-
temic therapies.139
HEART-TARGETED DRUG
DELIVERY SYSTEMS
Normally, cardiovascular diseases result from a decrease
in blood perfusion. In the heart, the activation of neo-
angiogenesis around the ischemic area promotes the deliv-
ery of oxygen and nutrients, leading to reduced cell
death and scar formation.77 Various therapeutic strategies
have been developed to protect the cardiac vasculature.
In 1991, Nabel et al. demonstrated that the endothelium
was a vital target for vascular therapy. The endothelium
is associated with normal and abnormal conditions, such
as tumor growth, angiogenesis, myocardial infarction, car-
diac and limb ischemia, atherosclerosis and restenosis.65
The clinical outcomes of patients with heart disease were
significantly improved after targeted therapeutics to the
infarcted myocardium.140 Recently, a number of pharma-
cological interventions for targeting the endothelium have
increased exponentially.141–143 Because vascular diseases
have been widely studied, various drugs have been inves-
tigated for potential clinical therapies, such as microRNA,
vascular endothelium growth factor (VEGF), serum and
glucocorticoid inducible kinase 1 (SGIK1), and various
cytokines. Despite years of study, many therapies have
been evaluated to be poorly tolerated, have many side
effects and have diminished efficacy. It is essential to
Figure 8. A self-assembly schematic of fluorine-
modified poly(amidoamine) dendrimers. Amine groups of
(a) poly(amidoamine) dendrimers were conjugated with
(b) HFAA to form (c) hepta-fluoroacylated poly(amidoamine)
terminal branches. The branch terminus and blue sphere the
represent the terminal primary amine and the hepta-fluoroacyl
substituent, respectively. The partially fluorinated dendrimers
(d) self-assembled in water and produced (e) dendrimers
under the appropriate conditions. The representative diameter
of the dendrimers in (e) shows the highly compressed cross
network of the fluorine-substituted dendrimers. Reprinted with
permission from [146], J. M. Criscione, et al., Self-assembly of
pH-responsive fluorinated dendrimer-based particulates for
drug delivery and noninvasive imaging. Biomaterials 30, 3946
(2009). © 2009, Elsevier Limited.
design a new, targeted drug carrier to increase the local
drug accumulation and to avoid the potential adverse
effects on neighboring tissues. Furthermore, heart-target
vehicles play a crucial role in protecting therapeutics from
immediate degradation in the blood. In this section, we
summarize the emerging research progress and results
on heart-targeted nanoscale drug delivery systems. The
chemical structure of the loaded molecules, types of tar-
get foci and pathways of nanoparticle administration into
the organ determined the options for the polymers for
nanoparticles.144
Dendrimers
Dendrimers are repeatedly branched molecules that are
characterized by their aesthetic three-dimensional structure.
The aesthetic structure is based on the evaluation of sym-
metry and polydispersity. Branching units extend radially
from a central core to form dendrimers. They were synthe-
sized in a stepwise and repetitive manner (Fig. 8).145146
The terminal groups are diversified and multi-
functionalized. The external active groups can be utilized
for the modification of dendrimers. The internal organiza-
tion is the branching points, which are of crucial impor-
tance. The preparations and characterization of dendrimers
determine their shapes, sizes and structures.147 The iden-
tification and characterization are performed via scan-
ning tunneling microscopy, atomic force microscopy and
photoluminescence.148 In 1973, the first dendrimer with
some functional groups was prepared.149 Since then, var-
ious modifications of the dendritic branches have been
performed in different fields.150 Dendrimers can entrap
2046 J. Biomed. Nanotechnol. 10, 2038–2062, 2014
Liu et al. Heart-Targeted Nanoscale Drug Delivery Systems
small chemicals and nanoscale particles in their inte-
rior to form host-guest complexes through electrostatic
or hydrophobic interactions.151152 Furthermore, the sur-
face of dendrimers can bind drugs through electrostatic
absorption due to similar polarity, such as occurs with car-
boxyl and amine groups. The desired functional group can
also be conjugated to the external terminal of dendrimers
via non-covalent or covalent modification. With excellent
biocompatibility, dendrimers are often used as drug deliv-
ery systems to deliver therapeutics to targeted tissues.
Recently, studies have shown that Starbust dendrimers
are non-immunogenic and can regulate the transfer and
expression of gene in vitro and in vivo.153 Bella Chanyshev
and her colleagues demonstrated the conjugation of chem-
ically functionalized nucleosides onto poly amidoamine
dendrimeric polymers to enhance cardioprotective potency
via the activation of A3 adenosine receptor (A3AR)
on the cardiomyocyte surface.154 Other researchers have
conjugated appropriate cardiac-targeted ligands to the
surface of dendrimers to achieve cardiac-targeted thera-
peutic effects. Wang et al. combined the technique of
DNA/dendrimer complexes and electroporation to enhance
gene transfection in murine cardiac grafts.155 Johnson
et al. fabricated S-nitroso-N-acetylpenicillamine-modified
polyamidoamine dendrimers (G4-SNAP) to reduce I/R
injury in an isolated, perfused rat heart. They found that
glutathione was able to enhance NO release from the
dendrimers to protect the affected tissue against radial
oxidation.156
Liposomes
Liposomes are structures made up of phospholipid bilay-
ers and contain closed vesicles or concentric spheres.
Liposomes can be classified as unilamellar or multilamel-
lar vesicles. In liposomes, the hydrophilic environment
enclosed by the lipid bilayers can be used to entrap water-
soluble drugs. Meanwhile, the hydrophobic environment
between the bilayers can be used to entrap lipid-soluble
drugs.157158 Liposome drug delivery systems have many
advantages in the formulation of potent drug to improve
therapeutic efficacy.159–161 These properties include bio-
compatibility, flexibility, controlled hydration, various
administration routes and stabilization of the entrapped
drug from hostile environments. However, liposomal drug
delivery suffers from rapid clearance by the reticuloen-
dothelial system if administered by parenteral injection into
the bloodstream.162 The conjugation of polyethyleneglycol
(PEG) and distearoyl phosphatidylethanolamine (DSPE) to
the liposomes can reduce their recognition by the reticu-
loendothelial system. Recently, liposomes were modified
by targeted ligands to decrease toxicity and improve depo-
sition in the desired tissues. These modifications led to new
advancements, including the specific delivery of liposomes
loaded with drugs to a desired cell and in the target tis-
sue through high-affinity ligands, such as peptides, pro-
teins and antibodies.158 In particular, the development of
heart-targeted liposomal carriers is promising to lower the
incidence of heart diseases.
In 2006, Verma et al. reported that anti-myosin mon-
oclonal antibody-doped liposomes loaded with ATP were
locally injected into the isolated rat heart before global
ischemia-reperfusion. The results confirmed the improved
post-ischemic contractile recovery.163 Recently, both Scott
et al. and Wang et al. confirmed that anti-P-selectin-
conjugated immunoliposomes containing VEGF could
significantly improve vascularization and cardiac func-
tion based on the overexpression of P-selection in the
infarcted myocardium.164165 Currently, my team is work-
ing on designing anti-cTnI antibody-modified liposomes
containing antisense oligodeoxynucleotide of microRNA-1
(AMO-1) to target the ischemic myocardium based on
the overexpression of cTnI in the infarcted myocardium.
In addition, diagnostic probes targeting v3integrin have
been used in various animal studies on atherosclerosis and
ischemia. Imaging of v3expression in ischemic myocar-
dial tissue has been performed in dogs and rats. An intra-
venous injection of RPT748 was administered, combining
a111In-complex with a non-peptide v3ligand.166167 The
uptake of 111In-complex colocalized with neoangiogenesis
in the ischemic foci, as demonstrated using in vivo and ex
vivo imaging techniques. Kohane’s group modified lipo-
somes with a ligand targeted to angiotensin II type1 (AT1).
Their results demonstrated that the carriers were able to
deliver active drug to the affected heart tissue after sys-
tematic administration in vivo (Fig. 9).168
Takahama et al. investigated the influence of various
liposomes on the distribution and activity of the ischemic/
reperfused myocardium. Stealth liposomes loaded with
adenosine were prepared by the thin film hydration
method. They assessed the targeting efficiency of lipo-
somes and myocardial infarction (MI) size after a 30-min
ligation followed by a 3-h reperfusion. Pharmacokinetic
data confirmed that the liposomes were able to effectively
accumulate in the foci and prolong the blood residence
time of adenosine. The results from biological studies
showed that PEGylated liposomal adenosine was able to
enhance the cardioprotective effects of adenosine against
I/R injury and to reduce its unfavorable hemodynamic
effects (Fig. 10).169170
Torchilin et al. constructed a rabbit model of acute
myocardial infarction and fabricated 111In-labeled stealth
liposomes modified with antimyosin antibody. They
observed the accumulation of PEG-coated immunolipo-
somes in the infarcted rabbit myocardium. The data con-
firmed that the proportion of PEG in the membrane of
the immunoliposomes was a vital factor. PEG influenced
the half time and targeting efficiency of carriers in the
body.171 These authors further investigated the effect of
various parameters, such as liposomes size, the presence
or absence of PEGylation and infarct-specific antimyosin
antibody, on carrier behavior in terms of biodistribu-
tion and infarct accumulation. The influence of various
J. Biomed. Nanotechnol. 10, 2038–2062, 2014 2047
Heart-Targeted Nanoscale Drug Delivery Systems Liu et al.
Figure 9. Images of nanoparticles targeting the infarcted myocardium. (A) The accumulation of nanoparticles in ischemic hearts,
suffered from 1, 4 and 7 days of ligation, injected with AT1 or scrambled (S) nanoscale particles. (B) Distribution of AT1 nanopar-
ticles in the LV of the infarcted heart 1 day after injection. Pink, nanoparticles; green, autofluorescence. Bar: 200 m. (C) Fluores-
cence intensity in isolated hearts 1 day after administration. Reprinted with permission from [168], T. Dvir, et al., Nanoparticles
targeting the infarcted heart. Nano Lett. 11, 4411 (2011). © 2011, American Chemical Society.
parameters from strong to weak was PEG, antibody and
size.172
Polymeric Drug Conjugates
Polymeric drug conjugates are characterized by the conju-
gation between drug molecules and water-soluble polymer
carriers. The employed polymers include methacrylamide,
amino acid, PEG and some linear polysaccharides.173–175
In the mid-1970s, Ringsdrof first proposed the concept
of the covalent conjugation of drugs to a hydrophilic
polymer, which was envisioned to achieve active target-
ing and the modulation of pharmacokinetics.176 Through
years of studies on polymer-drug conjugates, these new
Figure 10. The in vivo images of mouse hearts after acute myocardial infarction (MI) before and after injection of Gd-DTPA,
liposomes and micelles as captured by MRI. Typical MR images confirm the time-dependent deposition of the drugs in the
infarcted myocardium. The vessel portion of contrast enhancement is marked with arrows. Lateral (L), anterior (A), septal (S),
inferior (I) and septal (S) walls. Reprinted with permission from [170], L. E. Paulis, et al., Distribution of lipid-based nanoparticles
to infarcted myocardium with potential application for MRI-monitored drug delivery. J. Controlled Release (2012). © 2012, Elsevier
Limited.
delivery systems exhibited some novel features compared
with the parent drugs, decreasing adverse reaction and
increased clinical efficacy, ease of drug administra-
tion and patient compliance.177 The improved clinical
efficacy mainly depends on the enhanced permeabil-
ity and retention effect (EPR) of stealth polymers.178
Polymer-drug conjugates produce a 100-fold higher
concentration of the drug in the target tissue than
free drug.179 Thereby, the myocardium-recognition lig-
ands, such as antibodies, proteins and peptides, that
are conjugated on the water-soluble polymers can
enhance the targeted delivery of drugs into the infarcted
myocardium.
2048 J. Biomed. Nanotechnol. 10, 2038–2062, 2014
Liu et al. Heart-Targeted Nanoscale Drug Delivery Systems
Microparticles
Microparticles can be described as spherical structures
containing a matrix that is loaded with drugs through
encapsulation or entrapment methods. Accordingly, the
microparticles can be classified as either microsphere,
in which the drugs are dispersed into the matrix, or as
microcapsules, in which the drugs are confined in the inner
core. In this approach, the physicochemical properties of
the loaded drugs are determined through their encapsula-
tion inside polymers or dispersion into a polymer matrix.
These features allow them to easily penetrate through
different defensive barriers in the body.180 In addition,
microparticles are more stable in vivo than are liposomes.
Microparticles can be fabricated by reproducible formu-
lation processes that entrap water-soluble and fat-soluble
drugs and broaden their overall clinical application.181
Recently, the intracardiac injection of polymeric
microparticles of anti-inflammatory drugs blocked the
activation of macrophages and reduced the apoptosis or
necrosis of cardiomyocytes. The polymeric microparti-
cles of anti-inflammatory drugs showed excellent results
in the clinical therapy of myocardial infarction and other
inflammatory heart abnormalities.182183 In another study,
to improve the half-life and stability of cardioprotective
drugs, such as VEGF,165 Formiga et al. proposed the syn-
thesis of PLGA microparticles loaded with VEGF;165 they
then validated the use of these microparticles on vasculo-
genesis and cardiac tissue remodeling.184
Nanoparticles
Silica Nanoparticles
Silica nanoparticles are promising drug carriers due to their
excellent properties, such as chemical and mechanical sta-
bility, hydrophilicity and biocompatibility. The particles’
surface reactivity and zeta potential can also be tailored
through surface modification.185–187 Silica is bio-resorbed
via the hydrolysis of siloxane bonds into Si(OH)4, which
disperses into the blood and lymph system and is eventu-
ally excreted through the kidneys.188 Given that negatively
charged particles are repelled by the similarly charged cell
membrane, silica nanoparticles are useful to avoid fast
elimination from the body due to their nearly −40 mV zeta
potential at neutral pH.189190 In addition, silica nanoparti-
cles allow for the functional groups (e.g., amines, thiol) to
be modified on the surface; these groups can then react with
the corresponding functional groups of enzymes, proteins,
DNA and pharmaceutical substances.191192
It has been reported that mesoporous silica nanoparti-
cles had no influence on cell viability or on the integrity
of the plasma membrane when they were used to deliver
cysteine, hydrophobic dyes and genetic sequences into
cells.193–195 A recent study suggested that porous silica
microparticles could be rapidly metabolized by the body
through the erosion of the plasma-soluble silicic acid
on the surface of the nanoparticles.196 Recently, silica
nanoparticles have been designed to deliver drugs into
heart after surface functionalization.140 Galagudza et al.
evaluated the targeting efficiency of silica nanocarriers
to cardiac tissue. They confirmed that silica nanocarriers
exhibited no acute toxicity after administration. The parti-
cles accumulated in the foci within the affected heart tissue
with ischemia/reperfusion based on the passive targeting
mechanisms.197 In addition, they proposed that annexin V
attached to the surface of the silica nanocarriers was able
to achieve local deposition of nanocarriers in the affected
myocardium.177
Targeting nanocarriers to ischemic myocardium can sig-
nificantly improve the clinical outcome of individuals with
heart disease. However, the toxicities may be a drawback
of the silica nanoparticles in clinical applications. To over-
come this limitation, the Shlyakhto group investigated the
surface modification and characterization of silica nanocar-
riers, evaluated the acute hemodynamic effects of nanopar-
ticles, and examined the biodistribution of the carriers
in vivo. The results indicated that silica nanoparticles were
not toxic during acute intravenous administration.140
Duan et al. investigated the cardiovascular toxicity of
silica nanocarriers to endothelial cells and zebra fish. Their
results confirmed that the silica nanoparticles reduced the
level of p-VDGFR2 and p-ERK1/2. Meanwhile, the car-
riers also repressed the levels of NKX2.5 and MEF2C
(Fig. 11). All the data suggest that silica particles may
pose a risk to the cardiovascular system.198
Magnetic Nanoparticles
Magnetic nanoparticles (MNP) are widely studied carri-
ers that exhibit a variety of attributes. First, they can be
easily handled with the aid of an external magnetic field.
Second, it is possible for MNPs to be used in passive and
active drug delivery strategies after modification. Third,
MNPs can be visualized with magnetic resonance imag-
ing (MRI). Fourth, the enhancement of drug accumulation
in the target tissue leads to effective treatment at the
Figure 11. Cardiovascular influences of silica particles on
early, developing zebra fish embryos. The expression of
VEGFR2, p-VEGFR2, ERK1/2, p-ERK1/2, NKX2.5 and MEF2C
were evaluated by Western blot analysis (-actin as an inter-
nal control). Reprinted with permission from [198], J. Duan,
et al., Cardiovascular toxicity evaluation of silica nanoparticles
in endothelial cells and zebra fish model. Biomaterials (2013).
© 2013, Elsevier Limited.
J. Biomed. Nanotechnol. 10, 2038–2062, 2014 2049
Heart-Targeted Nanoscale Drug Delivery Systems Liu et al.
Figure 12. The in vivo imaging of MNB/PEI/DNA complexes 2 h after injection via the tail vein. The fluorescent signals were
overlaid in the image. The fluorescence signal was stronger in the left chest of the Mag+group (A) than the Mag−group (B).
Reprinted with permission from [209], W. Li, et al., Enhanced thoracic gene delivery by magnetic nanobead-mediated vector.
J. Gene. Med. 10, 897 (2008). © 2008, John Wiley and Sons.
therapeutically optimal doses.199 However, the applications
of MNPs are limited by some problems, such as inappro-
priate features and inadequate magnet systems. Therefore,
it is necessary to consider many factors when designing
heart-targeted magnetic drug delivery systems. These fac-
tors include the magnetic properties and the size of the
particles, the strength of the magnetic field, the drug load-
ing capacity, the accessibility to the target tissue and the
rate of blood flow.200
Ferric oxide nanoparticles are the only type of MNPs
approved for clinical use by the FDA. Their favorable
features include their facile single step synthesis, chemi-
cal stability in physiological conditions and flexibility of
chemical modification by coating of the iron oxide cores
with various shells.201 The common shells for MNPs are
gold, polymer, silane or dendrimer.202–205 In addition, it
has been demonstrated that iron oxides (magnetite and
maghemite) exist naturally in the human heart, spleen
and liver.206 Their existence in the body indicates that
they are biocompatible and non-toxic at physiological
concentrations.
Active targeting of drug-loaded MNPs to diseased heart
tissues relies on the attachment between ligands conju-
gated to the surface of MNPs and the diseased sites with
the adjustment of an external magnetic field.207 Recently,
a new method of magnetic force-improved gene delivery
exhibited more feasibility for gene transfer in the cardio-
vascular system (Fig. 12).208–210 In addition, in 2012 Zhang
et al. developed stable magnetic nanoparticle-adenoviral
vector complexes. They confirmed the possibility of deliv-
ering therapeutics into the infracted heart in the exter-
nal magnetic field for the treatment of acute myocardial
infarction.211
Cerium Oxide Nanoparticles
Cerium oxide nanoparticles (CeO2NPs) consist of a
cerium core surrounded by an oxygen lattice. They have
2050 J. Biomed. Nanotechnol. 10, 2038–2062, 2014
Liu et al. Heart-Targeted Nanoscale Drug Delivery Systems
Figure 13. Influence of CeO2nanocarriers on the inflammatory myocardium. (A) Histopathological staining of left ventricular
sections from control and vehicle- and CeO2-treated MCP mice. First panel: H&E staining; second panel: Masson’s trichrome
staining, blue indicated collagen deposition. (B) Monocyte/macrophage infiltration in the myocardium (monocytes/macrophages,
green). (C), (D) Statistical analysis of MAB1852-positive cells and TUNEL-positive cells in the myocardium, respectively. ∗P<0001
compared with wild-type controls; #P<005 compared with vehicle-treated MCP mice (n=5). Reprinted with permission from
[219], J. Niu, et al., Cardioprotective effects of cerium oxide nanoparticles in a transgenic murine model of cardiomyopathy.
Cardiovasc. Res. 73, 549 (2007). © 2007, Oxford University Press.
shown various applications in industrial and commercial
products, such as automotive catalytic converters and oxy-
gen sensors.212213 CeO2NPs have both Ce3+and Ce4+
oxidation states, which are able to perform an autoregen-
erative redox cycle. Oxygen defects on their surface offer
many active sites for free radical scavenging.214 The CeO2
NPs are gaining much attention in the biomedical field
due to their antioxidant properties.215 In healthy cells, the
cellular levels of reactive oxygen species (ROS) are finely
controlled. The accumulation of ROS is generally asso-
ciated with undesired effects, such as neurodegenerative
diseases, diabetes, atherosclerosis and aging.216 Moreover,
the elevation of ROS may lead to the increased production
of inflammatory cytokines, which are key players in the
J. Biomed. Nanotechnol. 10, 2038–2062, 2014 2051
Heart-Targeted Nanoscale Drug Delivery Systems Liu et al.
development of cardiomyopathy through activated nuclear
factor-B (NF-B).217218 Recently, studies have demon-
strated that the administration of CeO2NPs could protect
the heart from oxidative and inflammatory injury induced
by monocyte chemotactic protein-1 (MCP-1) (Fig. 13).219
In addition, Flemming et al. have demonstrated that CeO2
NPs could reduce the atherosclerotic burden associated
with exposure to standard diesel fuel.220
Pt-Modified TiO2Nanoparticles
Titanium dioxide (TiO2) has been extensively investigated
for its catalytic and electrochemical properties and has
been applied as a photocatalyst and gas sensor.221 TiO2has
also been used in solar energy cells and has been exam-
ined for use as an antitumor agent. TiO2and modified
TiO2nanomaterials have shown potential as drug carri-
ers and molecular imaging vehicles in the cardiovascular
system.222223 However, some studies have shown that TiO2
nanoparticles exhibit a certain cytotoxicity due to differ-
ent physical and chemical properties.224 It was reported
that Pt-doped TiO2nanoparticles exhibited an enhance-
ment in photocatalytic efficiency. higher photocatalytic and
efficiency and promise for cardiac imaging and targeted
medical treatments.225226
Polymeric Nanoparticles
The size of nanoparticles is between 10–100 nm.227–230
Major attention has been focused on biodegradable poly-
meric nanoparticles due to their easy penetration across
barriers, easy absorption into cells, controlled release and
increased stability of drugs, flexibility to target particular
organs/tissues and biocompatibility.231–236
Self-assembly is a method used to fabricate nanoscale
particles using the diblock or triblock copolymer with var-
ious hydrophobicities. In solution, these copolymers auto-
matically develop micelles.237 Recently, Garnacho et al.
fabricated platelet-endothelial cell adhesion molecule 1
(PECAM-1) antibody-modified nanocarriers with the
ability to target ECs (Fig. 14).238 Somasuntharam
et al. designed polyketal nanoparticles loaded with
Nox2-NADPH oxidase siRNA and evaluated cardiac func-
tion in infarcted mice after administration. They found
that the acid-degradable polyketal particles were able to
deliver Nox2-siRNA to the affected heart sites. Nox2-
siRNA nanoparticles could be effectively internalized by
macrophages, producing the significant inhibition of Nox2
expression and activity in vitro. The particles prevented the
upregulation of Nox2 and significantly improved the heart
function in vivo.239 Lipinski et al. fabricated gadolinium
(Gd)-containing lipid-based nanoparticles (NPs) modified
with CD36 antibody to target macrophages in the affected
heart. Compared with Gd-containing unmodified NPs and
Fc-NPs, targeted NPs were able to accumulate in the resi-
dent macrophages in the plaque based on confocal fluores-
cent microscopy; they also had a stronger contrast-to-noise
ratio.240
Figure 14. The influence of four distinct PECAM-1 extracel-
lular epitopes on the trafficking of anti-PECAM/nanocarriers
(NCs) in endothelial cells (ECs). ECs were incubated for1hat
37 C in media containing FITC-labeled anti-PECAM/NCs fol-
lowed by incubation with Texas red goat anti-mouse IgG to
counterstain non-internalized NCs on the cell surface. Merged
images illuminate the localization of single-marked anti-
PECAM/NCs (green, arrows) compared with double-marked
anti-PECAM/NCs nanoparticles (yellow, arrowheads) in the
cells. The dashed line was used to mark the cell bor-
ders. Bar: 10 m. Reprinted with permission from [238],
C. Garnacho, et al., Differential intra-endothelial delivery of
polymer nanocarriers targeted to distinct PECAM-1 epitopes.
J. Controlled Release 130, 226 (2008). © 2008, Elsevier Limited.
Micelles
Micelles are small, spherical or globular structures. They
are usually prepared by self-assembly with amphiphilic
block copolymers. In an aqueous environment, these poly-
mers automatically create a thermodynamically stable col-
loidal solution in the shape of a “core–shell” structure
when the threshold concentration of polymers is more
than the critical micelle concentration (CMC).241 The core
is composed of hydrophobic materials, including poly-L-
lysine, poly(-caprolactone), polylactide and polyglycol-
ide. It serves as a container for water-insoluble drugs.
The hydrophilic shell mainly consists of polyethylene gly-
col, which can be modified to load water-soluble drugs.
Polymeric drug carriers can carry low molecular weight,
hydrophobic drugs and biomacromolecules, such as nucleic
acids and proteins.242 Based on previous studies, poly-
meric micelle drug carriers were able to improve the sol-
ubility of hydrophobic drugs, control the release of drugs,
increase the stability of drugs and ensure biocompatibil-
ity. They can be designed to target particular organs or
tissues. The polymeric micelle drug delivery system has
been used to deliver anti-tumor drugs, such as tamoxifen,
paclitaxel, doxorubicin and cisplatin, to tumor cells.243–245
However, sometimes it is difficult to control the release
kinetics under specific conditions, and the micelles may
2052 J. Biomed. Nanotechnol. 10, 2038–2062, 2014
Liu et al. Heart-Targeted Nanoscale Drug Delivery Systems
Figure 15. Ex vivo micrographs of the infarct area in acute MI (one day old) after systematic administration with Gd-DTPA,
micelles and liposomes (red) by confocal laser scanning microscopy. Cyan =CD18 or CD31; green =CD68 or laminin. Bar =
100 m. The co-localization of liposomes (red) with blood vessels (cyan) was performed at higher magnification (the insets in D
and E). Reprinted with permission from [170], L. E. Paulis, et al., Distribution of lipid-based nanoparticles to infarcted myocardium
with potential application for MRI-monitored drug delivery. J. Controlled Release (2012). © 2012, Elsevier Limited.
be degraded in the presence of hostile enzymes. In addi-
tion, a polymeric micelle-based drug delivery system has
not yet been applied to heart-targeted therapy in the clinic.
Paulis et al. compared the distribution between micelles and
liposomes in the infarcted heart in mice. They used in vivo
MRI of paramagnetic lipids in both carriers. The micelles
(∼15 nm) and liposomes (∼100 nm) were used to evalu-
ate differences in the distribution patterns. The data con-
firmed that liposomes showed slower and more restricted
extravasation from the vessels, which indicates that lipo-
somes are a promising delivery system for pro-angiogenic
drug. However, micelles were able to penetrate the ves-
sels and went into the infarcted area, which suggests
that micelles are more attractive for the targeted delivery
of anti-remodeling and cardioprotective therapeutics
(Fig. 15).170
Stents with Nano-Coating
Metal stents have limited application due to the inflamma-
tory response, thrombosis and restenosis. It was reported
that drug-eluting stents (DES) could reduce the inci-
dence of restenosis to less than 10% in clinical trials.6466
Although DES reduced the percentage of thrombosis and
restenosis, drawbacks similar to those seen with metal
stents eventually appear after the drugs on the stent are
completely released. In addition, in 2004 Virmani et al.
proposed that the polymer coating on the stent surface is
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Heart-Targeted Nanoscale Drug Delivery Systems Liu et al.
involved in an inflammatory response at the site of injury
and leads to potential restenosis.246
To overcome these shortcomings, biodegradable poly-
mer stents were designed to inhibit restenosis before
implantation.247 They are degraded in situ after the ves-
sel is stabilized. Moreover, the vessel recovered its nor-
mal physiological vasomotor tone with the absence of
a permanent rigid object fixed in the arterial wall.248
Lincoff et al. demonstrated that stents composed of
poly-L-lactide (PLLA) produced minimal inflammation
and durable results in a porcine model.249 A limitation
of polymer-based stents is their low mechanical rigidity.
Bioresorbable stents are mainly constructed from poly-
mer and metallic alloys. It was reported that a magnesium
stent was absorbed within 3 weeks after implantation.250
In addition, porous aluminum oxide-coated stents encap-
sulated with drugs have exhibited inhibition to neointimal
growth.251 Although biodegradable polymeric stents are
often used in the interventional cardiology field, they still
need improvement to meet clinical requirements.
Microbubbles
Recently, various studies have demonstrated that the
ultrasound-targeted microbubble destruction (UTMD)
technique shows excellent features for drug and gene
delivery.252253 Microbubbles used in UTMD consist of
albumin, saccharide, biocompatible polymers, lipids and
other materials. Ultrasound contrast agent is one of
the materials used because of its capacity to reflect
ultrasound.254–256 Active agents can be encapsulated into
the microbubbles using different approaches, such as coat-
ing or binding to the microbubble surface. The sonopora-
tion produced by UTMD can transfer genes into cells.257
Microbubbles will oscillate and rupture when they are
exposed to ultrasound. Then the entrapped gene therapy
vector will be released from the microbubbles, producing
high local concentrations at the site of interest. Meanwhile,
the destruction of microbubbles may transiently induce
holes in the membrane, which increase the permeability
of vessels and biomembranes, thus facilitating the entry of
drugs or genes into cells.258259
It was reported that specific ligands for endothelial cell
adhesion could be modified on the surface of microbub-
bles for delivery.260261 Recently, a large number of studies
have supported the idea that UTMD is a feasible method in
the clinical therapy of cardiovascular diseases by improv-
ing gene transfection.262 For example, Chen et al. have
successfully transfected the human TB4 gene into nor-
mal rat hearts using UTMD.263 In another study, Chen
et al. confirmed that the combination of UTMD with PEI
could improve the transfection efficiency of naked genes
into the myocardium without causing any apparent adverse
reaction.263 Moreover, ultrasound-mediated microbubble
drug therapy for thrombolysis has already reached the
clinical arena, such as in the treatment of deep venous
thrombosis, the remission of arterial ischemia and the
relief of acute coronary syndromes and acute ischemic
stroke.95264–266
CLINICAL TRIALS AND
COMMERCIAL MARKET
Several drugs with different mechanisms have been used
to deliver drugs to the heart with appropriate nanoscale
carriers. The good news is that some heart-targeted
nanoscale drug carriers have successfully passed clin-
ical trials.140 Furthermore, some of them are already
commercially available on the market. For instance, the
intramuscular transplantation of the ultrasound-mediated
destruction of microbubbles combined with bone marrow-
derived mononuclear cells (BM-MNCs) has been clinically
applied for inducing angiogenesis in the ischemic tissue.267
In addition, stents are widely accepted as an effective treat-
ment for occluded arteries.268269 The drug-eluting stent
(DES) has been reported to effectively reduce the per-
centage of restenosis to less than 10% in initial clinical
trials.181182 Currently, there are two DES on the market:
the Cypher®stent and the Taxus®stent.
CONCLUSIONS AND FUTURE DIRECTION
We have reviewed the physiological properties of the
cardiovascular system, various heart diseases and new
advances in heart-targeted nanoscale drug delivery sys-
tems. A successful design for heart-targeted nanoscale
drug delivery systems is based on three parameters. First,
it is necessary to understand the fundamentals of various
heart diseases, including their etiology, pathological man-
ifestation, clinical features and desired therapies. Second,
suitable heart-targeted drug carriers need to be selected
and the active targeting properties of these carriers then
needs to be regulated to improve the stability of loaded
drugs. Finally, researchers should choose the appropriate
targeting ligands to ensure the specific interaction of the
nanocarriers with the complementary molecules on the
surface of the targeted cells. Successful targeted delivery
of nanocarriers to the heart is helpful to reduce toxicity
and to increase the availability of the drugs.171 Although
the heart-targeted delivery of nanocarriers is promising
for transporting drugs to affected cardiac tissue and for
controlling drug release in the body, these systems suf-
fer from limitations, such as toxicity, immunogenicity
and unwanted pharmacokinetic behavior.270–272 The desired
techniques of nanocarrier fabrication is aimed at ensuring
better uptake in the target cells, more desirable accumu-
lation of drugs in affected tissue than in unaffected sites,
and more effective avoidance of drug toxicity. Eventually,
an ideal tool for the targeted delivery of drugs into the
heart is emerging.
Acknowledgments: This research was supported by
grants from the Heilongjiang Provincial Natural Science
2054 J. Biomed. Nanotechnol. 10, 2038–2062, 2014
Liu et al. Heart-Targeted Nanoscale Drug Delivery Systems
Foundation (D201031), the Heilongjiang Provincial Health
Bureau Foundation (2009-265 and 2011-236) and the
Innovative Fund of Harbin Medical University Graduate
Student (YJSCX2012-202HLJ).
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