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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
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2038 Cardiovascular disease, particularly ischemic impairment,
Cardiovascular Physiological Properties . . . . . . . . . . . . . . . . . 2040 is an important cause of morbidity and mortality world-
Cardiac Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2040
wide and will become most common cause of death after
Cardiac Cells for Drug Targeting . . . . . . . . . . . . . . . . . . . 2042
Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . 2043 10 years.1 The heart is an organ of concern at the molec-
Ischemia and Infarction . . . . . . . . . . . . . . . . . . . . . . . . . 2043 ular level and is easily affected by disease in both child
Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2045 and adult populations.2–4 Human cardiac disease involves
Myocardial Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . 2045 abnormalities in morphogenesis, muscle repair and func-
Restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2045 tion and cardiac rhythm.5 A promising solution to heart
Heart-Targeted Drug Delivery Systems . . . . . . . . . . . . . . . . . . 2046
disease involves directly delivering cardioprotective drugs
Dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2046
Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2047 into the infarcted myocardium and cardiovascular system.
Polymeric Drug Conjugates . . . . . . . . . . . . . . . . . . . . . . . 2048 The need for improved therapies has led to the emergence
Microparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2049 of targeted drug delivery to the heart.
Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2049 In 1906, Erhlich et al. originally proposed the concept
Micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2052 of targeted delivery in the form of a magic bullet that
Stents with Nano-Coating . . . . . . . . . . . . . . . . . . . . . . . . 2053
would attack affected cells but without any influence on
Microbubbles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2054
Clinical Trials and Commercial Market . . . . . . . . . . . . . . . . . 2054 normal tissues.6 The strategies of targeted drug delivery
Conclusions and Future Direction . . . . . . . . . . . . . . . . . . . . . 2054 refer to the direction of active agents and their carriers into
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2054 the affected tissue with minimal effects on surrounding
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2055 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
Authors to whom correspondence should be addressed.
Emails: fisher1688@163.com, qunwang@iastate.edu
valid therapeutic effect due to the limited solubility of
Received: 13 January 2014 the drugs.12 In addition, biomolecules, such as oligonu-
Accepted: 26 January 2014 cleotides, proteins and peptides and small chemicals with
a short half-life in the circulation require the adminis- All of these drawbacks drive researchers forward to
tration of repeated doses to maintain active levels in the further develop and optimize new drug carriers. Targeted
vessels. Under some circumstances, drug levels in the drug delivery enhances the specific deposition of drugs
body exceed the minimum toxic concentration and gen- in the abnormal foci after administration and simultane-
erate adverse effects for the patient. Overall, the conven- ously decreases the adverse effects in healthy organs.16–22
tional application of drugs is limited by several hurdles, Drug carriers are vehicles for the protection of drugs dur-
such as weak effectiveness, poor biodistribution and low ing transportation after administration and for the mainte-
selectivity.13–15 nance of controlled-release in the body.23 24 The promising
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.
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.
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- appropriate drug delivery carriers and to select effective
gels and polymeric microparticles.25–28 Successful targeted targeting ligands that will ensure a specific interaction of
drug delivery can decrease toxicity and improve the solu- carriers with the complementary molecules on the targeted
bility and stability of the loaded drug.29 30 Classical target- cell membrane. The tissue-recognition ligands in the heart
ing nanoscale carriers usually consist of several functional have been widely studied and include PECAM-1, myosin,
elements, including drugs, targeting ligands and the bio- P-selection, cTnI and cTnC. This review summarizes the
compatible coating of nanoparticles.31–34 These elements properties, symptoms and therapies of various heart dis-
could avoid the quick clearance of nanocarriers by the eases and discusses the emerging developments of heart-
reticuloendothelial system. A conceptual illustration of the targeted nanoscale drug delivery systems.
design of drug-loaded nanoparticle targeting to the heart
is shown in Figure 1.
Recent therapeutic approaches to prevent heart fail- CARDIOVASCULAR PHYSIOLOGICAL
ure after myocardial infarction (MI) mainly rely on the PROPERTIES
systemic injection of proangiogenic peptides and stem Cardiac Physiology
cell therapy.35–37 Unfortunately, some data have confirmed Rhythmicity
the absence of effectiveness of these active biomacro- The rhythm of the heart refers to the heart beating.
molecules due to their short half-life and low stability. It should be very homogeneous in a healthy heart.
Therefore, a heart-targeted nanoparticle drug delivery sys- The cardiac pacemaker is the sinoatrial nodal cell,
tem is emerging and looks promising. The major task for which generates normal, homogeneous heart contractions
fabricating heart-targeted nanoparticles is to choose the (Fig. 2). The electrical signals derived from the sinoatrial
node are distributed over the heart surface by a special- catecholaminergic polymorphous ventricular tachycardia,
ized conduction system; these signals can be recorded long-QT or short-QT syndrome and Brugada syndrome.
as an electrocardiogram (ECG). Moreover, the sinoatrial However, there are ECG abnormalities with no explana-
cells are highly resistant to cardiac failure and ischemia.38 tion, such as prolonged QT interval, ventricular extrasys-
However, when the heart pacemaker, resulting heart rate tole on stress ECG, ST segment elevation in the precordial
and rhythm and impulse conduction exhibit pathological leads and negative or abnormal T waves.40 The clinical
changes, arrhythmias occur in the form of bradycardia, symptoms of various arrhythmias have been described by
tachycardia and other rhythm abnormalities. Standard lead previous investigators.41 42 The diagnosis and therapy of
II electrocardiograms are used to record the rhythm of the arrhythmias are carried out in many ways.43 44 In 2008,
heart in vivo for diagnosing arrhythmias. In 1988, Curtis Churchill et al. proposed that PKC isozymes may be the
and Walker defined the arrhythmia score to evaluate this therapeutic targets of chronic cardiac diseases.45 Moreover,
disease.39 it has been reported that an irregular ventricular rhythm
Many ion channel diseases are diagnosed through causes an alteration in excitation-contraction coupling,
ECG recordings. The ECG abnormalities mainly include which contributes to the progression of heart failure.46
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.
Blood Pressure and have shown potential application value for restoring
Blood pressure refers to the lateral pressure from blood blood flow.64–67
flow per unit area in blood vessels. It can be divided into
diastolic blood pressure (DBP) and systolic blood pressure Cardiac Cells for Drug Targeting
(SBP). Clinical diagnostics have shown that abnormalities Cardiac Muscle Cells
in SBP and DBP are associated with some heart diseases, Cardiomyocytes are highly specialized cells that are
such as stroke, myocardial infarction and heart failure. responsible for the bioelectric variations that generate
Hypertension is a major risk factor that increases the inci- autorhythmicity, excitability and conductibility. Autorhyth-
dence of cardiovascular disease (CVD), which impairs micity is the property that cardiomyocytes acquire
quality of life and usually leads to higher mortality.47–49 spontaneous diastolic depolarization followed by an elec-
In addition, hypertension in the elderly contributes to trical impulse in the absence of external electrical
numerous structural and functional changes to the vascu- stimuli.68 Under normal conditions, the sinoatrial node has
lature during arterial aging. These changes usually lead to the highest autonomy and determines the heart rate in var-
isolated systolic hypertension, diastolic heart failure and ious mammalian species, followed by the atrioventricular
small vessel disease in the brain and other organs.50 Other junction area and then the Purkinje fibers. Spontaneously
risk factors are involved in hypertension, such as dimin- originated action potentials (APs) are propagated via car-
ished kidney function, increasing age, diabetes mellitus, diomyocytes when the cardiac cells are exposed to a stim-
higher body mass index and genetic factors.51–54 ulus with a generative AP, which refers to the excitability
In the 1960s, safe and effective antihypertensive drugs of cardiac cells.69
were first developed and led to dramatic improvements in Gap junctions are specialized membrane structures.
the prognosis of patients with malignant hypertension.55 Intercellular ion channels in gap junctions form a path-
Over the next few decades, the use of an expanding arma- way of cell-to-cell communication. Gap junctions play an
mentarium of blood pressure-lowering drugs has effec- important role in the propagation of cardiac impulses.70
tively eradicated the risk of malignant hypertension.56 In addition, the suppression or enhancement of pacemaker
However, the issues related to drug interactions and the activities and automaticity may cause clinical arrhythmias.
side effects of antihypertensive medications, such as ortho- The individual ion channels, gap junctions and exchanger
static hypotension in the setting of autonomic dysreg- activities determine cardiac excitability and electrical
ulation, are of increasing concern. Recent studies have activity. Previous reports have demonstrated that primary
indicated that renal denervation was a new interventional heart disease, which has an increased arrhythmia risk, and
approach that significantly reduced blood pressure with- primary arrhythmia syndromes are caused by dysfunction
out causing major complications in patients with resistant of the ion channels in the cardiac muscle.71–74 Many data
hypertension.57 58 In addition, there is class I, level B evi- have supported that cardiovascular abnormalities, such as
dence that 150 minutes of weekly physical activity may coronary artery disease, stroke and heart failure, are asso-
be used to complement antihypertensive medication.59 ciated with changes in cardiac electrical excitability due to
transcriptional and post-translational modifications of ion
Blood Flow and Output channels and gap junction proteins.75 76 Typical nanoparti-
Blood flow is well known as a basis of the diagnosis of cle systems target thrombi in lining of artery are demon-
cardiac disease states and can be influenced by numer- strated in Figure 3.
ous factors.60 The evaluation of cardiac blood flow is use- In addition, some previous studies have also indicated
ful in the hemodynamic management of neonates. It is that the interactions and fine balance between various
an effective indicator of health or disease and a pathway transmembrane ion currents regulate cardiac repolarization
to assess the reaction to various stimuli and pharmaceuti- and, consequently, the duration of the ventricular action
cal interventions.61 62 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- Figure 3. Nanoparticles target thrombi in the lining of an
mediated microbubble destruction have been developed artery.
potential.77 78 First, K+ channels play an important role in smooth muscle cells (VSMC) and releases mediators that
determining the morphology and repolarization of the car- regulating vascular tone and growth, blood fluidity, platelet
diac action potential. At least eleven K+ currents have been function and coagulation.91 Under pathological conditions,
characterized pharmacologically by molecular cloning.79 endothelial damage or dysfunction generally leads to a loss
For example, the cardiac delayed rectifier K+ current (Ik ) of anti-aggregative, anti-thrombotic, anti-inflammatory and
mainly consists of two components, the rapidly activat- anti-VSMC activation/growth properties.92 Designed inter-
ing (Ikr ), which is blocked by the class III antiarrhyth- ference in these processes may yield optimistic therapeu-
mic agent E4031, and the slowly activating (Iks ), which is tic benefit in the treatment of diseases that are associated
inhibited by chromanol 293B.80 81 In addition, the inward with endothelial damage and dysfunction. Therefore,
rectifier K+ current (Ik1 ) influences terminal repolarization many diseases, including angiogenesis, atherosclerosis,
and stabilization of the resting membrane potential in car- tumor growth, myocardial infarction and limb and car-
diac cells.82 Changes in Ik1 currents density are relevant to diac ischemia, can be treated by the regulation of
arrhythmogenesis.83 endothelium.93–95 Vascular endothelial cells (VECS) are
Second, high-voltage, L-type Ca2+ channels and low- particular important targets for circulating drug delivery
voltage, T -type Ca2+ channels have been identified in the systems because of their large population and contiguity
sarcolemma of cardiac cells.84 85 The influx of Ca2+ ions with the blood stream.96
through Ca2+ channels contributes to cardiac excitability Various therapeutic approaches have been developed
and excitation-contraction coupling.12 Braz et al. proposed to fight against vascular diseases.97 Recently, some
that protein kinase C may affect cardiac excitation- researchers have proposed the targeted delivery of
contraction coupling through a negative feedback of sar- endothelial cells by overexpressing interleukin-8 receptors
coplasmic reticulum Ca2+ load in addition to its effects on A and B (IL8-RA and -RB). This approach prevented
cardiomyocyte excitability, further affecting cardiac per- inflammatory responses and promoted the structural recov-
formance during cardiac dysfunction and heart failure.86 ery of arteries following endothelial injury by reducing
It is implied that transient low-voltage, activated currents IL-8 in injured or infected tissues.96 However, only a small
(ICaT ) could trigger Ca2+ ion release from the sarcoplas- fraction of injected therapeutic agents bind to endothelial
mic reticulum and induce contraction of Purkinje cells.62 87 cells (EC) due to a lack of affinity for the endothelium
Previous studies have reported that the levels of re- or removal by hemopsonin. Another challenge for deliv-
expression of T -type Ca2+ channels are increased in cer- ering drugs to the endothelium is that many therapeutic
tain pathologic states, such as ventricular hypertrophy.63 88 agents require precise delivery to specific subcellular com-
Third, voltage-gated Na+ channels are the primary partments. The goal of endothelial targeting is to specially,
channels that control the rising phase of the action safely and effectively transport a drug to specific parts of
potential in excitable cells. Some researchers have dis- ECs to achieve local effects, thereby, improving pharma-
covered that the down-regulation of Ca2+ and Na+ chan- cological interventions, including those for metabolic and
nel currents through the protein kinase isozyme (II, ) oncological diseases.98 99 The design determinant of tar-
may lead to cardiac hypertrophy, heart failure and a geted drug delivery systems (DDS) is shown in Figure 4.100
disruption in cardiac excitability.79 Voltage-gated sodium A large number of molecules can serve as specific
channels (VGSCs) are a family of proteins with 9 iso- ligands for EC targeting, such as vascular endothelial
forms that regulate the inward Na+ current upon mem- growth factor (VEGF), cell adhesion molecule (CAM)
brane depolarization. Various inherited arrhythmias may and immunoglobulin G (IgG)-type antibodies.101 102 Drugs
be caused by VGSC dysfunction, such as long QT syn- loaded into liposomes or polymer vehicles or conjugated
drome and Brugada syndrome.89 Fibroblast growth factor with affinity moieties for targeting to ECs may also
homologous factors (FGFHFs), which are comprised of improve the treatment of vascular diseases. Recent research
four genes (FGF11–14), are intracellular proteins that has attempted to explore efficient targeted drug delivery
modulate VGSCs and are potential regulators responsible vehicles to the endothelium, such as liposomes, polymeric
for cardiac conduction abnormalities.90 Additionally, gap nanocarriers and ultrasound-mediated microbubbles.103–105
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- CARDIOVASCULAR DISEASES
lular Ca2+ homeostasis to maintain the normal electrical Ischemia and Infarction
and mechanical activities of the heart. Cardiovascular diseases are usually characterized by lower
blood perfusion. Coronary arteriosclerosis due to coro-
Endothelial Cells nary artery stenosis or occlusion is the leading cause
As a dynamic component of the cardiovascular system, of coronary heart disease. Coronary arteriosclerosis may
the endothelium lines the luminal surface of blood ves- result in myocardial infarction with ischemic death of
sels and plays an important role in cardiac health and dis- cardiomyocytes.106 107 To salvage the myocardium from
ease. It is a barrier between the blood vessels and vascular acute or chronic ischemia, reperfusion is the essential
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- (I/R) injury is another important factor responsible for
neous coronary angioplasty and/or coronary bypass.75 108 infarct size and cardiac dysfunction. The negative effects
Previous studies have shown that a pathological change of I/R mainly included intracellular calcium overload and
in the ischemic myocardium was expressed by cardiac oxidative stress, which eventually lead to cell death.112
troponin I (cTnI). As a current gold-standard marker, In addition, myocardial I/R also leads to arrhythmias and
cTnI is uniquely expressed only when cardiac damage has cardiac contractile dysfunction.113 The new mechanisms
occurred.109 Therefore, the pathological overexpression of and microRNA pathways of myocardial I/R injury are
cTnI can, as a target for the myocardium, be designed shown in Figure 5.114 It has been reported that the pri-
as a drug delivery system for targeting ischemic arrhyth- mary determinant of the outcome of an I/R insult is
mias. However, injury to the endothelium and cardiomy- the pressure, and associated mechanical stress/load, on
ocytes occurs after reperfusion.110 111 Ischemia-reperfusion the myocardium.115 The evaluation of I/R injury mainly
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.
Heart Failure
Heart failure (HF) is a complex pathophysiological syn-
drome. It arises from the debilitated function of the Figure 6. Hypertrophied heart.
heart to fill and/or eject blood sufficiently. The clini-
cal manifestations of HF are associated with myocardial to as myocardial hypertrophy. The cellular responses of
insult, including coronary artery disease, genetic factors cardiomyocytes to various signaling pathways are used to
or hypertension, and their attendant sequelae. It is esti- maintain cardiac homeostasis and to prevent pathologi-
mated that HF is the primary cause of over 55,000 deaths cal cardiac hypertrophy. In general, cardiomyocytes ini-
each year, and the incidence of symptomatic HF rises tiate a hypertrophic response to adapt to stress and to
with the increasing age.119 120 Chronic HF (CHF) generally improve cardiac function when the heart is suffering from
occurs due to continued left ventricular (LV) remodeling various stimuli, including mechanical, hemodynamic, hor-
and the progressive loss of function, leading to abnormali- monal and pathologic variations. The adaptive response is
ties in diastolic and/or systolic function.121 The myocardial triggered by a complex cascade of signaling pathways.126
injury evokes an increased orchestrated cascade of remod- Compared to the physiologically normal myocardium, the
eling stimuli within the heart and leads to alterations in hypertrophic myocardium needs more oxygen to main-
neurohormones, vascellum, the kidney and skeletal mus- tain blood circulation. Under this condition, the coronary
cle. Lymperopoulos et al. have articulated the idea that G arteries cannot provide enough blood supply, which even-
protein-coupled receptors (GPCRs) are the major neuro- tually leads to heart failure.
hormonal receptors that control cardiac function and phys- Myocardial hypertrophy is usually accompanied by the
iology. For example, the -adrenergic receptors (1 - and increased synthesis of proteins, assembly of sarcomeres,
2 -ARs) in the membranes of cardiomyocytes dominate perivascular and interstitial fibrosis and increased expres-
cardiac contractile function. Angiotensin II (AngII) type 1 sion of embryonic genes. As a result, hypertrophy even-
receptors (AT1 Rs), which are mainly present in the mem- tually leads to heart failure.127 Cardiac hypertrophy is an
branes of endothelial cell and cardiac fibroblasts, regulate important risk factor for the development of heart fail-
the cardiac structure and morphology. Heart rate is regu- ure with increased mortality.128 129 Recent studies have
lated by the balance between muscarinic cholinergic recep- revealed that the expression signatures of miRNAs have
tors and -adrenergic receptors.122 123 been linked to pathological cardiac hypertrophy.130 The
Given the weak potential of the available therapeutic data indicate that miRNAs are a new regulator in cardiac
approaches, it is essential to design new drug delivery sys- development and disease.
tems for the treatment of HF.124 Some studies have revealed
that CHF increases action potential duration (APD), which Restenosis
leads to early after depolarizations (EAD) and lethal ven- Restenosis is a serious complication of the vascular inter-
tricular tachyarrhythmias.2 123 The molecular mechanism ventional procedures that aim to restore blood flow across
may lie in that tumor necrosis factor- (TNF-) prolongs obstructed arteries (Fig. 7).131 Although angioplasty and
APD. This mechanism is a potential reason for electro- stent implants remove the occlusion and expand the inner
physiological abnormalities and sudden death in HF.125 diameter of the artery with improved hemodynamic flow
Recently, many researchers have focused on strategies rate, restenosis remains a limitation to the overall effi-
based on regulatory RNA (related to heart diseases) or gene cacy of vascular reconstruction and has a 30%–40%
transfer to the heart. For instance, in 2007 Yang et al. dis- incidence.132 Restenosis is characterized as an inflam-
covered that microRNA-1 (miR-1) had important physio- matory process that occurs after injury caused by stent
logical effects in relieving arrhythmias.83 replacement and balloon dilation during angioplasty.133 134
In general, restenosis is associated with neointimal for-
Myocardial Hypertrophy mation from smooth muscle cell (SMC) proliferation
In adult mammalian heart, the cardiomyocytes possess and migration. In addition, some new pathophysiologi-
poor proliferative capacity. The heart increases in size cal mechanisms of restenosis have been well elucidated.
in response to increased workload or stress, such as For example, some new signaling molecules (microRNAs)
aortic stenosis, hypertension, vascular heart disease and have been deemed to control the formation of restenosis.
myocardial infarction. A hypertrophied heart is showed in In the 1970s, the prevention of restenosis through
Figure 6. The increase in cardiomyocyte size is referred systemic drug therapy was first investigated. However,
small chemicals and nanoscale particles in their inte- heart-targeted liposomal carriers is promising to lower the
rior to form host-guest complexes through electrostatic incidence of heart diseases.
or hydrophobic interactions.151 152 Furthermore, the sur- In 2006, Verma et al. reported that anti-myosin mon-
face of dendrimers can bind drugs through electrostatic oclonal antibody-doped liposomes loaded with ATP were
absorption due to similar polarity, such as occurs with car- locally injected into the isolated rat heart before global
boxyl and amine groups. The desired functional group can ischemia-reperfusion. The results confirmed the improved
also be conjugated to the external terminal of dendrimers post-ischemic contractile recovery.163 Recently, both Scott
via non-covalent or covalent modification. With excellent et al. and Wang et al. confirmed that anti-P-selectin-
biocompatibility, dendrimers are often used as drug deliv- conjugated immunoliposomes containing VEGF could
ery systems to deliver therapeutics to targeted tissues. significantly improve vascularization and cardiac func-
Recently, studies have shown that Starbust dendrimers tion based on the overexpression of P-selection in the
are non-immunogenic and can regulate the transfer and infarcted myocardium.164 165 Currently, my team is work-
expression of gene in vitro and in vivo.153 Bella Chanyshev ing on designing anti-cTnI antibody-modified liposomes
and her colleagues demonstrated the conjugation of chem- containing antisense oligodeoxynucleotide of microRNA-1
ically functionalized nucleosides onto poly amidoamine (AMO-1) to target the ischemic myocardium based on
dendrimeric polymers to enhance cardioprotective potency the overexpression of cTnI in the infarcted myocardium.
via the activation of A3 adenosine receptor (A3AR) In addition, diagnostic probes targeting v 3 integrin have
on the cardiomyocyte surface.154 Other researchers have been used in various animal studies on atherosclerosis and
conjugated appropriate cardiac-targeted ligands to the ischemia. Imaging of v 3 expression in ischemic myocar-
surface of dendrimers to achieve cardiac-targeted thera- dial tissue has been performed in dogs and rats. An intra-
peutic effects. Wang et al. combined the technique of venous injection of RPT748 was administered, combining
DNA/dendrimer complexes and electroporation to enhance a 111 In-complex with a non-peptide v 3 ligand.166 167 The
gene transfection in murine cardiac grafts.155 Johnson uptake of 111 In-complex colocalized with neoangiogenesis
et al. fabricated S-nitroso-N -acetylpenicillamine-modified in the ischemic foci, as demonstrated using in vivo and ex
polyamidoamine dendrimers (G4-SNAP) to reduce I/R vivo imaging techniques. Kohane’s group modified lipo-
injury in an isolated, perfused rat heart. They found that somes with a ligand targeted to angiotensin II type1 (AT1).
glutathione was able to enhance NO release from the Their results demonstrated that the carriers were able to
dendrimers to protect the affected tissue against radial deliver active drug to the affected heart tissue after sys-
oxidation.156 tematic administration in vivo (Fig. 9).168
Takahama et al. investigated the influence of various
Liposomes liposomes on the distribution and activity of the ischemic/
Liposomes are structures made up of phospholipid bilay- reperfused myocardium. Stealth liposomes loaded with
ers and contain closed vesicles or concentric spheres. adenosine were prepared by the thin film hydration
Liposomes can be classified as unilamellar or multilamel- method. They assessed the targeting efficiency of lipo-
lar vesicles. In liposomes, the hydrophilic environment somes and myocardial infarction (MI) size after a 30-min
enclosed by the lipid bilayers can be used to entrap water- ligation followed by a 3-h reperfusion. Pharmacokinetic
soluble drugs. Meanwhile, the hydrophobic environment data confirmed that the liposomes were able to effectively
between the bilayers can be used to entrap lipid-soluble accumulate in the foci and prolong the blood residence
drugs.157 158 Liposome drug delivery systems have many time of adenosine. The results from biological studies
advantages in the formulation of potent drug to improve showed that PEGylated liposomal adenosine was able to
therapeutic efficacy.159–161 These properties include bio- enhance the cardioprotective effects of adenosine against
compatibility, flexibility, controlled hydration, various I/R injury and to reduce its unfavorable hemodynamic
administration routes and stabilization of the entrapped effects (Fig. 10).169 170
drug from hostile environments. However, liposomal drug Torchilin et al. constructed a rabbit model of acute
delivery suffers from rapid clearance by the reticuloen- myocardial infarction and fabricated 111 In-labeled stealth
dothelial system if administered by parenteral injection into liposomes modified with antimyosin antibody. They
the bloodstream.162 The conjugation of polyethyleneglycol observed the accumulation of PEG-coated immunolipo-
(PEG) and distearoyl phosphatidylethanolamine (DSPE) to somes in the infarcted rabbit myocardium. The data con-
the liposomes can reduce their recognition by the reticu- firmed that the proportion of PEG in the membrane of
loendothelial system. Recently, liposomes were modified the immunoliposomes was a vital factor. PEG influenced
by targeted ligands to decrease toxicity and improve depo- the half time and targeting efficiency of carriers in the
sition in the desired tissues. These modifications led to new body.171 These authors further investigated the effect of
advancements, including the specific delivery of liposomes various parameters, such as liposomes size, the presence
loaded with drugs to a desired cell and in the target tis- or absence of PEGylation and infarct-specific antimyosin
sue through high-affinity ligands, such as peptides, pro- antibody, on carrier behavior in terms of biodistribu-
teins and antibodies.158 In particular, the development of tion and infarct accumulation. The influence of various
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 delivery systems exhibited some novel features compared
size.172 with the parent drugs, decreasing adverse reaction and
increased clinical efficacy, ease of drug administra-
Polymeric Drug Conjugates tion and patient compliance.177 The improved clinical
Polymeric drug conjugates are characterized by the conju- efficacy mainly depends on the enhanced permeabil-
gation between drug molecules and water-soluble polymer ity and retention effect (EPR) of stealth polymers.178
carriers. The employed polymers include methacrylamide, Polymer-drug conjugates produce a 100-fold higher
amino acid, PEG and some linear polysaccharides.173–175 concentration of the drug in the target tissue than
In the mid-1970s, Ringsdrof first proposed the concept free drug.179 Thereby, the myocardium-recognition lig-
of the covalent conjugation of drugs to a hydrophilic ands, such as antibodies, proteins and peptides, that
polymer, which was envisioned to achieve active target- are conjugated on the water-soluble polymers can
ing and the modulation of pharmacokinetics.176 Through enhance the targeted delivery of drugs into the infarcted
years of studies on polymer-drug conjugates, these new myocardium.
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.
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 they are biocompatible and non-toxic at physiological
of MNPs are limited by some problems, such as inappro- concentrations.
priate features and inadequate magnet systems. Therefore, Active targeting of drug-loaded MNPs to diseased heart
it is necessary to consider many factors when designing tissues relies on the attachment between ligands conju-
heart-targeted magnetic drug delivery systems. These fac- gated to the surface of MNPs and the diseased sites with
tors include the magnetic properties and the size of the the adjustment of an external magnetic field.207 Recently,
particles, the strength of the magnetic field, the drug load- a new method of magnetic force-improved gene delivery
ing capacity, the accessibility to the target tissue and the exhibited more feasibility for gene transfer in the cardio-
rate of blood flow.200
vascular system (Fig. 12).208–210 In addition, in 2012 Zhang
Ferric oxide nanoparticles are the only type of MNPs
et al. developed stable magnetic nanoparticle-adenoviral
approved for clinical use by the FDA. Their favorable
vector complexes. They confirmed the possibility of deliv-
features include their facile single step synthesis, chemi-
cal stability in physiological conditions and flexibility of ering therapeutics into the infracted heart in the exter-
chemical modification by coating of the iron oxide cores nal magnetic field for the treatment of acute myocardial
with various shells.201 The common shells for MNPs are infarction.211
gold, polymer, silane or dendrimer.202–205 In addition, it
has been demonstrated that iron oxides (magnetite and Cerium Oxide Nanoparticles
maghemite) exist naturally in the human heart, spleen Cerium oxide nanoparticles (CeO2 NPs) consist of a
and liver.206 Their existence in the body indicates that cerium core surrounded by an oxygen lattice. They have
Figure 13. Influence of CeO2 nanocarriers 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 due to their antioxidant properties.215 In healthy cells, the
products, such as automotive catalytic converters and oxy- cellular levels of reactive oxygen species (ROS) are finely
gen sensors.212 213 CeO2 NPs have both Ce3+ and Ce4+ controlled. The accumulation of ROS is generally asso-
oxidation states, which are able to perform an autoregen- ciated with undesired effects, such as neurodegenerative
erative redox cycle. Oxygen defects on their surface offer diseases, diabetes, atherosclerosis and aging.216 Moreover,
many active sites for free radical scavenging.214 The CeO2 the elevation of ROS may lead to the increased production
NPs are gaining much attention in the biomedical field of inflammatory cytokines, which are key players in the
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- of anti-remodeling and cardioprotective therapeutics
tion, a polymeric micelle-based drug delivery system has (Fig. 15).170
not yet been applied to heart-targeted therapy in the clinic.
Paulis et al. compared the distribution between micelles and Stents with Nano-Coating
liposomes in the infarcted heart in mice. They used in vivo Metal stents have limited application due to the inflamma-
MRI of paramagnetic lipids in both carriers. The micelles
tory response, thrombosis and restenosis. It was reported
(∼15 nm) and liposomes (∼100 nm) were used to evalu-
that drug-eluting stents (DES) could reduce the inci-
ate differences in the distribution patterns. The data con-
firmed that liposomes showed slower and more restricted dence of restenosis to less than 10% in clinical trials.64 66
extravasation from the vessels, which indicates that lipo- Although DES reduced the percentage of thrombosis and
somes are a promising delivery system for pro-angiogenic restenosis, drawbacks similar to those seen with metal
drug. However, micelles were able to penetrate the ves- stents eventually appear after the drugs on the stent are
sels and went into the infarcted area, which suggests completely released. In addition, in 2004 Virmani et al.
that micelles are more attractive for the targeted delivery proposed that the polymer coating on the stent surface is
involved in an inflammatory response at the site of injury thrombosis, the remission of arterial ischemia and the
and leads to potential restenosis.246 relief of acute coronary syndromes and acute ischemic
To overcome these shortcomings, biodegradable poly- stroke.95 264–266
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- CLINICAL TRIALS AND
mal physiological vasomotor tone with the absence of COMMERCIAL MARKET
a permanent rigid object fixed in the arterial wall.248 Several drugs with different mechanisms have been used
Lincoff et al. demonstrated that stents composed of to deliver drugs to the heart with appropriate nanoscale
poly-L-lactide (PLLA) produced minimal inflammation carriers. The good news is that some heart-targeted
and durable results in a porcine model.249 A limitation nanoscale drug carriers have successfully passed clin-
of polymer-based stents is their low mechanical rigidity. ical trials.140 Furthermore, some of them are already
Bioresorbable stents are mainly constructed from poly- commercially available on the market. For instance, the
mer and metallic alloys. It was reported that a magnesium intramuscular transplantation of the ultrasound-mediated
destruction of microbubbles combined with bone marrow-
stent was absorbed within 3 weeks after implantation.250
derived mononuclear cells (BM-MNCs) has been clinically
In addition, porous aluminum oxide-coated stents encap-
applied for inducing angiogenesis in the ischemic tissue.267
sulated with drugs have exhibited inhibition to neointimal
In addition, stents are widely accepted as an effective treat-
growth.251 Although biodegradable polymeric stents are
ment for occluded arteries.268 269 The drug-eluting stent
often used in the interventional cardiology field, they still
(DES) has been reported to effectively reduce the per-
need improvement to meet clinical requirements.
centage of restenosis to less than 10% in initial clinical
trials.181 182 Currently, there are two DES on the market:
Microbubbles the Cypher® stent and the Taxus® stent.
Recently, various studies have demonstrated that the
ultrasound-targeted microbubble destruction (UTMD)
technique shows excellent features for drug and gene CONCLUSIONS AND FUTURE DIRECTION
delivery.252 253 Microbubbles used in UTMD consist of We have reviewed the physiological properties of the
albumin, saccharide, biocompatible polymers, lipids and cardiovascular system, various heart diseases and new
other materials. Ultrasound contrast agent is one of advances in heart-targeted nanoscale drug delivery sys-
the materials used because of its capacity to reflect tems. A successful design for heart-targeted nanoscale
ultrasound.254–256 Active agents can be encapsulated into drug delivery systems is based on three parameters. First,
the microbubbles using different approaches, such as coat- it is necessary to understand the fundamentals of various
ing or binding to the microbubble surface. The sonopora- heart diseases, including their etiology, pathological man-
tion produced by UTMD can transfer genes into cells.257 ifestation, clinical features and desired therapies. Second,
Microbubbles will oscillate and rupture when they are suitable heart-targeted drug carriers need to be selected
and the active targeting properties of these carriers then
exposed to ultrasound. Then the entrapped gene therapy
needs to be regulated to improve the stability of loaded
vector will be released from the microbubbles, producing
drugs. Finally, researchers should choose the appropriate
high local concentrations at the site of interest. Meanwhile,
targeting ligands to ensure the specific interaction of the
the destruction of microbubbles may transiently induce
nanocarriers with the complementary molecules on the
holes in the membrane, which increase the permeability
surface of the targeted cells. Successful targeted delivery
of vessels and biomembranes, thus facilitating the entry of
of nanocarriers to the heart is helpful to reduce toxicity
drugs or genes into cells.258 259
and to increase the availability of the drugs.171 Although
It was reported that specific ligands for endothelial cell the heart-targeted delivery of nanocarriers is promising
adhesion could be modified on the surface of microbub- for transporting drugs to affected cardiac tissue and for
bles for delivery.260 261 Recently, a large number of studies controlling drug release in the body, these systems suf-
have supported the idea that UTMD is a feasible method in fer from limitations, such as toxicity, immunogenicity
the clinical therapy of cardiovascular diseases by improv- and unwanted pharmacokinetic behavior.270–272 The desired
ing gene transfection.262 For example, Chen et al. have techniques of nanocarrier fabrication is aimed at ensuring
successfully transfected the human TB4 gene into nor- better uptake in the target cells, more desirable accumu-
mal rat hearts using UTMD.263 In another study, Chen lation of drugs in affected tissue than in unaffected sites,
et al. confirmed that the combination of UTMD with PEI and more effective avoidance of drug toxicity. Eventually,
could improve the transfection efficiency of naked genes an ideal tool for the targeted delivery of drugs into the
into the myocardium without causing any apparent adverse heart is emerging.
reaction.263 Moreover, ultrasound-mediated microbubble
drug therapy for thrombolysis has already reached the Acknowledgments: This research was supported by
clinical arena, such as in the treatment of deep venous grants from the Heilongjiang Provincial Natural Science
Foundation (D201031), the Heilongjiang Provincial Health 17. Z. Gu, A. A. Aimetti, Q. Wang, T. T. Dang, Y. Zhang, O. Veiseh,
Bureau Foundation (2009-265 and 2011-236) and the H. Cheng, R. S. Langer, and D. G. Anderson, Injectable nano-
network for glucose-mediated insulin delivery. ACS Nano 7, 4194
Innovative Fund of Harbin Medical University Graduate
(2013).
Student (YJSCX2012-202HLJ). 18. B. Büyüktimkin, Q. Wang, P. Kiptoo, J. M. Stewart, C. Berkland,
and T. J. Siahaan, Vaccine-like controlled-release delivery of
an immunomodulating peptide to treat experimental autoimmune
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