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biomedicines
Review
Targeted Strategy in Lipid-Lowering Therapy
Ezgi Dayar and Olga Pechanova *
Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences,
Sienkiewiczova 1, 813 71 Bratislava, Slovakia; ezgi.dayar@savba.sk
* Correspondence: olga.pechanova@savba.sk; Tel.: +421-911-938-910
Abstract: Dyslipidemia is characterized by a diminished lipid profile, including increased level of
total cholesterol and low-density lipoprotein cholesterol (LDL-c) and reduced level of high-density
lipoprotein cholesterol (HDL-c). Lipid-lowering agents represent an efficient tool for the prevention
or reduction of progression of atherosclerosis, coronary heart diseases and metabolic syndrome.
Statins, ezetimibe, and recently proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are
the most effective and used drugs in clinical lipid-lowering therapy. These drugs are mainly aimed
to lower cholesterol levels by different mechanisms of actions. Statins, the agents of the first-line
therapy—known as 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors—suppress
the liver cholesterol synthesis. Ezetimibe as the second-line therapy can decrease cholesterol by
inhibiting cholesterol absorption. Finally, the PCSK9 inhibitors act as an inducer of LDL excretion. In
spite of their beneficial lipid-lowering properties, many patients suffer from their serious side effects,
route of administration, or unsatisfactory physicochemical characteristics. Clinical demand for dose
reduction and the improvement of bioavailability as well as pharmacodynamic and pharmacokinetic
profile has resulted in the development of a new targeted therapy that includes nanoparticle carriers,
emulsions or vaccination often associated with another more subtle form of administration. Targeted
therapy aims to exert a more potent drug profile with lipid-lowering properties either alone or in
mutual combination to potentiate their beneficial effects. This review describes the most effective
lipid-lowering drugs, their favorable and adverse effects, as well as targeted therapy and alternative
treatments to help reduce or prevent atherosclerotic processes and cardiovascular events.
Citation: Dayar, E.; Pechanova, O.
Targeted Strategy in Lipid-Lowering Keywords: dyslipidemia; cholesterol; metabolic syndrome; statins; ezetimibe; PCSK9 inhibitors;
Therapy. Biomedicines 2022, 10, 1090. nanoparticles; targeted therapy
https://doi.org/10.3390/
biomedicines10051090
Academic Editor: Anca Sima
1. Introduction
Received: 14 April 2022
Accepted: 3 May 2022
Metabolic disorders are disorders that adversely affect the distribution of macronu-
Published: 8 May 2022
trients such as lipids, carbohydrates, and proteins. They are basically a consequence of
abnormal chemical reactions in the body that alter the normal metabolic process. While
Publisher’s Note: MDPI stays neutral
congenital metabolic disorders are caused by genetic defects, acquired metabolic disor-
with regard to jurisdictional claims in
ders are associated with external factors, such as an unhealthy lifestyle, little physical
published maps and institutional affil-
activity, and excessive caloric intake (for review see [1]). Eckel et al. (2010) documented
iations.
that human lifestyle is associated with an inherited epigenetic pattern, which affects gene
expression, and protein activity that leads to the development of metabolic disorders [2].
Metabolic syndrome is the most common metabolic disorder and represents a cluster of
Copyright: © 2022 by the authors.
conditions that occur together and increase the risk of heart disease, stroke, and type 2
Licensee MDPI, Basel, Switzerland. diabetes. These conditions include increased blood pressure, high blood glucose, obesity,
This article is an open access article and dyslipidemia [3,4]. Dyslipidemia, manifested by elevated low-density lipoprotein
distributed under the terms and cholesterol (LDL-c), is the primary cause of the development and progression of atheroscle-
conditions of the Creative Commons rosis. Atherosclerosis is initiated by multiple interactions between oxidatively modified
Attribution (CC BY) license (https:// lipids and lipoproteins, inflammatory factors, and components of the immune system in the
creativecommons.org/licenses/by/ arterial wall that result in the formation of fatty streaks and fibrous plaques. Plaque buildup
4.0/). and rupture can eventually lead to progressive stenosis and thrombosis. Atherosclerosis
Biomedicines 2022, 10, 1090. https://doi.org/10.3390/biomedicines10051090 https://www.mdpi.com/journal/biomedicinesBiomedicines 2022, 10, 1090 2 of 18
may progress silently for a longer period of time until it causes a first cardiovascular event.
Analyses of coronary arteries have indicated that dyslipidemia and obesity were predictive
of earlier and greater extent of atherosclerosis in large vessels, increase of coronary fatty
streaks, and even recurrent coronary events [5,6].
Consequently, dyslipidemia has become a key intervention in the prevention of car-
diovascular diseases. In this meaning, therapeutic lifestyle changes and the use of lipid-
lowering drugs are the most recommended options for avoiding coronary heart diseases.
The main effect of lipid-lowering drugs is the reduction of the plasma low-density lipopro-
tein or the enhancement of high-density lipoproteins [5,6]. 3- hydroxy-3-methylglutaryl-
CoA (HMG-CoA) reductase inhibitors, Niemann-Pick C1-like 1 (NPC1L1) protein inhibitors,
and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are among the most
effective and hitherto most used drugs in lipid-lowering therapy. These substances affect
respective lipid metabolic pathways and reduce the production or absorption of cholesterol
and LDL [7]. However, in addition to their beneficial pleiotropic properties, they have
also adverse side effects. Therefore, the goal of a targeted therapy is the reduction of
the dose of lipid-lowering drugs while simultaneously achieving a sufficiently effective
impact. However, many patients show intolerance to these drugs, so routine treatment
needs to be replaced by appropriate alternatives. This review describes the most effective
lipid-lowering drugs, their beneficial and adverse side effects, as well as targeted therapy
and alternative treatments.
2. Routine Lipid-Lowering Therapy
2.1. Statins
Statin therapy represents the gold standard of dyslipidemia treatment. Statins are
prescribed as the first-line pharmacological therapy for the reduction of cardiovascular
risk [8,9]. The mechanism by which statins act to reduce liver cholesterol production is
based on the competitive inhibition of rate-controlling enzyme in cholesterol synthesis
HMG-CoA reductase. This enzyme catalyzes the conversion of HMG-CoA to a mevalonic
acid, a necessary step in the biosynthesis of cholesterol (Figure 1). Among other products
of this pathway are also ubiquinones including coenzyme Q [9,10]. HMG-CoA reductase
is active during higher blood glucose level. The basic function of insulin and glucagon
is the maintenance of glucose homeostasis. Thus, in controlling blood sugar levels, they
indirectly affect the activity of HMG-CoA reductase [11].
Apart from cholesterol-lowering effects, statins also have a wide range of well-
documented pleiotropic effects including the improvement of the endothelial function
and anti-inflammatory, anti-thrombotic, and immunomodulatory effects for vascular en-
dothelial as well as smooth muscle cells [8,12]. The improvement of the endothelial function
is predominantly associated with positive effects of statins on nitric oxide (NO)/reactive
oxygen species (ROS) balance, upregulation of endothelial nitric oxide synthase (eNOS)
and tetrahydrobiopterin stabilization [8,13–15], while anti-inflammatory effects of statins
are attributed to their ability to modulate cytokine production [16].
According to the guidelines of the American College of Cardiology (ACC)/American
Heart Association (AHA), the dose and the type of statin treatment regimen differ by
requiring the reduction of LDL-c rate. However, for all statins, the maximum U.S. Food
and Drug Administration (FDA)-approved dose is 80 mg, except for rosuvastatin, which
is 40 mg/day. For patients who need a reduction in LDL-c of over 50%, atorvastatin
40–80 mg, simvastatin 80 mg, rosuvastatin 20 mg or combination statin with ezetimibe
10/40 mg are prescribed [17,18]. In spite of highly beneficial effects of statins, they have a
low bioavailability. Long-term treatment especially with higher doses may therefore lead
to serious side effects such as myopathy, muscle inflammation, joint pains, hemorrhagic
stroke, increase of liver enzymes, memory loss, and some neurological disorders [12,19].
The original definition of statin-induced myopathy is the unexplained muscle pain or
weakness accompanied by more than 10 times higher creatine kinase concentration. Statin-
induced rhabdomyolysis is a severe form of myopathy with more than 40 times higherBiomedicines 2022, 10, x FOR PEER REVIEW 3 of 18
Biomedicines 2022, 10, 1090 3 of 18
accompanied by more than 10 times higher creatine kinase concentration. Statin-induced
rhabdomyolysis is a severe form of myopathy with more than 40 times higher than the
basal the
than activity
basalofactivity
creatineofkinase andkinase
creatine muscleandfibermuscle
necrosis which
fiber often which
necrosis results often
in myoglo-
results in
binuria and acute
myoglobinuria andrenal failure
acute renal[20]. In addition,
failure prolongation
[20]. In addition, of statin of
prolongation therapy
statin leads to aleads
therapy
decrease
to in coenzyme
a decrease Q concentration
in coenzyme of up to
Q concentration of40% with
up to corresponding
40% consequences
with corresponding (for
consequences
review
(for see [21].
review see [21].
Figure 1.
Figure 1. The
Themechanism
mechanismbybywhichwhich statins
statinsactact
to to
reduce liver
reduce cholesterol
liver production
cholesterol is based
production on the
is based on the
competitive inhibition
competitive inhibition of rate-controlling enzyme
of rate-controlling enzyme in cholesterol synthesis
in cholesterol synthesis 3-hydroxy-3-methylglu-
3-hydroxy-3-methylglutaryl-
taryl-CoA (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to a mevalo-
CoA (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to a mevalonic acid,
nic acid, a necessary step in the biosynthesis of cholesterol. Ezetimibe inhibits the absorption of
acholesterol
necessaryfromstepsmall
in theintestine
biosynthesis
leading oftocholesterol.
the reduction Ezetimibe inhibits
in intestinal the absorption
cholesterol transmissionof cholesterol
to the
liver [19,22].
from The main
small intestine mechanism
leading to the isreduction
associated in with the inhibition
intestinal of the
cholesterol Niemann-Pick
transmission to theC1-like 1
liver [19,22].
(NPC1L1)
The main protein,
mechanism the key factor of cholesterol
is associated absorption.of
with the inhibition Proprotein convertase C1-like
the Niemann-Pick subtilisin/kexin
1 (NPC1L1)
type 9 (PCSK9)
protein, the key inhibitors
factor ofinhibit the binding
cholesterol of PCSK9
absorption. with low-density
Proprotein lipoprotein
convertase (LDL)-recep-
subtilisin/kexin type 9
tors and prevent the degradation of LDL-receptors. The inhibition of PCSK9 is
(PCSK9) inhibitors inhibit the binding of PCSK9 with low-density lipoprotein (LDL)-receptors and targeting also via
small interfering RNA (siRNA) against PCSK9 synthesis and expression, small molecules, and vac-
prevent the degradation of LDL-receptors. The inhibition of PCSK9 is targeting also via small
cination against PCSK9.
interfering RNA (siRNA) against PCSK9 synthesis and expression, small molecules, and vaccination
2.2. Ezetimibe
against PCSK9.
Ezetimibe inhibits the absorption of cholesterol from small intestine leading to the
2.2. Ezetimibe
reduction in intestinal cholesterol transmission to the liver [19,22]. The main mechanism
is associated
Ezetimibewith the inhibition
inhibits of the NPC1L1
the absorption protein, from
of cholesterol the key factor
small of cholesterol
intestine leadingab-
to the
sorption (Figure
reduction 1) located
in intestinal on the gastrointestinal
cholesterol transmission totract epithelial
the liver cellsThe
[19,22]. andmain
hepatocytes
mechanism
[8,9].
is The lower
associated level
with of inhibition
the cholesterolof in the
the liver
NPC1L1cells protein,
leads them thetokey
absorb more
factor of cholesterol
cholesterol ab-
from circulation
sorption (Figure resulting
1) locatedinondecrease blood cholesterol
the gastrointestinal tractlevel [23]. cells and hepatocytes [8,9].
epithelial
Ezetimibe
The lower levelwas originally developed
of cholesterol in the liverascells
a potent
leads inhibitor
them toofabsorb
acyl-coenzyme A choles-from
more cholesterol
terol acyltransferase
circulation resulting toin block spontaneous
decrease cholesterol
blood cholesterol efflux,
level [23].which may be responsible
for cholesterol
Ezetimibeesterification
was originally in macrophages
developed as[24] and results
a potent in formation
inhibitor of intracellular
of acyl-coenzyme A choles-
cholesteryl ester, and foam cells [25]. Later it was described as an inhibitor
terol acyltransferase to block spontaneous cholesterol efflux, which may be responsible of cholesterol
uptake
for from theesterification
cholesterol small intestine inby binding to the
macrophages NPC1L1
[24] transporter
and results [26]. of intracellular
in formation
Major indication of ezetimibe is the elevation of total cholesterol,
cholesteryl ester, and foam cells [25]. Later it was described as an inhibitor LDL andofapolipo-
cholesterol
uptake from the small intestine by binding to the NPC1L1 transporterand
protein B (ApoB) levels [19]. Ezetimibe also blocks aminopeptidase N interrupts a
[26].
caveolin 1–annexin
Major indication A2ofcomplex
ezetimibe involved in cholesterol
is the elevation of totaltransport [23].LDL
cholesterol, Latestandliterature
apolipopro-
tein B (ApoB) levels [19]. Ezetimibe also blocks aminopeptidase N and interruptsclearly
data suggest that ezetimibe may exert several extra-intestinal effects, but these are a caveolin
1–annexin A2 complex involved in cholesterol transport [23]. Latest literature data suggest
that ezetimibe may exert several extra-intestinal effects, but these are clearly limited to the
inhibition of macrophage migration, reduction of ROS levels and plaque size [8].Biomedicines 2022, 10, 1090 4 of 18
Ezetimibe belongs to the class II of antihyperlipidemic drugs and is recommended in
second-line therapy for coronary artery diseases prevention after statins [9,22]. Numerous
clinical trials showed that ezetimibe could be used either as monotherapy or in combination
with statins. It has been used as the first option for patients who are unable to tolerate
statins or suffer from their side effects [22,27,28]. The recommended daily dose of ezetimibe
10 mg/day orally is well-tolerated either as monotherapy or in combination with statins or
fenofibrates [29].
To date, there is little documented evidence of serious side effects of ezetimibe. Due to
insufficient data, ezetimibe is contraindicated and is not recommended for patients with
moderate to severe hepatic impairment. However, in monotherapy trials, liver function
tests were found to be similar like placebo [28,30]. Studies of Slim and Thompson (2008) and
Havranek et al. (2006) have documented the coherence between ezetimibe and myopathy,
the second one even pointed to the same effect of ezetimibe and statins in relation to
myopathy [31,32].
2.3. PCSK9 Inhibitors
PCSK9, a secretory protease, is a member of the proprotein convertase family. PCSK9
is initially secreted as an inactive enzyme precursor which undergoes autocatalytic cleavage
in the endoplasmic reticulum of hepatic cells for activation. It moves out of the endoplasmic
reticulum to be further handled by the Golgi apparatus before entering the circulation.
PCSK9 is secreted into plasma by hepatocytes and has the ability to degrade LDL receptors,
inhibiting recycling of receptors to the cell surface (Figure 1). This process thus inhibits
uptake of plasma LDL [33,34]. The expression of PCSK9 is induced by sterol regulatory
element-binding protein 2 (SREBP-2), leading to LDL-receptor degradation [35]. As result,
PCSK9 has become an important cholesterol reduction target. PCSK9 inhibitors inhibit the
binding of PCSK9 with LDL-receptors and prevent the degradation of LDL-receptors [36].
There are several strategies that target the inhibition of PCSK9 with different mech-
anisms such as monoclonal antibodies, synthetic small interfering RNA (siRNA) against
PCSK9, vaccination, and small molecules. From human monoclonal antibodies, evolocumab
and alirocumab were approved by FDA in 2015 and are currently being marketed. In addi-
tion to their ability to decrease LDL-c levels, they may affect the lipid profile by increasing
HDL, reducing total cholesterol, and lipoprotein A levels, thus lowering plaque volume.
Bococizumab, the third of monoclonal antibodies has been withdrawn by Pfizer while
under the evaluation of phase III clinical trials. Although it was able to decrease LDL-c
level to 54% [37], after 12-month follow up, it did not demonstrate any benefits regarding
the primary end point of major adverse cardiovascular events [38].
Alirocumab is available as a 75 mg/mL pre-filled pen or syringe and is administered
every two weeks by subcutaneous injection at a dose of 75–150 mg [39]. Evolocumab is avail-
able as a 140 mg/mL single use prefilled syringe or as an autoinjector activated every two
weeks. The monthly dose of evolocumab is more than a double of the dose of two-weekly
injections because the drug has non-linear pharmacokinetics. Its plasma concentrations
do not increase in proportion to the administered dose [39,40]. No adverse effects were
reported concerning monoclonal antibodies except injection-site reaction [41] which is
related to immunogenicity [42]. It is already accepted that PCSK9 monoclonal antibodies
which are already approved have the highest effectiveness comparing long-term statin
therapy or statin-ezetimibe combination or ezetimibe alone therapy regimen [27,43,44].
According to the recent studies, monoclonal antibodies have the potential to be used as
an alternative to statins [43,45]. However, subcutaneously drug administration, high cost,
inaccessibility, and limited long-term clinical outcomes are major obstacles to their wider
clinical use [44,46,47].Biomedicines 2022, 10,
Biomedicines2022, 10, 1090
x FOR PEER REVIEW 5 of 185 of 18
3.3.Targeted
TargetedTherapies
Therapies
3.1.Statin-Loaded
3.1. Statin-Loaded Nano-Based
Nano-Based Drug
Drug Delivery
Delivery System
System
According
Accordingtotodifferent
different human
human studies, long-term
studies, statin
long-term treatment
statin oftenoften
treatment causes sev- sev-
causes
eral adverse effects described shortly in the Part 2 [12,19]. In clinical practice, in such cases,
eral adverse effects described shortly in the Part 2 [12,19]. In clinical practice, in such
statin doses are reduced, combined with ezetimibe or PCSK9 inhibitors, and/or vitamins
cases, statin doses are reduced, combined with ezetimibe or PCSK9 inhibitors, and/or
or coenzyme Q10 are added to the treatment regimen respectively. In addition, there are
vitamins or coenzyme Q10 are added to the treatment regimen respectively. In addition,
several
there arestatin-intolerant patients whopatients
several statin-intolerant are unable whoto are
tolerate statins
unable at any dose.
to tolerate Consider-
statins at any dose.
ing its low water
Considering solubility,
its low water rapid metabolism,
solubility, low bioavailability,
rapid metabolism, and several clinical
low bioavailability, and several
complications of statins, it
clinical complications ofisstatins,
desirable
it istodesirable
improve the therapeutic
to improve theefficacy of the efficacy
therapeutic drug andof the
reduce
drug andits side effects
reduce its by developing
side effects bydifferent
developing therapeutic approaches,
different therapeutic such as nanomed-
approaches, such as
icine options [48–50].
nanomedicine optionsToday, several
[48–50]. nano-formulations,
Today, including polymeric
several nano-formulations, nanoparti-
including polymeric
cles, lipid-based lipid-based
nanoparticles, nanoparticles, chitosan-basedchitosan-based
nanoparticles, nanoparticles, nanoliposomes, nanoemul-
nanoparticles, nanoliposomes,
sions, nanotransfersomal
nanoemulsions, carriers, self-nanoemulsifying
nanotransfersomal systems, and cerium
carriers, self-nanoemulsifying oxideand
systems, nano-cerium
particles have been formulated
oxide nanoparticles have beentoformulated
increase thetobioavailability and therapeuticand
increase the bioavailability efficacy of
therapeutic
statins
efficacy(Figure 2). (Figure 2).
of statins
Figure 2. Proposed statin-loaded nanoparticle systems in targeted lipid-lowering therapy.
Figure 2. Proposed statin-loaded nanoparticle systems in targeted lipid-lowering therapy.
3.1.1. Polymeric Nanoparticles
Polymeric Nanoparticles
Among biodegradable polymeric nanoparticles, poly(lactic-co-glycolic acid) (PLGA)
whichAmong biodegradable
is approved by FDApolymeric nanoparticles,
(for review poly(lactic-co-glycolic
see [51]) was investigated usingacid) (PLGA)
different statins.
which is approved by FDA (for review see [51]) was investigated
Statin-loaded PLGA nanoparticles displayed a superior profile concerning theusing different statins.
bioavail-
Statin-loaded PLGA nanoparticles
ability, drug release, dosing, and displayed
minimizing a superior
adverse profile
effects concerning the hyperlipidemic
[52,53]. In the bioavaila-
bility, drug release, dosing, and minimizing adverse effects [52,53]. In the hyperlipidemic
rat model, administration of atorvastatin-loaded PLGA nanoparticles every 3 days exhib-
rat model, administration of atorvastatin-loaded PLGA nanoparticles every 3 days exhib-
ited the same efficacy as the once-daily treatment of Lipicure- commercial formulation of
ited the same efficacy as the once-daily treatment of Lipicure- commercial formulation of
atorvastatin calcium. As a result, the daily dose of atorvastatin was reduced by 66% with
atorvastatin calcium. As a result, the daily dose of atorvastatin was reduced by 66% with
PLGA formulation [52]. Moreover, pitavastatin-loaded PLGA nanoparticles attenuated the
PLGA formulation [52]. Moreover, pitavastatin-loaded PLGA nanoparticles attenuated
increase of inflammatory inducible nitric oxide synthase (iNOS) activity [54]. Apart from
the increase of inflammatory inducible nitric oxide synthase (iNOS) activity [54]. Apart
their anti-inflammatory effect, statin-loaded PLGA nanoparticles reduce the progression of
from their anti-inflammatory effect, statin-loaded PLGA nanoparticles reduce the pro-
hypertension and proliferation of pulmonary smooth muscle cells [55], while exhibiting
gression of hypertension and proliferation of pulmonary smooth muscle cells [55], while
cardioprotective properties without any adverse effects in different animal models of car-
exhibiting cardioprotective properties without any adverse effects in different animal
diovascular
models diseases [56,57].
of cardiovascular Similarly,
diseases acid-polycaprolactone-based
[56,57]. delivery of simvastatin
Similarly, acid-polycaprolactone-based deliv-
was able to markedly reduce the chemotaxis of vascular smooth
ery of simvastatin was able to markedly reduce the chemotaxis of vascular smoothmuscle cells muscle
and intimal
hyperplasia
cells and intimal [58].hyperplasia
Pitavastatin-loaded PLGA nanoparticles
[58]. Pitavastatin-loaded PLGA were able to repair
nanoparticles injured
were able to vas-
culature via the activation of PI3K signaling pathway promoting the re-reendothelialization
repair injured vasculature via the activation of PI3K signaling pathway promoting the re-
and reducing intimal
reendothelialization andhyperplasia [59]. The
reducing intimal increased[59].
hyperplasia phosphorylation of Akt [59,60] and
The increased phosphoryla-
tion of Akt [59,60] and eNOS upregulation [54,61] have been mainly responsible for
eNOS upregulation [54,61] have been mainly responsible for these effects. these
In agreement
effects. In agreement with these studies, combined therapy with simvastatin- and coen- poly-
with these studies, combined therapy with simvastatin- and coenzyme Q10-loaded
zyme
meric Q10-loaded
nanoparticles polymeric
enhanced nanoparticles
PI3K-Akt-eNOS enhanced PI3K-Akt-eNOS
pathway by increasingpathway by
the expressions
of Akt and eNOS both in the heart and aorta of obese Zucker rats [62]. Rosuvastatin-
loaded poly(L-lactide-co-caprolactone) nanoparticles increased the reendothelialization
and reduced the thrombotic potential via increased vascular endothelial growth factorBiomedicines 2022, 10, 1090 6 of 18
signaling [63]. Later, atorvastatin calcium-loaded poly(ε-caprolactone) nanoparticles were
developed and their sustained drug release, improved efficacy, better drug bioavailability,
and reduced adverse effects comparing pure atorvastatin have also been confirmed [64,65].
In high-fat diet induced rats, atorvastatin calcium nanoparticles enhanced the NO pro-
duction and decreased the lipid peroxidation in the liver while simultaneously decreasing
the interleukin-1 beta and interleukin-6 levels [66]. Recently, cellulose-based polymer
nanoparticles have shown a 3.5-fold enhancement in drug bioavailability. After successful
preclinical studies, atorvastatin-loaded ethyl cellulose nanoparticles are considered as a
candidate for further clinical trials [49,67].
3.1.2. Chitosan Nanoparticles
Chitosan is known as a biopolymer that coats liposomes to enhance their stability
and leads to controlled release of drugs. It increases the nanoformulation efficiency and
accessibility of loaded-drug [68]. Chitosan itself may lower cholesterol which has been
confirmed in both experimental animal and human studies [69]. Atorvastatin calcium-
loaded chitosan nanoparticle formulation showed sustained drug release up to 7 days [70].
In an experimental animal study, rosuvastatin-chitosan nanoparticles were found to be
more effective in improving the lipid profile than the pure drug [71]. Recently, novel
oral chitosan-based atorvastatin nanocrystals formulation with improved bioavailability
have been successfully developed and anti-hyperlipidemic activity has been found to
be higher than in marketed Lipitor [72]. In an alternative approach, long-circulating
polyethylene glycol (PEG) chitosan nanoparticles showed more than a 72-h drug release
profile. Moreover, pharmacodynamic parameters of this formulation were superior to the
pure drug [73].
3.1.3. Cerium Oxide Nanoparticles
Cerium oxide nanoparticles have the capacity to eliminate ROS and actually are
known as a ROS scavenger. This particular system could accumulate in kidneys and tar-
get mitochondria to eliminate excessive ROS [74]. Moreover, cerium oxide nanoparticles
interfered with the adipogenic pathway and hindered the accumulation of triglycerides.
Transcriptional analysis following in vivo treatment revealed a down-regulation of Lep,
Bmp2, Twist1, Angpt2, and Ddit3, and an up-regulation of Irs1 and Klf4 expression. Overall,
cerium oxide nanoparticles contributed to a slowing of weight gain and lowered the plasma
levels of insulin, leptin, glucose, and triglycerides [75]. In this sense, ceria nanoparticles
coated with ROS-responsive organic polymer (mPEG-TK-PLGA) and loaded with atorvas-
tatin demonstrated a greater antioxidant and anti-apoptotic activity than the pure drug,
and effectively decreased oxidative stress and inflammatory processes in acute kidney
injury mice model [74].
3.1.4. Lipid-Base Nanoparticles
Among the lipid-based nanoparticle formulations, solid lipid nanoparticles (SLN)
and nanostructured lipid carrier (NLC) are well-studied promising delivery systems [76].
Comparing free statins, oral bioavailability and absorption of statin-loaded SLNs were
markedly enhanced [77–79]. A sustained release of simvastatin from the lipid core of
nanoparticles was confirmed as well [80]. In high-fat diet induced hyperlipidemic rats,
the treatment of atorvastatin-loaded SLNs combined with coenzyme Q10 and vitamin E
showed superior effect on lipid profile. Atorvastatin-loaded SLNs alone administration
illustrated weaker effect in reducing triglycerides and LDL levels than the combined
therapy with coenzyme Q10 and vitamin E [81].
Since the NLCs formulation has produced and evolved from SLNs, several studies
compared the effects of drug profile between SLNs and NLCs. According to the results,
statin-loaded NLCs exhibited superior pharmaco-technical properties in regards to sus-
tained and gradual drug release than SLNs [76,82]. Moreover, displaying greater results in
lowering total cholesterol, LDL, triglycerides, and elevating HDL was observed in compari-Biomedicines 2022, 10, 1090 7 of 18
son with the standard drug [82]. 5-weeks-of-simvastatin-loaded NLCs treatment exhibited
the recovery of blood lipid levels, inhibition of smooth muscle cell apoptosis, and the delay
in the onset of atherosclerosis in hyperlipidemic rats [83]. Statin-loaded NLCs formulations
also exerted prolonged reduction in the total cholesterol and non-high-density lipoprotein
cholesterol levels [84]. The pharmacodynamic and pharmacokinetic profile of NLCs with
statins has been tested in several studies confirming that this treatment approach could
be used to improve the statin oral delivery and bioavailability, clinical efficacy, and anti-
hyperlipidemic activity [84–87].
Statin-loaded HDL nanoparticles showed the inhibition of inflammation progression
and a decrease of atherosclerotic plaques while simultaneously achieving these effects
without any hepatotoxicity. Injectable reconstituted HDL nanoparticle carrier vehicle was
able to deliver statin directly to the atherosclerotic plaques [88,89].
3.1.5. Nanoliposomes, Nanoemulsions, Nanotransfersomal Carriers
In high-fat diet rats, simvastatin-loaded lipid core nanocapsules exhibited greater
efficiency than same lovastatin-loaded nanocapsules [90]. In studies with novel nano-
formulations indicated that simvastatin-loaded nanoliposomes exerted a higher plasma sim-
vastatin concentration than the pure drug [91] and nanoemulsion of simvastatin promised
higher oral bioavailability with almost 100% of drug release [92].
Chen et al. suggested that the lipophilic emulsifier is crucial for the oral absorption
of the drug. In their study, the lipophilic emulsifier named Myverol and soybean phos-
phatidylcholine were used and successfully formulated lovastatin-loaded NLCs. According
to the results, lovastatin administration of Myverol-containing NLCs were found to be
more stable in the gastric environment compared to soybean phosphatidylcholine. When
compared with the free drug, lovastatin-loaded NLCs from Myverol exhibited greater
plasma concentrations [85].
In another unique study, the effect of transdermal delivery system was investigated in
hyperlipidemic rats. The developed nanotransfersomal carrier exerted potent effects on
hyperlipidemia without serious side effects on liver in comparison to an oral atorvastatin
treatment. Interestingly, in hyperlipidemic rats, pure atorvastatin had no effect on lipid
profile. On the other hand, nanotransfersomal atorvastatin decreased significantly total
cholesterol, triglycerides, and LDL-c levels. This pioneer study showed for the first-time
amelioration of dyslipidemia by the treatment with transdermal atorvastatin nanotransfer-
somal gel system. Transfersomes may open a window of opportunity for the well-controlled
transdermal delivery of drugs that produce side effects following oral administration [93].
3.1.6. Self-Nanoemulsifying Drug Delivery System
Self-nanoemulsifying drug delivery system (SNEDDS) of statins could be a novel
formulation to enhance drug profile. SNEDDS of statins improved the drug dissolution
rate [94], increased the oral bioavailability approximately 2.4-fold [94,95] and the expansion
of drug release 4-fold [96] compared to the pure statins. Statin-loaded SNEDDS system has
exerted remarkable antihyperlipidemic properties by normalizing serum lipid levels [97]
and overall, it has a valuable potential to improve the oral absorption as well as the
pharmacodynamic efficacy compared to the pure drug [98,99].
According to the previous findings, it is obvious that statin nano-therapy using differ-
ent nanotechnology systems may contribute to the reduction or elimination of common
adverse effects related to the statin treatment and helps statin delivery as well as their
positive pleiotropic effects.
3.2. Ezetimibe-Loaded Nano-Based Drug Delivery Systems
According to the Biopharmaceutics Classification System, ezetimibe belongs to the
class II/IV of compounds which display a low aqueous solubility and absorption and high
permeability resulting in poor bioavailability [100]. In the literature, many approaches can
be found concerning upgrade ezetimibe drug profile (Figure 3).3.2. Ezetimibe-Loaded Nano-Based Drug Delivery Systems
According to the Biopharmaceutics Classification System, ezetimibe belongs to the
class II/IV of compounds which display a low aqueous solubility and absorption and high
Biomedicines 2022, 10, 1090
permeability resulting in poor bioavailability [100]. In the literature, many approaches can
8 of 18
be found concerning upgrade ezetimibe drug profile (Figure 3).
Figure 3. Proposed
Figure ezetimibe-loaded
3. Proposed nanoparticle
ezetimibe-loaded systems
nanoparticle in targeted
systems lipid-lowering
in targeted therapy.
lipid-lowering therapy.
3.2.1. Lipid Carrier Systems
Lipid Carrier Systems
Lipid carrier systems have been documented as suitable delivery systems to increase
Lipid carrier systems have been documented as suitable delivery systems to increase
the bioavailability of ezetimibe. Comparing to marketed product and drug suspension,
the bioavailability of ezetimibe. Comparing to marketed product and drug suspension,
ezetimibe-loaded SLNs showed greater stability. According to the results, stability of
ezetimibe-loaded SLNs showed greater stability. According to the results, stability of
ezetimibe-loaded SLNs remained unchanged for 3 months. However, slow and limited
ezetimibe-loaded SLNs remained unchanged for 3 months. However, slow and limited
ezetimibe release lead to decreasing its bioavailability [101]. On the contrary, in high-fat
ezetimibe release lead to decreasing its bioavailability [101]. On the contrary, in high-fat
diet rats, ezetimibe-loaded NLCs increased drug bioavailability even with reduced dose
diet rats, ezetimibe-loaded NLCs increased drug bioavailability even with reduced dose
compared to the pure drug. Simultaneously, triglyceride, HDL-c, LDL-c and cholesterol
compared to the
levels were pure drug.and
normalized Simultaneously,
liver functionstriglyceride,
were improved. HDL-c, LDL-c and cholesterol
Ezetimibe-loaded SLNs are
levels were normalized and liver functions
ready today for clinical evaluation [102]. were improved. Ezetimibe-loaded SLNs are
ready today for clinical evaluation [102].
3.2.2. Green-Based Nanocarriers
Green-Based Nanocarriers
Nowadays, the attention has been drawn to biosustainable and biodegradable systems
Nowadays,
like green-based the nanocarriers.
attention has Itbeen
hasdrawn to biosustainable
been documented and biodegradable
that biodegradable sys-
nanoparticle
tems like green-based
adjusted nanocarriers.
drug therapeutic valueItby
has been documented
increasing that biodegradable
its bioavailability, solubility,nanopar-
and release
ticletime
adjusted drug therapeutic
[103]. Using valuealternative
linseed mucilage by increasing
in theitsdevelopment
bioavailability, solubility,nanoparticle
of polymeric and re-
lease time [103]. pharmaceutical
formulation, Using linseed mucilage alternative
properties in theofdevelopment
and efficacy ezetimibe were of polymeric
enhanced.na- This
noparticle formulation, pharmaceutical properties and efficacy of ezetimibe
study concludes that linseed mucilage seems to be a resourceful alternate for the delivery were en-
hanced. This study
of therapeutic concludes
agents with that
poorlinseed mucilage [104].
water solubility seems to be a resourceful alternate for
the delivery of therapeutic agents with poor water solubility [104].
3.2.3. Nanoemulsions, Nanosuspensions, Nanocrystals
Nanoemulsions, Nanosuspensions,
Also, nanoemulsions andNanocrystals
nanosuspensions of ezetimibe illustrated better drug absorp-
Also, nanoemulsions and nanosuspensions
tion than the marketed formulation and belong of to
ezetimibe
possible illustrated
alternativesbetter drug ab-the
in improving
sorption than the marketed formulation and belong to possible alternatives in improving
drug profile [105,106]. Ezetimibe nanosuspensions completely dissolved in the dissolution
the medium
drug profile [105,106].
within Ezetimibe
1 h, while pure drugnanosuspensions
was dissolved completely
only up to 42%dissolved
duringinthe
thesame
disso-
time.
lution medium within 1 h, while pure drug was dissolved only up to 42% during the sameThe
Better drug dissolution resulted in improved oral bioavailability of ezetimibe [107].
time.drug release
Better drugprofile of nano-ezetimibe
dissolution from volatile
resulted in improved oralmicroemulsion
bioavailabilitytemplate was increased
of ezetimibe [107].
significantly >98% in 30 min [108].
Similarly, nanocrystals of ezetimibe remarkably increased its solubility and displayed
a superior pharmacodynamic activity upon oral administration. Solubility, dissolution,
and pharmacodynamics in lipid lowering activity using ezetimibe nanocrystals were
preferable [109]. Dual drug nanocrystals loaded nano-embedded microparticles with a
combination of simvastatin and ezetimibe were also studied. Nanocrystals of both drugs
demonstrated a significant enhancement of dissolution in comparison to their physical
mixture [110].Biomedicines 2022, 10, 1090 9 of 18
3.2.4. Self-Nanoemulsifying Drug Delivery
It has been proven that self-nanoemulsifying granule system of ezetimibe ensured
128% protection while pure ezetimibe can offer only 58%. In high-fat diet rats, this formula-
tion yielded a higher reduction in the total cholesterol levels due to enhancement of drug
solubility and absorption. On the other hand, there was no significant difference in the
HDL levels after 14-days of treatment, by reason it had no direct action on the blood HDL
levels like statins [111]. Great potential of optimized super saturable SNEDDS (S-SNEDDS)
has been reported for the first time by Gao and Morozowich (2006) [112]. Later, Bandy-
opadhyay and Singh (2012) investigated the impact of the same formulation and presented
the enhancement of the drug absorption [113].
3.2.5. Solid Dispersion Nanoparticle Formulation
Solid dispersion nanoparticle formulation is another approach to find out an effective
oral drug delivery system. Ezetimibe-hydroxypropyl cellulose (HPC) solid dispersion
nanoparticle system enhanced absorption and low dissolution rate of pure ezetimibe with
about 7.5% increasement in maximum dissolution and 9.9% increasement of dissolution
efficiency [114]. Torrado-Salmeron et al. described ezetimibe self-micellizing solid dis-
persion with a non-ionic emulsifier and solubilizer called Kolliphor. Results showed that
serum levels of total cholesterol, LDL, and triglycerides were significantly improved when
compared to pure ezetimibe in high-fat induced hyperlipidemic rats [115]. The same group
of authors also investigated the comparison between solid dispersion of ezetimibe and
micellar system of ezetimibe with Kolliphor. The second one showed greater solubility and
better oral bioavailability accompanied by an improvement of the lipid profile with half
dose of ezetimibe and using different formulation of micellar system [116].
A comprehensive study that examined the differences between ezetimibe-loaded
different formulation approaches such as SNEDDS, surface modified solid dispersion
(SMSD), and solvent evaporated solid dispersion (SESD) revealed higher total ezetimibe
plasma concentrations and aqueous solubility as compared with the pure ezetimibe. All
formulations significantly ameliorated dissolution of the drug in the following order:
SNEDDS ≥ SESD > SMSD (200-fold for SNEDDS, 110-fold for SESD, and 80-fold for
SMSD). Because SESD gave higher area under curve from zero to infinity than did SNEDDS
and SMSD, this system was mostly recommended as a drug delivery system for the oral
administration of ezetimibe [117].
Statin combination therapy with ezetimibe may significantly reduce the incidence
of severe atherosclerotic events [118]. Indeed, combination of ezetimibe and atorvastatin
loaded nano-solid dispersions improved efficiency, serum lipid levels, and reduced the
toxic effects of cholesterol on the liver tissue [119,120]. Interestingly, atorvastatin even
enhanced solubility of ezetimibe and its dissolution profile. On the other hand, atorvastatin
release was decreased in the presence of ezetimibe [120]. Micellar system of ezetimibe and
atorvastatin combination therapy using nano solid dispersions with Kolliphor showed
significantly greater impact on lipid profile than the same dose of pure drugs [121].
3.3. PCSK9 Inhibition Targeting
With the exception of monoclonal antibodies, the inhibition of PCSK9 is targeting via
siRNA against PCSK9 synthesis and expression, small molecules, and vaccination against
PCSK9 (Figure 4). While siRNA is in the phase III clinical stage, the last two brand-new
approaches are still in the preclinical study stage [122–124].With the exception of monoclonal antibodies, the inhibition of PCSK9 is targeting via
siRNA against PCSK9 synthesis and expression, small molecules, and vaccination against
PCSK9 (Figure 4). While siRNA is in the phase III clinical stage, the last two brand-new
Biomedicines 2022, 10, 1090
approaches are still in the preclinical study stage [122–124]. 10 of 18
Figure 4. Proposed PCSK9 inhibition targeting in lipid-lowering therapy.
Figure 4. Proposed PCSK9 inhibition targeting in lipid-lowering therapy.
3.3.1. siRNA: Inclisiran
siRNA: Inclisiran
Inclisiran is the first siRNA-based drug that acts as an inhibitor of PCSK9 expression.
It specificallyistargets
Inclisiran the firstandsiRNA-based
binds to PCSK9 drug that acts asleading
mRNA an inhibitor
to PCSK9of PCSK9 expression.
degradation and
Itresulting
specifically targets and binds to PCSK9 mRNA leading
in diminished PCSK9 protein levels and long-lasting reduction of LDL-c to PCSK9 degradation andeven
re-
sulting
up to 3–6in diminished
months [125–127].PCSK9 protein levelsbiological
It has a long and long-lasting
half-life that reduction
induced of LDL-c
sustained even up
LDL-c
tolowering,
3–6 months [125–127]. It has a long biological half-life
which seems to be more preferable than monoclonal antibody therapy [128]. that induced sustained LDL-c
lowering, whichefficacy,
Inclisiran seems to be more and
toleration, preferable than
its ability to monoclonal
reduce LDL-cantibody levels have therapy [128].
been displayed
Inclisiran efficacy,
by preclinical studies, toleration,
Phase I andand Phase its ability to reduce
II clinical trials. PhaseLDL-cIII levels have
clinical been
trials aredis-
still
played by preclinical
in progress [126,129]. studies, Phase to
According I and
thePhase
ORION-1 II clinical trials. Phase
randomized III clinical
clinical trial, onetrials
or are
two
still in progress
injections [126,129].
of inclisiran canAccording
remarkably to the ORION-1
reduce PCSK9randomized
and LDL, decrease clinicalatherogenic
trial, one orlipids,
two
injections of inclisiran can remarkably reduce PCSK9 and LDL,
improve lipoprotein profiles and appear to be safe and well tolerated [130]. Patients with decrease atherogenic li- a
pids,
highimprove lipoprotein
cardiovascular profiles and
risk received one appear to be safe
or two doses and wellfor
of inclisiran tolerated
6 months. [130].
TheirPatients
results
with a highthat
showed cardiovascular
PCSK9 and risk LDL-creceived
levelsone were or markedly
two doses reduced of inclisiran from forthe
6 months.
baselineTheir [131].
results showed that PCSK9 patients
After one-year-follow-up, and LDL-c who levels weretwo-dose-inclisiran
received markedly reduced have from still
the remained
baseline
[131]. After one-year-follow-up,
the reductions on the PCSK9 and patients
LDL-c who received
levels. two-dose-inclisiran
According to the results,have twice still re-
a year
mained the reductions
administration on thecould
of inclisiran PCSK9 and LDL-c
maintain levels.
to stable According
reductions to the results,
in LDL-c twice a
levels [132].
year administration
Novartis recently of inclisiran couldinclisiran
introduced maintain to and stable reductions
received its firstin LDL-c
approval levels [132].
from the
Novartis
European recently
Union introduced
in 2020 inclisiran
for patients with and received
primary its first approval fromand
hypercholesterolemia the dyslipi-
Euro-
pean
demia Union in 2020
[128,129]. for patients
It could be usedwithwithprimary
either a hypercholesterolemia
statin or a statin-ezetimibe and dyslipidemia
[129]. Among
[128,129]. It couldinjection
its side effects, be used sitewithreactions,
either a statin or asite
injection statin-ezetimibe
pain, erythema [129].
andAmong
rash have its side
been
effects,
reported.injection
Othersite thanreactions, injection
these possible site pain,
adverse erythema
effects, such asand rash haverisk
an increased been ofreported.
cardiovas-
Other
cular than
eventsthese
or organ possible adverse
toxicity, effects,
are still unknown,such butas an areincreased
being thoroughlyrisk of cardiovascular
tested in clinical
events or organ toxicity, are still unknown, but are being thoroughly tested in clinical trials
trials [127,129].
[127,129].
In a preclinical study testing the use of lipid-containing nanoparticles with the precur-
sor In a preclinical
ALN-PCS it hasstudy
been testing
shownthe thatuse thisofsystem
lipid-containing
was able to nanoparticles
reduce PCSK9 with
mRNAthe pre- and
cursor
protein ALN-PCS it has been
concentrations shown
by 70% andthatLDL-c this concentrations
system was ableby to60%.
reduce PCSK9
These mRNA
effects lasted and for
protein concentrations by 70% and LDL-c concentrations by 60%. These effects lasted for
3 weeks after a single intravenous administration in the animal models. This treatment
3 was
weeksalso after
ablea to single
reduceintravenous administration
total cholesterol and apoB inlevels
the animal[133]. models.
A phaseThis treatment
I clinical study
that observed the effects of ALN-PCS did not show any
was also able to reduce total cholesterol and apoB levels [133]. A phase I clinical study serious adverse effects. On the
contrary, PCSK9 and LDL-c levels were significantly reduced
that observed the effects of ALN-PCS did not show any serious adverse effects. On the for at least 6 months [134].
According
contrary, to theand
PCSK9 meta-analysis
LDL-c levelsofwere randomized clinical
significantly trials, for
reduced in patients
at least 6withmonthsfamilial
[134]. hy-
percholesterolemia and/or atherosclerosis, the drug found to be effective, safe, and well
tolerated at lower LDL-c levels and exerted only mild adverse effects along with injection
site reaction [135].Biomedicines 2022, 10, 1090 11 of 18
3.3.2. Vaccination against PCSK9
Vaccination strategies could be a better alternative than monoclonal antibodies be-
cause their approach is less expensive and does not require frequent administration
intervals [136,137]. The peptide-based PCSK9 vaccine has been shown to induce the pro-
duction of antibodies that improve the lipid profile for up to 24 to 40 weeks, according
to data from animal studies [138,139]. According to the study of Landlinger, the PCSK9
vaccine reduced plasma lipids and systemic and vascular inflammation by reducing plasma
inflammatory markers and vascular endothelial growth factor leading to weakening of
atherosclerotic lesions in the aorta [140]. Similarly, in a peptide-vaccinated mice, an effective
immune response was associated with a significantly improved lipid profile [141]. In vacci-
nated hypercholesterolemic mice, Wu et al. have shown a reduction in total cholesterol and
LDL-c [142]. Recently, phase I clinical trial is conducted to assess the safety and tolerability
of anti-PCSK9 vaccine strategy in healthy subjects. The results have not been published
yet [143].
Momtazi-Borojeni et al. introduced a nanoliposomal anti-PCSK9 vaccine [144] and in
the first approach administered it to healthy animals to observe antibody production [145].
After detection of antibody production, immunized rats were administered intraperi-
toneally with streptozotocin to induce diabetes mellitus. It is reported that vaccinated
rats showed lower plasma LDL-c levels compared to non-vaccinated diabetic rats. Hy-
perglycemia was suppressed in vaccinated rats [146]. In hypercholesterolemic mice, the
nanoliposomal vaccine against PCSK9 promoted antibodies that inhibited the interaction
between PCSK 9 and the LDL receptor and also led to a reduction in LDL and triglycerides.
In addition, a reduction in inflammatory cells as well as a reduction in the size of atheroscle-
rotic lesions have been observed [147]. Ortega-Rivera et al. established technology for a
single-dose multi-target vaccination strategy targeting ‘cholesterol checkpoint’ proteins in-
cluding PCSK9, ApoB, and cholesteryl ester transfer protein (CETP). The candidate vaccine
was developed using virus-like particles from bacteriophage Q-beta that exhibit PCSK9,
ApoB and CETP antigens. Decreased plasma PCSK9 and ApoB levels, in vitro CETP
inhibition and decreased total plasma cholesterol were observed after vaccination [148].
3.3.3. Small Molecule PCSK9 Targeting
Agents of small molecule PCSK9 targeting could be a new alternative of lipid-lowering
drugs. They are potentially safer and have more advantages such as small size, low cost, and
easier production than the other respective treatments [149,150]. Despite that, development
of small molecule PCSK9 targeting is still in the preclinical stage [151].
Shifa Biomedical has developed the first small molecule that targets PCSK9, called P-4.
It successfully inhibits PCSK9 and LDL binding and reduces circulating LDL-c levels. Due
to the low solubility and permeability in the water, a new nano-formulation P-4 called P-21
has been developed to overcome these obstacles. The P-4 formulation had better plasma
bioavailability, than P-21. However, targeted delivery of the P-21 nano-formulation to the
hepatocytes showed higher bioavailability in the liver. The LDL-c lowering efficacy of P-21
was about 90% and much higher than that of P-4. In addition, it led to a 2-fold increase
in HDL-c after two weeks of oral treatment. The development of a small molecule nano-
formulation represents a new alternative to lipid profile modification with the potential for
significant benefits for clinical practice [152].
4. Conclusions
Nowadays, statins are the key medication for treatment of dyslipidemia in patients
who have or are at substantial risk for atherosclerotic cardiovascular diseases. However,
with the intensity of statin treatment, intolerance to their use has the increasing tendency.
Therefore, new lipid-lowering drugs that interfere with various mechanisms of lipid path-
ways are being evaluated. Clinical trials have documented that ezetimibe and PCSK9
inhibitors can successfully lower LDL-c level and contribute to lowering cardiovascular
events. However, recent studies have shown that also these drugs may have some sideBiomedicines 2022, 10, 1090 12 of 18
effects, or the route of their administration is unsatisfactory. To improve the therapeutic
efficacy of the lipid-lowering drugs and reduce their side effects different nanoparticle
systems with targeted strategy have been developed and described. Thus, enhancing the
pleiotropic effects of lipid-lowering drugs by suitable targeted strategy may represent a
promising tool for the treatment of atherosclerotic cardiovascular diseases.
Author Contributions: Conceptualization, E.D. and O.P.; Formal analysis, E.D. and O.P.; Writing—
original draft preparation, E.D. and O.P.; Writing—review and editing, E.D. and O.P.; supervision,
O.P.; project administration, O.P.; funding acquisition, O.P. All authors have read and agreed to the
published version of the manuscript.
Funding: This work was supported by the national grant agencies APVV 14-0932 and VEGA
2/0112/19; 2/0132/20; 1/0035/19; 2/0151/18 and by the The European Regional Development
Fund “Vývoj biomodelov pre zlepšenie hodnotenia účinnosti liekov a látok, ktoré majú potenciál
pri liečbe COVID-19 (BIOVID-19)”—ITMS2014+:313011AVG3 and “Centrum pre biomedicínsky
výskum—BIOMEDIRES—II. etapa”—ITMS2014+:313011W428, and ITMS project code 313021T081
(supported by the Integrated Infrastructure Operational Programme funded by the ERDF).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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