Subscriber access provided by UNIV OF NEBRASKA - LINCOLN
Review
Recent advances in dendrimer research for cardiovascular diseases Maomao Yu, Xu Jie, Lu Xu, Cong Chen, Wanli Shen, Yini Cao, Guan Lian, and Rong QI Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.5b00979 • Publication Date (Web): 27 Aug 2015 Downloaded from http://pubs.acs.org on September 1, 2015
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Biomacromolecules is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
Recent advances in dendrimer research for cardiovascular diseases
1 2
Maomao Yu †
3
Xu Jie ‡
Lu Xu †
Cong Chen †
Guan Lian ‡
4
Wanli Shen ‡
Yini Cao †
Rong Qi †‡*
5 6
†
Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China
7 8
‡
School of Pharmacy, Shihezi University, Shihezi 832000, China
9 10 11 12 13 14 15 16
* Corresponding author
17
Mailing address: Rong Qi, 38 Xueyuan Road, Peking University Institute of Cardiovascular
18
Science, Peking University Health Science Center, Beijing 100191, China.
19
Tel: (+) 8610-8280-5164
20
E-mail:
[email protected] 21 22 23 24 25 26 27 28 29 30 1
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1
Abstract:
2
Dendrimers, as a type of artificially synthesized polymers, have been increasingly
3
attracting attention in many research fields, including the material and medical sciences,
4
due to their unique characteristics that include their highly branched and well-defined
5
molecular architecture, multivalency and tunable chemical compositions. These advantages
6
make dendrimers potential carriers for the delivery of therapeutic and diagnostic agents.
7
Herein, we review the recent advances in dendrimer research for the prevention and
8
treatment of cardiovascular diseases, with special focus on their applications as carriers for
9
drug and gene delivery, as contrast agents and as potential new drugs.
10 11
Keywords: dendrimers; cardiovascular diseases; gene and drug delivery; contrast agents;
12
potential drugs
2
ACS Paragon Plus Environment
Page 2 of 35
Page 3 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1
Introduction
2
Dendrimers are a class of spherical polymers with multiple branches and topological
3
features. Their unique properties are attracting increasing interest among scientists in many
4
relevant fields1, 2. The term dendrimer comes from the Greek word dendron (meaning trees)
5
and was chosen to name the polymers due to their structural shape. A typical dendrimer is
6
composed of three different parts, which confer many fascinating advantages:3 a focal core
7
of either a single atom or an atomic group, building blocks composed of repeating units
8
emanating from the core like branches, and multiple peripheral functional groups (Fig. 1).
9
In contrast to other linear, cross-linked and branched polymers, dendrimers exhibit many
10
attractive characteristics determined by their controllable preparation, such as a
11
multi-branched three dimensional structure with a defined molecular weight, a much lower
12
polydispersity and a higher functionality, which distinguish dendrimers from other
13
polymers and give them many promising applications in various fields, including material
14
science and medical science. For example, the repeating units of dendrimers provide a
15
flexible space created within the voids of dendritic building blocks that can encapsulate
16
various small guest molecules such as drugs4. A large number of peripheral functional
17
groups of dendrimers can interact with the external environment, thereby defining their
18
macroscopic properties5. The step-by-step synthesis of dendrimers allows them
19
site-selective modification and functionalization of the terminal groups. Specifically,
20
targeted molecules could be covalently or non-covalently conjugated to dendrimers to form
21
targeted delivery systems.
22 23
Figure 1. Structure of dendrimers. 3
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 4 of 35
1
As promising non-viral gene delivery carriers, dendrimers have many apparent
2
advantages, such as their high solubility, enhanced stability, non-immunogenicity, and
3
mediating and enhancing the delivery of diverse nucleic acids including DNAs and RNAs,
4
over other viral vectors (e.g., retroviral and adenoviral vectors) and non-viral carriers (e.g.,
5
plasmids and liposomes)6. In 1993, Haensler and Szoka first reported poly(amidoamine)
6
(PAMAM) dendrimer-based gene transfection7. Today gene transfer reagents such as
7
PolyFect and SuperFect, which are based on activated dendrimers and optimized for DNA
8
transfection, are already commercially available.
9
Dendrimers are also used to deliver drugs either by encapsulating drugs in their interior
10
void spaces or by conjugating drugs to their surface functional groups. By constructing
11
dendrimer-based
12
bioavailabilities of the drugs can potentially be improved, and their side effects could be
13
ameliorated to some extent. Compared to liposomes, an another widely used carrier,
14
dendrimers have higher drug delivery efficiencies and lower drug leakage percentages6,
15
which make them effective in the trans-dermal, oral and ocular delivery of drugs with
16
improved pharmacokinetic profiles of the loaded drugs8,9. As for oral delivery, researchers
17
concluded that PAMAM dendrimer could efficiently help the loaded drugs traverse
18
epithelial monolayers via both paracellular and transcellular pathways10.
drug
delivery
systems,
the
solubilities,
oral absorptions and
19
In addition to gene and drug delivery, the unique structural properties of dendrimers
20
allow them to be used as templates or stabilizers to synthesize dendrimer-entrapped
21
contrast agents in CT or MR imaging applications for disease diagnosis11. Contrast agents
22
modified by dendrimers have extended imaging times, increased biocompatibilities and
23
improved imaging specificities. In addition, to our surprise, dendrimers themselves are
24
found to be bioactive and can be used as potential drugs in diverse medical fields.
25
In recent years, the conjugation of dendrimers with multiple copies of targeting ligands
26
such as antibodies and active moieties including drugs and dyes has provided a popular
27
method for exploiting novel materials useful for both the diagnosis and treatment of
28
disease12-14. Dendrimer conjugates supply the possibility to vary the active size and
29
functionality on the scaffold and therefore tune the solubility, toxicity, and biodistribution15,
30
which gives dendrimers many advantages including an enhanced targeting ability, 4
ACS Paragon Plus Environment
Page 5 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1
increased and varied bioactivity, the ability to report the location of action, and optimal
2
impact at the target when applied as scaffolds in drug and gene delivery as well as contrast
3
agent design. However, most of the conjugation designs for dendrimers would encounter
4
the following inherent challenge common to theranostics as well as dendrimers: the
5
heterogeneity introduced by the attachment of functional ligands to dendrimer scaffolds16,
6
which means that it is difficult to control the ligand/nanoparticle ratio. The heterogeneity
7
may decrease the specificity and targeting ability, cause uncertain therapeutic effects and
8
influence the biodistribution, thus hindering the application of dendrimer conjugates in the
9
diagnosis and treatment of diseases17, 18. The major approaches to overcome problems with
10
heterogeneity in multivalent conjugates include high density conjugates, the exhaustive
11
conversion of small numbers of terminal reaction sites, high ligand densities and so on,
12
which could be used to minimize the production of complex mixtures and a wide array of
13
products during the synthesis of dendrimer conjugates16.
14
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, particularly
15
in ageing populations, and their incidence is still on the rise. As multi-functional polymers,
16
dendrimers have been popularly studied for their potential to be utilized for the diagnosis,
17
prevention and treatment of CVDs. The objective of this paper is to review the recent
18
advances of dendrimer research in cardiovascular diseases, with a special focus placed on
19
dendrimers and their conjugates used as drug and gene delivery carriers, contrast agents
20
and potential drugs.
21
Recent advances of dendrimers in gene delivery
22
In terms of etiology, the current paradigm is that CVDs are associated with the
23
dysfunction of certain mutable genes. Silencing “bad” genes using RNA interference
24
technology and upregulating “good” genes are effective tools to correct or compensate for
25
functions of the mutable genes, and these two methods are generally called gene therapy19.
26
Increasing efforts have been put into exploring new and effective strategies of gene therapy
27
for CVDs. Dendrimers, as popular gene carriers, are promising agents for application in the
28
gene therapy of CVDs. Specifically, dendrimers having primary amine end groups can
29
interact with and compact DNA plasmids or siRNA by electrostatic interactions, thus
30
forming nano-composites favoring the cell uptake process and releasing DNA or siRNA 5
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1
into the cells to complete the following transcription and translation 20.
2
Myocardial infarction (MI) is a class of CVDs that accounts for 1 in every 6 deaths in
3
the US alone with a total of approximately 1.5 million deaths annually21, 22. Those who
4
survive the initial insult and are characterized by the regional loss of myocardium and
5
function, and they have a high probability of developing heart failure in subsequent years.
6
Vascular endothelial growth factor (VEGF) is a crucial factor to promote angiogenesis and
7
increase the blood supply in an ischemic heart. Upregulation of VEGF expression in a local
8
ischemic area of the heart through angiogenic gene therapy may be an effective way to
9
improve heart function and reduce left ventricular dilation following acute myocardial
10
ischemia and infarction.23 However, exorbitant expression of VEGF may lead to severe
11
side effects including the development of vascular tumors, which may also cause heart
12
failure24, thus limiting the efficacy and safety of gene therapy in the myocardium.
13
Therefore, the key factor for success in clinical angiogenic gene therapy is to establish a
14
safe and highly effective delivery system to target the VEGF gene, which requires
15
hypoxia-regulated VEGF expression, the protection of VEGF from degradation, the
16
limitation of rapid renal clearance and the improvement of intracellular delivery with
17
minimal side-effects.
18
Dendrimers as gene delivery carriers have already been studied in the treatment of MI.
19
Won et al. developed a new post-translationally regulated hypoxia-responsible VEGF
20
plasmid, PAM-ABP/VEGF (ABP = arginine-grafted bio-reducible poly (disulfide amine)),
21
in which PAM-ABP was a dendrimer-type bio-reducible polymer used as a VEGF carrier.
22
PAM-ABP, which demonstrated superior condensing ability for plasmid VEGF through the
23
formation of compacted and nanosized polyplexes, could enhance cellular uptake and be
24
less susceptible to reducing agents. Therefore, it resulted in a greater transfection efficiency
25
compared to ABP alone
26
new dendrimeric VEGF plasmid protected rat cardiomyocytes against apoptosis, preserved
27
their left ventricular (LV) function and prevented LV from remodeling more effectively27.
25
. Compared to a hypoxia-inducible RTP-VEGF plasmid26, this
28
Hyperbranched-PAMAM (h-PAMAM) dendrimer, an analog of PAMAM dendrimer in
29
structure, shows an excellent DNA protection ability, low cytotoxicity and high gene
30
transfection efficiency28. Zhu et al. adopted h-PAMAM dendrimer as a carrier to deliver 6
ACS Paragon Plus Environment
Page 6 of 35
Page 7 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1
hypoxia-regulated human VEGF-165 plasmids into skeletal myoblasts (SkMs) to
2
controllably express the VEGF gene. Then, these gene-manipulated SkMs were
3
transplanted into infarct myocardium for cardiac repair in a MI model29. The
4
H-PAMAM-based VEGF gene delivery system exhibited a high transfection efficiency and
5
minor cytotoxicity in primary SkMs. The transfected SkMs could constantly express the
6
VEGF gene for 18 days under in vitro hypoxia conditions. As for in vivo circumstances, the
7
intramyocardial transplantation of transfected SkMs significantly reduced the number of
8
apoptotic myocardiocytes, improved the survival of grafted cells, decreased the infarct size
9
and interstitial fibrosis, and increased the blood vessel density, which inhibited left
10
ventricle remodeling and improved heart function during the late phase following
11
infarction.
12
To overexpress VEGF in a manner similar to the manipulation mentioned in SkMs29,
13
Paul et al. developed a new gene delivery system consisting of human adipose tissue
14
derived stem cells (h-ASCs) that were genetically modified with the self-assembled
15
nanocomplex of recombinant baculovirus and PAMAM dendrimer (Bac-PAMAM)30. In
16
vitro results confirmed that this system could efficiently transduce h-ASCs and express
17
functionally active VEGF. In vivo results on chronically infarcted rat hearts confirmed
18
higher myocardial VEGF gene expression with significantly enhanced neovasculature after
19
treating rats with h-ASCs-VEGF. In addition, the ejection fraction in the hearts of
20
h-ASCs-VEGF-treated rats also significantly improved. The reason why baculoviruses and
21
PAMAM dendrimer were used together as a VEGF delivery system may be that adeno- and
22
retro-viral vectors could work in coordination with polymers through a non-covalent
23
complexation as superior gene delivery vectors31,
24
interactions between the viral surface and mammalian cell membranes enhance the cellular
25
entry of the polyplexes33. On the other hand, the PAMAM dendrimer itself functions as a
26
highly efficient cationic carrier for gene delivery.
27
32
. On the one hand, electrostatic
CVDs are controlled and influenced by numerous factors in the “cardiovascular
28
continuum”34,
35
29
renin-angiotensin-aldosterone system (RAAS), involved in the pathogenesis of CVDs. RAAS
30
activation following a cardiovascular ischemic injury is supposed to promote blood pressure
. Apart from VEGF, there is another important hormone system, the
7
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1
recovery, but its continuous stimulation can cause vasoconstriction, vascular and cardiac
2
hypotrophy, and fibrosis36. Angiotensin II (Ang II), an end product of RAAS, regulates most
3
of the effects of RAAS. Overexpression of Ang II can cause adverse cardiac remodeling,
4
progressive ventricular dysfunction and finally heart failure37. Therefore, the inhibition of
5
Ang II activation may be feasible for the prevention and treatment of CVDs. Ang II type 1
6
receptor (AT1R), a major receptor that mediates most adverse effects of Ang II38, could be a
7
potential silencing target to attenuate the worse cardiac function after heart injury. Liu et al.
8
employed PAMAM dendrimer as a carrier for AT1R siRNA to silence AT1R expression in a
9
rat ischemia-reperfusion (I/R) model19. In this study, they developed a non-cytotoxic and
10
efficient “tadpole” siRNA delivery system composed of a cationic generation 4 (G4)
11
PAMAM dendrimer penetrating peptide (CPP) and oligo arginine (R9) cross-linked by
12
polyethylene glycol (PEG). The remarkableness of this delivery system was that PAMAM
13
moieties regulated siRNA complexation and endosome escape, CPP improved cell
14
internalization, and PEG segments with disulfide linkages in the three parts enhanced the
15
biocompatibility of the system. Loading AT1R siRNA in this dendrimer-based delivery
16
system had better downregulation effects on AT1R expression in vitro in cardiomyocytes
17
than ATIR siRNA alone. Moreover, in vivo siRNA delivery by this system prevented an
18
increase in AT1R expression and recovered cardiac function after I/R injury more
19
significantly than groups treated with saline or dendrimers alone.
20 21
Figure 2. Schematic diagram of gene therapy of MI delivered by dendrimer-based delivery 8
ACS Paragon Plus Environment
Page 8 of 35
Page 9 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1
system.
2
The adhesion molecules P- and E-selectin express on activated endothelial cells, and they
3
can be the targets of gene therapy for inflammatory diseases such as the majority of types of
4
CVDs. Theoharis et al. investigated the potential targeting of a PAMAM dendrimer-based
5
P/E-selectin expression system using a monoclonal antibody to recognize the targeted
6
molecules39. Specifically, they used biotin and avidin to cross-link anti-E/P-selectin
7
monoclonal antibodies to pre-form Superfect (PAMAM dendrimer)-DNA complexes, which
8
were then used to transfect reporter genes into CHO cells, cytokine-activated primary human
9
saphenous vein endothelial cells (HSVEC) and whole vein segments to express E/P-selectin.
10
The results showed that this dendrimer-based targeting system increased the transfection
11
efficiency of the reporter genes. Hopefully, this gene therapy technique not only shows great
12
potential in the treatment of CVDs but can also target other diseased cells or tissues by using
13
different antibodies.
14
Although dendrimers have great advantages as non-viral gene delivery carriers as
15
mentioned above, cationic dendrimers are associated with cytotoxicity, hemolysis and liver
16
toxicity40,
17
characteristics as gene delivery carriers, we conjugated PEG (molecular weight = 5,000) to
18
G5 and G6 PAMAM dendrimers42. Compared with the unconjugated dendrimers, PEG
19
conjugation significantly decreased the in vitro and in vivo cytotoxicities as well as the
20
hemolysis of G5 and G6 dendrimers, especially at higher PEG molar ratios. Among all of the
21
PEGylated PAMAM dendrimers, 8% PEG-conjugated G5 and G6 dendrimers resulted in the
22
most efficient muscular gene expression in neonatal mice as well as in 293A cells. In addition,
23
these PEG-conjugated G5 and G6 PAMAM dendrimers could protect siRNA from being
24
digested by RNase and exhibited high transfection efficiencies of FITC-labeled siRNA in the
25
primary vascular smooth muscle cells (VSMC) and mouse peritoneal macrophages. In vivo
26
results showed that the intramuscular delivery of GFP-siRNA using PEG-conjugated
27
dendrimers significantly suppressed GFP expression in both transiently adenovirus infected
28
C57BL/6 mice and GFP transgenic mice43.
41
, which limits their applications in vitro and in vivo. To improve their
29
The exact mechanism of the internalization of dendrimer-gene polyplexes into cells still
30
remains unclear and controversial. Most of the studies on dendrimer-gene polyplexes have 9
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 10 of 35
1
reported that the internalization process is possibly mediated by several endocytosis
2
pathways, including macropinocytosis, phagocytosis, clathrin-mediated endocytosis
3
(CME)44 and caveolin-mediated endocytosis (CvME45. The ultimate fate of dendrimer-gene
4
polyplexes is resolved by lysosomes, and then, DNA escapes from the complex and enters
5
the nucleus to complete the following process of transcription and translation (Figure 3).
6
However, recent studies have strongly suggested alternative pathways for similar polymer
7
systems. Fichter et al. investigated the intracellular trafficking of linear polyethyleneimine
8
(PEI) and Glycofect polyplexes through sorting organelles such as the Golgi and
9
endoplasmic reticulum (ER) in H9c2(2-1) cells, and they showed that both PEI and
10
Glycofect could promote an alternative active transport pathway involving inter-organelle
11
transport via the Golgi and ER. Specifically, polyplexes tended to be sorted into the Golgi
12
and likely underwent retrograde transport to the ER via coat protein complex I (COPI)
13
vesicles while bypassing lysosomes in a manner similar to that of viruses after
14
internalization initiated by the clathrin- and caveolae-mediated pathways shown in Fig. 346,
15
which was also confirmed by other studies47. It has been reported in several studies that
16
endosomes can fuse with acidic lysosomes where the cargo could be degraded48-50. Rehman
17
et al. have investigated the interactions of polyplexes with HeLa cells by live cell imaging
18
to clarify the internalization mechanism of polyplexes. The results presented direct
19
evidence in support of the proton sponge effect, which directly mediated nucleic acid
20
delivery by highly buffering polyplexes including dendrimer-gene polyplexes
21
Grandinetti et al. examined the mechanism of the entry of polyplexes into the nucleus, and
22
they found that polycations such as PEI may cause permeabilization of the nuclear
23
membrane, thus allowing physical penetration and the entry of nanomedicine into the
24
nucleus. However, this effect is certainly reliant on the chemical structure and molecular
25
weight of the polymer-based vehicle52.
10
ACS Paragon Plus Environment
51
.
Page 11 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1 2
Figure 3. Internalization pathways of dendrimer-gene complex into cells and the following
3
transcription and translation process.
4
Our group has been long committed to figuring out the possible mechanisms of the
5
internalization of dendrimer/gene polyplexes into cells. We explored the GM1/caveolin-1
6
(GM1 = monosialotetrahexosylganglioside) lipid raft mediated endocytosis (GM1/CAV-1
7
LRME) mechanism for G5 and G7 PAMAM dendrimer polyplexes employing Cos-7,
8
293A, C6, HeLa, KB, and HepG2 cell lines, but we found that there was no evidence for
9
GM1/CAV-1 LRME involvement in the internalization of G5 and G7 polyplexes into these
10
cell lines45. Recently, we found that downregulation of syndecan-4 and upregulation of
11
caveolin-1 significantly improved the internalization of G5 and G7 PEG-PAMAM
12
dendrimer polyplexes into HepG2 cells; meanwhile, for C2C12 cells, the uptake of the
13
PEG-PAMAM polyplexes was affected by Syn-4 but not CAV-1, and the upregulation of
14
Syn-4 would contribute to gene delivery. (Figure 4)53. All of our results supplied guidelines
15
on how to use strategies to improve the in vivo gene delivery efficiency of PAMAM
16
dendrimers in clinical gene therapy.
11
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1 2
Figure 4. Different effects of syndecan-4 and caveolin-1 on the internalization of
3
dendrimer-gene complex into cells. Reprinted from ref 53. Copyright 2014, with permission
4
from Elsevier.
5
Dendrimers can be combined with other gene delivery systems, such as virus and other
6
polymers, to achieve a better transfection efficacy and higher biocompatibility. Moreover,
7
dendrimers can be modified with targeted molecules, such as certain antibodies, to deliver
8
genes to the targeted diseased tissues. With the development of synthetic chemistry and
9
nanotechnology, more and more types of multi-functional and multi-target systems based on
10
dendrimers will be applied as gene carriers in the prevention and treatment of CVDs with a
11
good targeting ability and minimal side effects.
12
Recent advances of dendrimers in drug delivery
13
An ideal drug delivery carrier must be biochemically inert and non-toxic as well as
14
protect the payload (drug) from dissociation until it reaches the target site. In fact, their
15
unique molecular architecture and branched surface groups make dendrimers excellent
16
nanoscale carriers for the efficient delivery of drugs and biological molecules, especially
17
for solving solubility and absorption problems of drugs54. The original dendrimers
18
(PAMAM, PPI, PEI and their derivatives) in later generations are rarely used directly in
19
drug delivery systems due to their cytotoxicities55. Dendrimers commonly used in drug
20
delivery are mainly modified in the following three ways: PEGylation; targeting groups,
21
such as folic acid (FA) receptor; and stimuli-sensitive functional groups, such as those 12
ACS Paragon Plus Environment
Page 12 of 35
Page 13 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1
sensitive to pH stimuli. All of these modifications make dendrimers suitable for use as drug
2
carriers, which is reflected in their lower toxicities, reduced immunogenicities, higher
3
biocompatibilities and larger drug-loading capacities.
4
Dendrimers could carry drugs in non-covalent and covalent manners. The non-covalent
5
manner means drugs can be non-covalently encapsulated in the interior void spaces of the
6
dendrimers through electrostatic, hydrophobic or hydrogen bonding interactions.
7
Meanwhile, the covalent manner refers to the covalent conjugation of drugs to the terminal
8
groups of dendrimers (Figure 5). In 1994, Meijer et al. reported that guest molecules such
9
as dyes were captured within the internal cavities of the dendritic boxes when these boxes
10
were constructed in the presence of guest molecules, which was confirmed by nuclear
11
magnetic resonance-relaxation and optical data56. Thereafter, Meijer et al. investigated the
12
multiple monovalent conjugation of dendritic host–guest complexes by X-ray
13
crystallography and molecular dynamics simulations, and the results showed that the guest
14
molecules can bind to the dendrimer in a variety of ways, including hydrogen bonds and
15
acid–base interactions57. After internalization into cells, dendrimer-drug complexes would
16
be digested by lysosomes, and the drug would be released (Figure 5).
17 18
Figure 5. Different ways dendrimers carry drugs and internalization process of
19
dendrimer-drug complex.
20
Simvastatin (SMV) is a specific inhibitor of HMG CoA reductase and an effective 13
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1
cholesterol-lowering drug with few adverse effects and drug interactions58, 59. SMV is
2
generally used in the clinical setting to treat hypercholesterolemia and reduce coronary
3
events through mechanisms of antioxidant, anti-inflammatory and anti-proliferative
4
effects60. However, SMV is a water insoluble drug and has irregular intestinal absorption,
5
which make its oral bioavailability less than 5%54. Therefore, there is the need for a
6
delivery system that not only delivers the drug efficiently but also improves the
7
pharmacokinetic properties of SMV.
8
Kulhari et al. constructed three different PAMAM dendrimer (NH2, OH and PEG)-based
9
SMV nano-complexes for the in vitro enhancement of water solubility and controlled
10
release as well as the in vivo improvement of the oral absorption of SMV54. The
11
pharmacodynamic results showed that the increased percentage of plasma cholesterol was
12
lower with PAMAM dendrimer formulations compared to pure SMV. The reductions in
13
triglyceride and low density lipoprotein levels were also more prominent with the
14
dendrimer-SMV formulations. Moreover, dendrimer-SMV formulations showed better
15
pharmacokinetic performances than a pure SMV suspension, including a higher peak
16
plasma SMV concentration and a longer mean SMV residence time. Furthermore, SMV
17
absorption and elimination rates were significantly reduced, indicating the controlled
18
release of SMV from the dendrimer complexes. Qi et al. found that the formulation
19
composed of SMV and G5-NH2 PAMAM dendrimers could significantly improve the
20
solubility and transepithelial transport of SMV, thereby causing the enhancement of the oral
21
bioavailability. According to the in vitro experiments, an increase in SMV/G5-NH2
22
transport on Caco-2 cells was modulated by the inhibitory effect on P-gp in addition to the
23
intercellular pathway of interrupting occluding-1 and opening the tight junction (TJ)61
24
(Figure 6). Based on these findings, PAMAM dendrimers may be used as potential carriers
25
for SMV delivery to increase its oral bioavailability. Probucol, similar to SMV, has a poor
26
water solubility (only 5 ng/mL in water) and a low oral absorption efficiency
27
(bioavailability only 2-8%)
28
dendrimers63.
62
, which could also be enhanced by being incorporated into
14
ACS Paragon Plus Environment
Page 14 of 35
Page 15 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1 2
Figure 6. Effects of G5-NH2 on SMV water solubility (A), pharmacokinetics parameters
3
(B), transport across the Caco-2 cell monolayers (C) and possible molecular mechanism for
4
its transepithelial transport (D). Reproduced from ref 61. Copyright 2015, with permission
5
from Elsevier.
6
Nifedipine, another drug for the treatment of the CVDs, is a calcium channel blocking
7
drug, which is mainly administered to hypertension and angina patients. The major problem
8
associated with the formulation and effectiveness of nifedipine is that this drug has a poor
9
aqueous solubility, 5-6 µg/mL over a pH range of 4-13, which may account for its low and
10
irregular bioavailability in human bodies64,
65
11
generation (G0–G3) of PAMAM dendrimers with both amine and ester termination could
12
significantly increase the aqueous solubility of nifedipine at a pH of 7, and the
13
ester-terminated dendrimers were more efficient than the amine-terminated ones possessing
14
the same number of surface functional groups66. They concluded that this pH- and surface
15
functional group-dependent increase in the solubility of nifedipine caused by the
16
dendrimers was likely due to changes in the degree of protonation of the dendrimers. In
17
conclusion, PAMAM dendrimers could potentially be a solubilizer for nefidipine to
18
intensify its therapeutic effects in the treatment of CVDs.
. Devarakonda et al. found that early
19
In addition to VEGF and Ang II mentioned in the gene delivery section of this article,
20
adenosine could possibly be another potential target to treat MI. Adenosine is released in 15
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1
large amounts during MI and plays a major role in the mediation of preconditioning and
2
other cardioprotective effects in most animal species including humans67-69. There are four
3
subtypes of adenosine receptors (ARs), but only three of them (A1, A2 and A3 ARs) are
4
functionally expressed in cardiomyocytes70. Researchers found that activation of
5
cardiomyocyte A1 and A3 ARs could effectively reduce infarct size and improve
6
contractile dysfunction in various animal models of I/R injury, and A2 AR agonists exhibit
7
cardioprotective functions via anti-inflammatory effects71.
8
PAMAM dendrimers can serve as biocompatible polymeric nanocarriers for bioactive
9
molecules of interest, such as nucleoside derivatives, which activate a certain type of ARs.
10
Through their attachment to dendrimers, the cardioprotective potencies or effectiveness of
11
these nucleoside ligands of ARs could be greatly improved. Keene et al. constructed a new
12
multivalent dendrimeric conjugate of an AR agonist and investigated the cardioprotective
13
effects of activated A3AR on HL-1 cardiomyocytes72. In this study, they synthesized a
14
conjugate of G5.5 PAMAM dendrimer with a N6-chain-functionalized adenosine agonist.
15
They found that this conjugate non-selectively activated the A3AR, inhibited
16
forskolin-stimulated cAMP formation, and protected HL-1 cells from apoptosis induced by
17
H2O2. Moreover, Chanyshev et al. investigated the effects of the three different conjugates
18
of PAMAM dendrimer and A3 AR agonists, named MRS5216, MRS5246 and MRS5539,
19
on cultured rat primary cardiac cells and isolated hearts73. The results showed that all three
20
conjugates protected ischemic rat cardiomyocytes from hypoxia injury and significantly
21
decreased the infarct size in the isolated rat hearts with improving rates of pressure product,
22
contraction and relaxation. Wan et al. also found that MRS5246 was effective in increasing
23
the recovery of function of isolated mouse hearts after 20 min of ischemia followed by 45
24
min of reperfusion, including a statistically significant improvement in the left ventricular
25
developed pressure (LVDP)74.
26
The unique structure of dendrimers gives them many fascinating advantages, which
27
make dendrimers the most promising drug delivery carriers applied in the prevention and
28
treatment of CVDs. By encapsulating drugs in or conjugating them to dendrimers, the
29
solubilities, biocompatibilities, bioavailabilities and pharmacokinetic profiles of the drugs
30
could be greatly improved, and therefore, they would be more effective and safe in clinical 16
ACS Paragon Plus Environment
Page 16 of 35
Page 17 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1
applications.
2
Recent advances of dendrimers in contrast agents
3
In the past few decades, imaging technology has been rapidly developed and provides
4
physiological and pathological information with high sensitivity and specificity for the
5
diagnosis of diseases75. The main imaging modalities include optical imaging, computed
6
tomography (CT), magnetic resonance (MR), position emission tomography (PET) and
7
single photon emission computed tomography (SPECT). For better and more specific
8
imaging, several requirements are proposed for contrast agents, which generally include a
9
long half-decay time, a relatively low renal toxicity and a high specificity. With the
10
development of nanotechnology, researchers are trying to apply nanoparticles (NPs) as
11
contrast agents76. These NP systems have many advantages over the conventional contrast
12
agents, such as a prolonged blood circulation time, facile surface functionalization, an
13
extended imaging time, the desired biocompatibility and enhanced imaging specificity77.
14
Dendrimers, as a popular nanomaterial, are broadly involved in the design and
15
exploitation of contrast agents. Specifically, literally atom-by-atom modifications on the
16
cores, interiors and surface groups of dendrimers permit rational manipulation of
17
dendrimer-based agents to optimize the physical characteristics, biodistribution,
18
receptor-mediated targeting and controlled release of payload contrast agents.
19
Modifications with targeted elements enable contrast agents to localize preferentially to
20
areas of interest or organs for target-specific imaging as well as excretion pathways that do
21
not interfere with the desired applications. Their unique structural properties allow
22
dendrimers to be used as templates or stabilizers to synthesize dendrimer-entrapped Au
23
NPs8,
24
Simultaneously, the surface periphery of dendrimers can be modified with Gd (III) chelator
25
to form Gd (III) complexes for the subsequent T1 MR imaging of tumors82. Thus, the
26
applications of dendrimers in contrast agents mainly involve combining dendrimers with
27
other contrast agents such as Cu, Ag and Au. These dendrimer-based contrast agent systems
28
were colloidally stable and non-cytotoxic. They also exhibited an extended blood
29
circulation time as well as a relatively short clearance time from organs. They displayed
30
both r1 relaxivity in the MR imaging mode and X-ray attenuation properties in the CT
78, 79
or dendrimer-stabilized Au or Ag NPs80,
81
for CT imaging applications.
17
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1
imaging mode.
2
To recognize cancer cells overexpressing FA receptors by synchrotron X-ray
3
fluorescence analysis, Zhang et al. prepared metal nanoclusters using a dendrimer modified
4
with folic acid (FA)83. They investigated the imaging properties of this dendrimer–folate–
5
copper conjugate in KB cells, and they found that the metal nanoclusters in the dendrimer
6
exhibited excellent folic acid receptor targeting properties. Moreover, Kojima et al. studied
7
the effect of PEGylation and generation on the relaxivity and pharmacokinetics of
8
dendrimer-based MRI contrast agents84, and they found that surface-PEGylated
9
Gd-PAMAM dendrimers had decreased plasma clearance and prolonged retention in the
10
blood pool. Moreover, later generation of dendrimers conjugated with PEG with a shorter
11
chain length led to a higher relaxivity, which might provide some advice for the choice of
12
dendrimers in the design of contrast agents.
13
Atherosclerosis (AS), a chronic inflammatory vascular disease, is a high-risk factor for
14
myocardial infarction and cerebrovascular events. Apart from drug therapy, researchers
15
increasingly realize the importance of molecular imaging in monitoring the progression of
16
AS, which can facilitate the diagnosis of AS and improve the management of patients85.
17
Macrophage accumulation and the ingestion of lipids into foam cells are substantially
18
important hallmarks in the pathogenesis of AS86. Thus, imaging systems detecting and
19
quantifying macrophage accumulation will provide diagnostic and prognostic information
20
for atherosclerotic plaque.
21
Macrophages piled in an AS lesion always express many biomarkers, such as p32
22
protein87, which could be a potential target for the non-invasive identification of AS
23
progression. Recently, Hamzah et al. demonstrated that LyP-1 was a promising peptide for
24
targeting p32, which is over-expressed on plaque-associated macrophages88, but the
25
inadequacy of this study was that the binding affinity of LyP-1 was relatively low in the
26
aorta. To improve the accumulation efficacy of LyP-1 targeting on AS, Seo et al. designed
27
and synthesized a dendrimer with multiple LyP-1 ligands on a solid phase using lysine as
28
a core structural element89, which was named as (LyP-1)4-dendrimer-64Cu. Then, the
29
(LyP-1)4-dendrimer-64Cu was intravenously injected into ApoE-/- atherosclerotic mice.
30
After two hours of circulation, PET-CT co-registered images demonstrated a greater 18
ACS Paragon Plus Environment
Page 18 of 35
Page 19 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1
uptake of the (LyP-1)4-dendrimer-64Cu than the (ARAL)4-dendrimer-64Cu, where ARAL is
2
another type of peptide like LyP-1 except for the ability to bind to p32 in the aortic root
3
and descending aorta. Ex vivo images and biodistribution acquired at three hours after
4
injection also demonstrate a significantly higher uptake of the (LyP-1)4-dendrimer-64Cu in
5
the aorta. Similarly, the subcutaneous injection of LyP-1 dendrimeric carriers resulted in
6
preferential accumulation in plaque-containing regions over 24 h. Taken together, these
7
results suggested that the (LyP-1)4-dendrimer can be applied as a nanocarrier of contrast
8
media for the in vivo PET imaging of plaque and that LyP-1 could be further exploited for
9
the delivery of therapeutics with other multivalent carriers or NPs. Given that
10
macrophages play an important role in development and progression of the major types of
11
CVDs90, we can apply this targeted imaging system to other types of CVDs (Figure 7).
12 13
Figure 7. Dendrimer based targeting contrast agents to recognize the activated
14
macrophages in AS.
15
In brief, dendrimer-based contrast agents are desirable components for molecular
16
imaging contrast media due to their ability to deliver an imaging payload with target
17
specificity. In the future, it would be expected that a greater number of and better imaging
18
agents other than metals could conjugate to dendrimers to obtain better image quality and
19
help diagnose more diseases.
20
Dendrimers as potential drugs
21
Over the past few years, dendrimers have been found to be bioactive and can be used as 19
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 20 of 35
1
potential drugs in diverse medical fields. Karolczaka et al. found that G4 PAMAM
2
dendrimers could reduce hyperglycemia and restore impaired blood brain barrier (BBB) in
3
streptozotocin (STZ) diabetic rats91. They demonstrated, for the first time, that G4 PAMAM
4
protected the BBB against diabetes-induced functional disturbances. Although this research
5
focused on diabetes, it might provide useful ideas and methods for the application of
6
PAMAM dendrimers in restoring impaired BBB permeability in strokes, a type of CVD
7
and the third leading cause of death and disability in developed countries92. Labieniec et al.
8
assessed the effects of G4 PAMAM on the heart and liver mitochondria in diabetic rats93.
9
They investigated the liver, myocardium and plasma of diabetic rats treated with G4
10
PAMAM by using statistical scale biochemical parameters including creatinine, CoQ9,
11
CoQ10, albumin, urea, total cholesterol, HbA1 and tocopherol. The results showed that G4
12
PAMAM alleviated long-term markers of hyperglycemia and reduced blood and tissue
13
lipophilic antioxidants in diabetic rats but did not restore heart or liver mitochondrial
14
function. This series of research on diabetes gives us many clues about dendrimers as drug
15
or gene delivery carriers in hyperglycemia and diabetes therapy.
16
Dendrimers have been reported to have anti-inflammatory activities. Tomalia, who
17
reported the synthesis of PAMAM dendrimers for the first time, unexpectedly found
18
unmodified PAMAM dendrimers bearing simple surface functional groups (e.g., -NH2 and
19
-OH) had in vivo anti-inflammatory activities on three different inflammatory disease
20
models, which were the carrageenan-induced paw edema model, cotton pellet granuloma
21
model and adjuvant-induced arthritis model94. Myriam et al. used two different
22
experimental arthritis models, IL-1ra−/− mice and mice that had undergone K/BxN serum
23
transfer, to assess the therapeutic potentials of azabisphosphonate (ABP)–capped
24
dendrimers in the treatment of rheumatoid arthritis (RA)95. The results showed that
25
dendrimer
26
anti-inflammatory activation to attenuate RA severity, reduced the levels of inflammatory
27
cytokines, and protected cartilage and bone from destruction and erosion. Marchand et al.
28
also found that non-symmetrical azadiphosphonate-capped dendrimers with various
29
substituents on their nitrogen atoms (methyl, allyl or butyl) were able to activate human
30
monocytes in the short term96, which agrees well with the studies on dendrimer ABP95.
ABP
selectively
targeted
monocytes
and
20
ACS Paragon Plus Environment
directed
them
toward
Page 21 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1
Tang et al. investigated the anti-inflammatory effects of two types of PAMAMs including
2
G4.5-COOH and G5-OH on pancreas injury in a caerulein-induced acute pancreatitis (AP)
3
mouse model. They showed that both dendrimers significantly ameliorated the severity of
4
pancreas injury through downregulating the expression of pro-inflammatory cytokines97.
5
Furthermore, Dai et al. found that the G4 PAMAM dendrimers (with no targeting ligands)
6
had an unusual neuroinflammation targeting ability and could localize in activated
7
microglia and astrocytes (cells responsible for neuroinflammation) in a rabbit cerebral
8
palsy model, which supplied useful strategies for the targeted delivery of therapeutics in
9
disorders such as cerebral palsy and other inflammatory cerebral diseases98. Although the
10
above findings on the anti-inflammatory activity of dendrimers were confirmed in various
11
diseases other than CVDs, they may still be used against CVD inflammatory diseases such
12
as AS.
13
Not only do the dendrimers themselves have attractive biomedical activities, but their
14
derivatives also present some types of bioactivities. Esteban et al.99 synthesized two types
15
of G4 PAMAM dendrimer derivatives, G4-arginine-Tos (Tos = tocopherol succinate) and
16
G4-lysine-Cbz (Cbz = carbamazepine), and evaluated their effects on interactions with
17
serum metabolites, the viability of red blood cells and antithrombotic properties. They
18
found that both of the derivatives acted as potent inhibitors of platelet aggregation induced
19
by adenosine diphosphate (ADP). G4-arginine-Tos also showed inhibition of platelet
20
aggregation induced by collagen, thrombin receptor-activated peptide (TRAP-6) and
21
arachidonic acid. Moreover, G4-arginine-Tos presented the inhibition of platelet secretion
22
and thrombus formation under flow conditions. Therefore, G4-arginine-Tos derivatives
23
could be hopefully used as a potential antithrombotic drugs in the future. In other research,
24
Lee et al.100 reported two antioxidant dendrimers with surfaces rich in multiple phenolic
25
hydroxyl groups and benzylic hydrogens, which contributed to their potent free
26
radical-quenching properties. The biggest advantage of these two derivatives was that they
27
could minimize the pro-oxidant effects, which were the common problem of antioxidants.
28
To their delight, these two dendrimers exhibited potent radical scavenging properties.
29
Moreover, they also protected low-density lipoproteins, lysozymes and DNA from free
30
radical damage. 21
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 22 of 35
1
The reason why dendrimers can be potential drugs may be due to their multiple
2
peripheral functional groups, especially at the cationic terminals101. For example,
3
Karolczak et al. thought that the hypoglycemic effect of PAMAM dendrimers in diabetes
4
was due to the modification of their surface free amino groups with excessive glucose
5
moieties91, which resulted in the reduction of the plasma glucose level and then attenuated
6
the impaired BBB permeability. More mechanisms behind the fascinating bioactivities of
7
dendrimers need to be discovered in the future. Of course, the in vivo applications of
8
dendrimers as potential drugs should be safe and biocompatible. Therefore, the
9
pharmacokinetic features and distributions of dendrimers in the human body after a long
10
continuous repetitive application need to be explored in detail102.
11
Table 1. Application lists of dendrimers and their derivatives as potential new drugs
Dendrimers
Bioactive effects
G4 PAMAM
hypoglycemic effect; restore the
streptozotocin(STZ)
multiple peripheral functional groups,
impaired BBB
diabetic rats
especially the cationic terminals of dendrimers
alleviation of long-term diabetic
streptozotocin(STZ)
markers; decrease of blood and
diabetic rats
G4 PAMAM
Animal models
Mechanism
Reference 91
93
—
tissue lipophilic antioxidants G4 PAMAM
anti-inflammatory activity
(-NH2, -OH)
paw edema model, cotton pellet
the nature of the dendrimer surface functional
granuloma model and arthritis
groups; inhibitory effects on the nitric oxide
model
production
94
(ABP)–capped
anti-inflammatory activity;
arthritis models: IL-1ra−/− mice
selectively target to monocytes and direct them
dendrimer
anti-osteoclastic activity
and mice undergone K/BxN
toward anti-inflammatory activation;
serum transfer
increase amounts of anti-inflammatory
95
cytokines G4 PAMAM
neuroinflammation targeting in
a rabbit cerebral palsy model
activated microglia and astrocytes
Dendrimers are taken up by the activated microglial
G4.5-COOH
protective effects against acute
caerulein-induced
and G5-OH
pancreatitis
model
AP
mouse
and
the
98
pro-inflammatory
97
astrocytes
in
periventricular regions decrease
PAMAM
cells
cytokines;
expression
of
inhibition
of
the
nuclear
translocation of NF-κB in macrophages G4-Arginine-To
potent inhibitors of platelet
platelet aggregation induced by
s
aggregation; inhibition of platelet
ADP, collagen, TRAP-6 and
secretion and thrombus formation
arachidonic acid
potent inhibitors of platelet
platelet aggregation induced by
aggregation
ADP
G4-Lysine-Cbz
surface-modifie
potent free radical-quenching
d dendrimers
property; minimize the
—
pro-oxidant effects 22
ACS Paragon Plus Environment
—
99
—
99
—
100
Page 23 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
1 2
Conclusions and Future Perspectives
3
In the past few decades, dendrimers have played important roles as gene and drug
4
delivery carriers applied in the treatment of CVDs, especially in MI. Dendrimers can also
5
be used in diagnostic imaging by conjugating with other imaging agents, which is
6
meaningful for the early detection and prevention of CVDs. In addition to the traditional
7
use of dendrimers as scaffolds for drugs and genes, their own bioactivities are attracting
8
increasing attention in diverse fields, including in the treatment of CVDs. Dendrimers show
9
great potential in the application of CVD prevention and treatment as well as in other
10
realms of human diseases in the future.
11
The application of dendrimers in clinical treatment still faces great challenges. The key
12
problem is that the long-term pharmacokinetics and biodistribution of dendrimers in human
13
bodies are not very clear; thus the safety, biocompatibility and biodegradation of
14
dendrimers in human bodies still remain to be explored for their bioapplication. Moreover,
15
dendrimers could be conjugated with other targeting molecules such as antibodies to
16
improve their targeting ability and delivery efficiency, but the heterogeneity introduced by
17
the attachment of functional ligands to dendrimers should be emphasized and solved in
18
future research. Other delivery systems, such as viruses, liposomes and polymers, can be
19
combined with dendrimers to form multi-functional and multi-target delivery systems,
20
which could dramatically increase the delivery efficiency. However, their safety and
21
biocompatibility should also be carefully considered. Still, to our delight, more efforts from
22
researchers are directed at modifying and perfecting dendrimers for their clinical
23
applications. We would expect dendrimers to have a bright future not only in the diagnosis
24
and treatment of CVDs but also in other medical applications, thus bringing tremendous
25
benefits to patients and disease management.
26
Conflict of Interest:
27 28 29 30
We declare that we have no conflict of interest. Acknowledgement: We thank the National Natural Science Foundation of China (No. 81270368,81360054) for financial support. 23
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Reference 1.
Tomalia DA, Baker H, Dewald J, A new class of polymers: starburst-dendritic
macromolecules. Polym. J. 1985, 17, 117-32. 2.
Tomalia DA, Birth of a new macromolecular architecture: dendrimers as quantized
building blocks for nanoscale synthetic polymer chemistry. Prog Polym Sci 2005, 30, 294-324. 3.
Janga Woo-Dong, Kamruzzaman Selimb KM, Leea Chi-Hwa, Kang Inn-Kyu,
Bioinspired application of dendrimers: From bio-mimicry to biomedical applications. Prog Polym Sci 2009, 34, 1-23. 4.
Caminade AM, Laurent R, Majoral JP, Characterization of dendrimers. Adv Drug Deliv
Rev 2005, 57, 2130-2146. 5. Singh I, Rehni AK, Kalra R, Joshi G, Kumar M, Dendrimers and their pharmaceutical applications--a review. Pharmazie 2008, 63, (7), 491-6. 6. Gao, Y.; Gao, G.; He, Y.; Liu, T.; Qi, R., Recent advances of dendrimers in delivery of genes and drugs. Mini Rev Med Chem 2008, 8, (9), 889-900. 7. Haensler J, Szoka FC Jr., Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug Chem 1993, 4, (5), 372-379. 8. Peng, C.; Zheng, L.; Chen, Q.; Shen, M.; Guo, R.; Wang, H.; Cao, X.; Zhang, G.; Shi, X., PEGylated dendrimer-entrapped gold nanoparticles for in vivo blood pool and tumor imaging by computed tomography. Biomaterials 2012, 33, (4), 1107-19. 9. Yao W, Sun K, Mu H, Liang N, Liu Y, Yao C, Liang R, Wang A, Preparation and characterization of puerarin-dendrimer complexes as an ocular drug delivery system. Drug Dev Ind Pharm 2010, 36, (9), 1027-35. 10. Sadekar S, Ghandehari H, Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery. Adv Drug Deliv Rev 2012, 64, (6), 571-88. 11. Wen, S.; Li, K.; Cai, H.; Chen, Q.; Shen, M.; Huang, Y.; Peng, C.; Hou, W.; Zhu, M.; Zhang, G.; Shi, X., Multifunctional dendrimer-entrapped gold nanoparticles for dual mode CT/MR imaging applications. Biomaterials 2013, 34, (5), 1570-80. 12. Lee CC, MacKay JA, Fréchet JM, Szoka FC, Designing dendrimers for biological applications. Nat Biotechnol 2005, 23, (12), 1517-26. 24
ACS Paragon Plus Environment
Page 24 of 35
Page 25 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
13. Roglin, L.; Lempens, E. H.; Meijer, E. W., A synthetic "tour de force": well-defined multivalent and multimodal dendritic structures for biomedical applications. Angew Chem 2011, 50, (1), 102-12. 14. van der Meel, R.; Vehmeijer, L. J.; Kok, R. J.; Storm, G.; van Gaal, E. V., Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status. Adv Drug Deliv Rev 2013, 65, (10), 1284-98. 15. Parat A, Bordeianu C, Dib H, Garofalo A, Walter A, Bégin-Colin S, Felder-Flesch D. Dendrimer-nanoparticle conjugates in nanomedicine. Nanomedicine (Lond) 2015,10(6), 977-92. 16. van Dongen, M. A.; Dougherty, C. A.; Banaszak Holl, M. M., Multivalent polymers for drug delivery and imaging: the challenges of conjugation. Biomacromolecules 2014, 15, (9), 3215-34. 17. Mullen, D. G.; Fang, M.; Desai, A.; Baker, J. R.; Orr, B. G.; Banaszak Holl, M. M., A quantitative assessment of nanoparticle-ligand distributions: implications for targeted drug and imaging delivery in dendrimer conjugates. ACS nano 2010, 4, (2), 657-70. 18. Mullen, D. G.; Banaszak Holl, M. M., Heterogeneous ligand-nanoparticle distributions: a major obstacle to scientific understanding and commercial translation. Acc Chem Res 2011, 44, (11), 1135-45. 19. Liu, J.; Gu, C.; Cabigas, E. B.; Pendergrass, K. D.; Brown, M. E.; Luo, Y.; Davis, M. E., Functionalized dendrimer-based delivery of angiotensin type 1 receptor siRNA for preserving cardiac function following infarction. Biomaterials 2013, 34, (14), 3729-36. 20. Wu, J.; Huang, W.; He, Z., Dendrimers as carriers for siRNA delivery and gene silencing: a review. Scientific World Journal 2013, 2013, 630-54. 21. Go, A. S.; Mozaffarian, D.; Roger, V. L.; Benjamin, E. J.; Berry, J. D.; Borden, W. B.; Bravata, D. M.; Dai, S.; Ford, E. S.; Fox, C. S.; Franco, S.; Fullerton, H. J.; Gillespie, C.; Hailpern, S. M.; Heit, J. A.; Howard, V. J.; Huffman, M. D.; Kissela, B. M.; Kittner, S. J.; Lackland, D. T.; Lichtman, J. H.; Lisabeth, L. D.; Magid, D.; Marcus, G. M.; Marelli, A.; Matchar, D. B.; McGuire, D. K.; Mohler, E. R.; Moy, C. S.; Mussolino, M. E.; Nichol, G.; Paynter, N. P.; Schreiner, P. J.; Sorlie, P. D.; Stein, J.; Turan, T. N.; Virani, S. S.; Wong, N. D.; Woo, D.; Turner, M. B.; American Heart Association Statistics, C.; Stroke Statistics, S., Heart 25
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 26 of 35
disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation 2013, 127, (1), e6-e245. 22. Garza, M. A.; Wason, E. A.; Zhang, J. Q., Cardiac remodeling and physical training post myocardial infarction. World J Cardiol 2015, 7, (2), 52-64. 23. Bull, D. A.; Bailey, S. H.; Rentz, J. J.; Zebrack, J. S.; Lee, M.; Litwin, S. E.; Kim, S. W., Effect of Terplex/VEGF-165 gene therapy on left ventricular function and structure following myocardial infarction. VEGF gene therapy for myocardial infarction. J Control Release 2003, 93, (2), 175-81. 24. Melly LF, Marsano A, Frobert A, Boccardo S, Helmrich U, Heberer M, Eckstein FS, Carrel TP, Giraud MN, Tevaearai HT, Banfi A. Controlled angiogenesis in the heart by cell-based expression of specific vascular endothelial growth factor levels. Hum Gene Ther Methods 2012, 23,346-56. 25. Hye Yeong Nama, K. N., Minhyung Leeb, Sung Wan Kima, David A. Bullc, Dendrimer type bio-reducible polymer for efficient gene delivery. J Control Release 2012, 160, (3), 592-600. 26. Yockman, J. W.; Choi, D.; Whitten, M. G.; Chang, C. W.; Kastenmeier, A.; Erickson, H.; Albanil, A.; Lee, M.; Kim, S. W.; Bull, D. A., Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct. Gene Ther 2009, 16, (1), 127-35. 27. Won, Y. W.; McGinn, A. N.; Lee, M.; Nam, K.; Bull, D. A.; Kim, S. W., Post-translational regulation of a hypoxia-responsive VEGF plasmid for the treatment of myocardial ischemia. Biomaterials 2013, 34, (26), 6229-38. 28. Wu, D.; Liu, Y.; Jiang, X.; Chen, L.; He, C.; Goh, S. H.; Leong, K. W., Evaluation of hyperbranched poly(amino ester)s of amine constitutions similar to polyethylenimine for DNA delivery. Biomacromolecules 2005, 6, (6), 3166-73. 29. Zhu, K.; Guo, C.; Xia, Y.; Lai, H.; Yang, W.; Wang, Y.; Song, D.; Wang, C., Transplantation of novel vascular endothelial growth factor gene delivery system manipulated skeletal myoblasts promote myocardial repair. Int J Cardiol 2013, 168, (3), 2622-31. 30.
Paul,
A.;
Shao,
W.;
Abbasi,
S.;
Shum-Tim,
D.;
26
ACS Paragon Plus Environment
Prakash,
S.,
PAMAM
Page 27 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
dendrimer-baculovirus nanocomplex for microencapsulated adipose stem cell-gene therapy: in vitro and in vivo functional assessment. Mol Pharm 2012, 9, (9), 2479-88. 31. Hong SH, Park SJ, Lee S, Cho CS, Cho MH, Aerosol gene delivery using viral vectors and cationic carriers for in vivo lung cancer therapy. Expert Opin Drug Deliv 2015, 12, (6), 977-91. 32. Mok H, Park JW, Park TG, Microencapsulation of PEGylated adenovirus within PLGA microspheres for enhanced stability and gene transfection efficiency. Pharm Res 2007, 24, (12), 2263-9. 33. Sung LY, Chen CL, Lin SY, Li KC, Yeh CL, Chen GY, Lin CY, Hu YC, Efficient gene delivery into cell lines and stem cells using baculovirus. Nat Protoc 2014, 9, (8), 1882-99. 34. Menown IB. Contemporary management of coronary heart disease. J R Coll Physicians Edinb 2010, 40, 44-7. 35. Dzau, V. J.; Antman, E. M.; Black, H. R.; Hayes, D. L.; Manson, J. E.; Plutzky, J.; Popma, J. J.; Stevenson, W., The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part I: Pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation 2006, 114, (25), 2850-70. 36. Probstfield, J. L.; O'Brien, K. D., Progression of cardiovascular damage: the role of renin-angiotensin system blockade. Am J Cardiol 2010, 105, (1 Suppl), 10A-20A. 37. Ferrario, C. M.; Strawn, W. B., Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 2006, 98, (1), 121-8. 38. Xu J, Sun Y, Carretero OA, Zhu L, Harding P, Shesely EG, Dai X, Rhaleb NE, Peterson E, Yang XP,
Effects of cardiac overexpression of the angiotensin II type 2 receptor on
remodeling and dysfunction in mice post-myocardial infarction. Hypertension 2014, 63, (6), 1251-9. 39. Theoharis, S.; Krueger, U.; Tan, P. H.; Haskard, D. O.; Weber, M.; George, A. J., Targeting gene delivery to activated vascular endothelium using anti E/P-Selectin antibody linked to PAMAM dendrimers. J Immunol Methods 2009, 343, (2), 79-90. 40. Li Y1, Zeng X, Wang S, Sun Y, Wang Z, Fan J, Song P, Ju D. Inhibition of autophagy protects against PAMAM dendrimers-induced hepatotoxicity. Nanotoxicology 2015, 9, 344-55. 27
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
41. Wu LP, Ficker M, Christensen JB, Trohopoulos PN, Moghimi SM. Dendrimers in Medicine: Therapeutic Concepts and Pharmaceutical Challenges. Bioconjug Chem 2015, 26(7), 1198-211. 42. Qi, R.; Gao, Y.; Tang, Y.; He, R. R.; Liu, T. L.; He, Y.; Sun, S.; Li, B. Y.; Li, Y. B.; Liu, G., PEG-conjugated PAMAM dendrimers mediate efficient intramuscular gene expression. AAPS J 2009, 11, (3), 395-405. 43. Tang, Y.; Li, Y. B.; Wang, B.; Lin, R. Y.; van Dongen, M.; Zurcher, D. M.; Gu, X. Y.; Banaszak Holl, M. M.; Liu, G.; Qi, R., Efficient in vitro siRNA delivery and intramuscular gene silencing using PEG-modified PAMAM dendrimers. Mol Pharm 2012, 9, (6), 1812-21. 44. Albertazzi, L.; Serresi, M.; Albanese, A.; Beltram, F., Dendrimer internalization and intracellular trafficking in living cells. Mol Pharm 2010, 7, (3), 680-8. 45. Qi, R.; Mullen, D. G.; Baker, J. R.; Holl, M. M., The mechanism of polyplex internalization into cells: testing the GM1/caveolin-1 lipid raft mediated endocytosis pathway. Mol Pharm 2010, 7, (1), 267-79. 46. Fichter, K. M.; Ingle, N. P.; McLendon, P. M.; Reineke, T. M., Polymeric nucleic acid vehicles exploit active interorganelle trafficking mechanisms. ACS nano 2013, 7, (1), 347-64. 47. Reilly, M. J.; Larsen, J. D.; Sullivan, M. O., Polyplexes traffic through caveolae to the Golgi and endoplasmic reticulum en route to the nucleus. Mol Pharm 2012, 9, (5), 1280-90. 48. Dominska, M.; Dykxhoorn, D. M., Breaking down the barriers: siRNA delivery and endosome escape. J Cell Sci 2010, 123, (Pt 8), 1183-9. 49. van der Aa, M. A.; Huth, U. S.; Hafele, S. Y.; Schubert, R.; Oosting, R. S.; Mastrobattista, E.; Hennink, W. E.; Peschka-Suss, R.; Koning, G. A.; Crommelin, D. J., Cellular uptake of cationic polymer-DNA complexes via caveolae plays a pivotal role in gene transfection in COS-7 cells. Phar Res 2007, 24, (8), 1590-8. 50. Khalil, I. A.; Kogure, K.; Akita, H.; Harashima, H., Uptake pathways and subsequent intracellular trafficking in nonviral gene delivery. Phar Rev 2006, 58, (1), 32-45. 51. Zia ur Rehman, Dick Hoekstra,Inge S. Zuhorn, Mechanism of Polyplex- and Lipoplex-Mediated Delivery of Nucleic Acids: Real-Time Visualization of Transient Membrane Destabilization without Endosomal Lysis. ACS nano 2013, 7, (5), 3767-3777. 52. Grandinetti, G.; Smith, A. E.; Reineke, T. M., Membrane and nuclear permeabilization by 28
ACS Paragon Plus Environment
Page 28 of 35
Page 29 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
polymeric pDNA vehicles: efficient method for gene delivery or mechanism of cytotoxicity? Mol Pharm 2012, 9, (3), 523-38. 53. Shen, W.; van Dongen, M. A.; Han, Y.; Yu, M.; Li, Y.; Liu, G.; BanaszakHoll, M. M.; Qi, R., The role of caveolin-1 and syndecan-4 in the internalization of PEGylated PAMAM dendrimer polyplexes into myoblast and hepatic cells. Eur J Pharm Biopharm 2014, 88, (3), 658-63. 54. Kulhari, H.; Kulhari, D. P.; Prajapati, S. K.; Chauhan, A. S., Pharmacokinetic and pharmacodynamic studies of poly(amidoamine) dendrimer based simvastatin oral formulations for the treatment of hypercholesterolemia. Mol Pharm 2013, 10, (7), 2528-33. 55. Jevprasesphant R, Penny J, Jalal R, Attwood D, McKeown NB, D'Emanuele A, The influence of surface modification on the cytotoxicity of PAMAM dendrimers. Int J Pharm 2003, 252, (1-2), 263-6. 56. Jansen, J. F.; de Brabander-van den Berg, E. M.; Meijer, E. W., Encapsulation of guest molecules into a dendritic box. Science 1994, 266, (5188), 1226-9. 57. Chang, T.; Pieterse, K.; Broeren, M. A.; Kooijman, H.; Spek, A. L.; Hilbers, P. A.; Meijer, E. W., Structural elucidation of dendritic host-guest complexes by X-ray crystallography and molecular dynamics simulations. Chemistry 2007, 13, (28), 7883-9. 58. Kolovou GD, Katerina A, Ioannis V, Cokkinos DV. Simvastatin: two decades in a circle. Cardiovasc Ther 2008, 26(2), 166-78. 59. Rohilla A, Ahmad A, Khan MU, Khanam R. A comparative study on the cardioprotective potential of atorvastatin and simvastatin in hyperhomocysteinemic rat hearts. Eur J Pharmacol 2015, 764, 48-54. 60. Bonetti, P. O.; Lerman, L. O.; Napoli, C.; Lerman, A., Statin effects beyond lipid lowering--are they clinically relevant? Eur Heart J 2003, 24, (3), 225-48. 61. Qi, R.; Zhang, H.; Xu, L.; Shen, W.; Chen, C.; Wang, C.; Cao, Y.; Wang, Y.; van Dongen, M. A.; He, B.; Wang, S.; Liu, G.; Banaszak Holl, M. M.; Zhang, Q., G5 PAMAM dendrimer versus liposome: A comparison study on the in vitro transepithelial transport and in vivo oral absorption of simvastatin. Nanomedicine 2015, 11, (5), 1141-51. 62. Betge, S.; Lutz, K.; Roskos, M.; Figulla, H. R., Oral treatment with probucol in a pharmacological dose has no beneficial effects on mortality in chronic ischemic heart failure 29
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
after large myocardial infarction in rats. Eur J Pharmacol 2007, 558, (1-3), 119-27. 63. Ma, Q.; Han, Y.; Chen, C.; Cao, Y.; Wang, S.; Shen, W.; Zhang, H.; Li, Y.; van Dongen, M. A.; He, B.; Yu, M.; Xu, L.; Banaszak Holl, M. M.; Liu, G.; Zhang, Q.; Qi, R., Oral Absorption Enhancement of Probucol by PEGylated G5 PAMAM Dendrimer Modified Nanoliposomes. Mol Pharm 2015, 12, (3), 665-74. 64. Boje, K. M.; Sak, M.; Fung, H. L., Complexation of nifedipine with substituted phenolic ligands. Phar Res 1988, 5, (10), 655-9. 65. Emara, L. H.; Badr, R. M.; Elbary, A. A., Improving the dissolution and bioavailability of nifedipine using solid dispersions and solubilizers. Drug Dev Ind Pharm 2002, 28, (7), 795-807. 66. Devarakonda, B.; Hill, R. A.; de Villiers, M. M., The effect of PAMAM dendrimer generation size and surface functional group on the aqueous solubility of nifedipine. Int J Pharm 2004, 284, (1-2), 133-40. 67. Jacobson KA, Gao ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 2006, (3), 247-64. 68. Mubagwa, K.; Flameng, W., Adenosine, adenosine receptors and myocardial protection: an updated overview. Cardiovasc Res 2001, 52, (1), 25-39. 69. Cohen, M. V.; Downey, J. M., Adenosine: trigger and mediator of cardioprotection. Basic Res Cardiol 2008, 103, (3), 203-15. 70. Sachdeva S, Gupta M, Adenosine and its receptors as therapeutic targets: An overview. Saudi Pharm J 2013, 21, (3), 245-53. 71. Patel, R. A.; Glover, D. K.; Broisat, A.; Kabul, H. K.; Ruiz, M.; Goodman, N. C.; Kramer, C. M.; Meerdink, D. J.; Linden, J.; Beller, G. A., Reduction in myocardial infarct size at 48 hours after brief intravenous infusion of ATL-146e, a highly selective adenosine A2A receptor agonist. Am J Physiol Heart Circ Physiol 2009, 297, (2), H637-42. 72. Keene, A. M.; Balasubramanian, R.; Lloyd, J.; Shainberg, A.; Jacobson, K. A., Multivalent dendrimeric and monomeric adenosine agonists attenuate cell death in HL-1 mouse cardiomyocytes expressing the A(3) receptor. Biochem Pharmacol 2010, 80, (2), 188-96. 73. Chanyshev, B.; Shainberg, A.; Isak, A.; Litinsky, A.; Chepurko, Y.; Tosh, D. K.; Phan, K.; 30
ACS Paragon Plus Environment
Page 30 of 35
Page 31 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
Gao, Z. G.; Hochhauser, E.; Jacobson, K. A., Anti-ischemic effects of multivalent dendrimeric A(3) adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart. Pharmacol Res 2012, 65, (3), 338-46. 74. Wan, T. C.; Tosh, D. K.; Du, L.; Gizewski, E. T.; Jacobson, K. A.; Auchampach, J. A., Polyamidoamine (PAMAM) dendrimer conjugate specifically activates the A3 adenosine receptor to improve post-ischemic/reperfusion function in isolated mouse hearts. BMC Pharmacol 2011, 11, 11. 75. Schindler, T. H.; Schelbert, H. R.; Quercioli, A.; Dilsizian, V., Cardiac PET imaging for the detection and monitoring of coronary artery disease and microvascular health. JACC Cardiovasc Imaging 2010, 3, (6), 623-40. 76. Baptista, P.; Pereira, E.; Eaton, P.; Doria, G.; Miranda, A.; Gomes, I.; Quaresma, P.; Franco, R., Gold nanoparticles for the development of clinical diagnosis methods. Anal Bioanal Chem 2008, 391, (3), 943-50. 77. Liu, Y.; Miyoshi, H.; Nakamura, M., Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles. Int J Cancer 2007, 120, (12), 2527-37. 78. Wang, H.; Zheng, L.; Peng, C.; Guo, R.; Shen, M.; Shi, X.; Zhang, G., Computed tomography imaging of cancer cells using acetylated dendrimer-entrapped gold nanoparticles. Biomaterials 2011, 32, (11), 2979-88. 79. Wang, H.; Zheng, L.; Guo, R.; Peng, C.; Shen, M.; Shi, X.; Zhang, G., Dendrimer-entrapped gold nanoparticles as potential CT contrast agents for blood pool imaging. Nanoscale Res Lett 2012, 7, 190. 80. Liu, H.; Shen, M.; Zhao, J.; Guo, R.; Cao, X.; Zhang, G.; Shi, X., Tunable synthesis and acetylation of dendrimer-entrapped or dendrimer-stabilized gold-silver alloy nanoparticles. Colloids Surf B Biointerfaces 2012, 94, 58-67. 81. Liu H, W. H., Guo R, Cao XY, Zhao JL, Luo Y,, Size-controlled synthesis of dendrimer-stabilized silver nanoparticles for X-ray computed tomography imaging applications. Poly Chem 2010, 1, 1677-83. 82. Swanson, S. D.; Kukowska-Latallo, J. F.; Patri, A. K.; Chen, C.; Ge, S.; Cao, Z.; Kotlyar, A.; East, A. T.; Baker, J. R., Targeted gadolinium-loaded dendrimer nanoparticles for 31
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 32 of 35
tumor-specific magnetic resonance contrast enhancement. Int J Nanomedicine 2008, 3, (2), 201-10. 83. Zhang, Y.; Xu, X.; Wang, L.; Lin, J.; Zhu, Y.; Guo, Z.; Sun, Y.; Wang, H.; Zhao, Y.; Tai, R.; Yu, X.; Fan, C.; Huang, Q., Dendrimer-folate-copper conjugates as bioprobes for synchrotron X-ray fluorescence imaging. Chem Commun(Camb) 2013, 49, (88), 10388-90. 84. Kojima, C.; Turkbey, B.; Ogawa, M.; Bernardo, M.; Regino, C. A.; Bryant, L. H., Jr.; Choyke, P. L.; Kono, K.; Kobayashi, H., Dendrimer-based MRI contrast agents: the effects of PEGylation on relaxivity and pharmacokinetics. Nanomedicine 2011, 7, (6), 1001-8. 85. Owen, D. R.; Lindsay, A. C.; Choudhury, R. P.; Fayad, Z. A., Imaging of atherosclerosis. Annu Rev Med 2011, 62, 25-40. 86. Randolph, G. J., Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res 2014, 114, (11), 1757-71. 87. Fogal, V.; Zhang, L.; Krajewski, S.; Ruoslahti, E., Mitochondrial/cell-surface protein p32/gC1qR as a molecular target in tumor cells and tumor stroma. Cancer Res 2008, 68, (17), 7210-8. 88. Hamzah, J.; Kotamraju, V. R.; Seo, J. W.; Agemy, L.; Fogal, V.; Mahakian, L. M.; Peters, D.; Roth, L.; Gagnon, M. K.; Ferrara, K. W.; Ruoslahti, E., Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 2011, 108, (17), 7154-9. 89. Seo, J. W.; Baek, H.; Mahakian, L. M.; Kusunose, J.; Hamzah, J.; Ruoslahti, E.; Ferrara, K. W., (64)Cu-labeled LyP-1-dendrimer for PET-CT imaging of atherosclerotic plaque. Bioconjug Chem 2014, 25, (2), 231-9. 90. Fernandez-Velasco,
M.;
Gonzalez-Ramos,
S.;
Bosca,
L.,
Involvement
of
monocytes/macrophages as key factors in the development and progression of cardiovascular diseases. Biochem J 2014, 458, (2), 187-93. 91. Karolczak, K.; Rozalska, S.; Wieczorek, M.; Labieniec-Watala, M.; Watala, C., Poly(amido)amine dendrimers generation 4.0 (PAMAM G4) reduce blood hyperglycaemia and restore impaired blood-brain barrier permeability in streptozotocin diabetes in rats. Int J Pharm 2012, 436, (1-2), 508-18. 92. van der Worp, H. B.; van Gijn, J., Clinical practice. Acute ischemic stroke. N Engl J Med 32
ACS Paragon Plus Environment
Page 33 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
2007, 357, (6), 572-9. 93. Labieniec, M.; Ulicna, O.; Vancova, O.; Kucharska, J.; Gabryelak, T.; Watala, C., Effect of poly(amido)amine (PAMAM) G4 dendrimer on heart and liver mitochondria in an animal model of diabetes. Cell Biol Int 2010, 34, (1), 89-97. 94. Chauhan, A. S.; Diwan, P. V.; Jain, N. K.; Tomalia, D. A., Unexpected in vivo anti-inflammatory activity observed for simple, surface functionalized poly(amidoamine) dendrimers. Biomacromolecules 2009, 10, (5), 1195-202. 95. Hayder, M.; Poupot, M.; Baron, M.; Nigon, D.; Turrin, C. O.; Caminade, A. M.; Majoral, J. P.; Eisenberg, R. A.; Fournie, J. J.; Cantagrel, A.; Poupot, R.; Davignon, J. L., A phosphorus-based dendrimer targets inflammation and osteoclastogenesis in experimental arthritis. Sci Transl Med 2011, 3, (81), 81ra35. 96. Marchand, P.; Griffe, L.; Poupot, M.; Turrin, C. O.; Bacquet, G.; Fournie, J. J.; Majoral, J. P.; Poupot, R.; Caminade, A. M., Dendrimers ended by non-symmetrical azadiphosphonate groups: synthesis and immunological properties. Bioorg Med Chem Lett 2009, 19, (14), 3963-6. 97. Tang, Y.; Han, Y.; Liu, L.; Shen, W.; Zhang, H.; Wang, Y.; Cui, X.; Wang, Y.; Liu, G.; Qi, R., Protective effects and mechanisms of G5 PAMAM dendrimers against acute pancreatitis induced by caerulein in mice. Biomacromolecules 2015, 16, (1), 174-82. 98. Dai, H.; Navath, R. S.; Balakrishnan, B.; Guru, B. R.; Mishra, M. K.; Romero, R.; Kannan, R. M.; Kannan, S., Intrinsic targeting of inflammatory cells in the brain by polyamidoamine dendrimers upon subarachnoid administration. Nanomedicine (Lond) 2010, 5, (9), 1317-29. 99. Duran-Lara, E.; Guzman, L.; John, A.; Fuentes, E.; Alarcon, M.; Palomo, I.; Santos, L. S., PAMAM dendrimer derivatives as a potential drug for antithrombotic therapy. Eur J Med Chem 2013, 69, 601-8. 100. Lee, C. Y.; Sharma, A.; Uzarski, R. L.; Cheong, J. E.; Xu, H.; Held, R. A.; Upadhaya, S. K.; Nelson, J. L., Potent antioxidant dendrimers lacking pro-oxidant activity. Free Radic Biol Med 2011, 50, (8), 918-25. 101. Jedrych, M.; Borowska, K.; Galus, R.; Jodlowska-Jedrych, B., The evaluation of the biomedical effectiveness of poly(amido)amine dendrimers generation 4.0 as a drug and as 33
ACS Paragon Plus Environment
Biomacromolecules
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
drug carriers: a systematic review and meta-analysis. Int J Pharm 2014, 462, (1-2), 38-43. 102. Labieniec, M.; Watala, C., Use of poly(amido)amine dendrimers in prevention of early non-enzymatic modifications of biomacromolecules. Biochimie 2010, 92, (10), 1296-305.
34
ACS Paragon Plus Environment
Page 34 of 35
Page 35 of 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Biomacromolecules
126x71mm (600 x 600 DPI)
ACS Paragon Plus Environment