scispace - formally typeset
SciSpace - Your AI assistant to discover and understand research papers | Product Hunt

Journal ArticleDOI

Passive targeting of lipid-based nanoparticles to mouse cardiac ischemia–reperfusion injury

01 Mar 2013-Contrast Media & Molecular Imaging (Contrast Media Mol Imaging)-Vol. 8, Iss: 2, pp 117-126

TL;DR: Owing to their specific accumulation in the infarcted myocardium, lipid-based micelles and liposomes are promising vehicles for (visualization of) drug delivery in myocardial infarction.

AbstractReperfusion therapy is commonly applied after a myocardial infarction. Reperfusion, however, causes secondary damage. An emerging approach for treatment of ischemia-reperfusion (IR) injury involves the delivery of therapeutic nanoparticles to the myocardium to promote cell survival and constructively influence scar formation and myocardial remodeling. The aim of this study was to provide detailed understanding of the in vivo accumulation and distribution kinetics of lipid-based nanoparticles (micelles and liposomes) in a mouse model of acute and chronic IR injury. Both micelles and liposomes contained paramagnetic and fluorescent lipids and could therefore be visualized with magnetic resonance imaging (MRI) and confocal laser scanning microscopy (CLSM). In acute IR injury both types of nanoparticles accumulated massively and specifically in the infarcted myocardium as revealed by MRI and CLSM. Micelles displayed faster accumulation kinetics, probably owing to their smaller size. Liposomes occasionally co-localized with vessels and inflammatory cells. In chronic IR injury only minor accumulation of micelles was observed with MRI. Nevertheless, CLSM revealed specific accumulation of both micelles and liposomes in the infarct area 3 h after administration. Owing to their specific accumulation in the infarcted myocardium, lipid-based micelles and liposomes are promising vehicles for (visualization of) drug delivery in myocardial infarction.

Topics: Liposome (53%)

Summary (2 min read)

1. INTRODUCTION

  • The best treatment option for acute myocardial infarction is currently early reperfusion of the affected myocardium.
  • An emerging approach for further treatment of IR injury involves the delivery of therapeutic compounds to the myocardium to promote cell survival and constructively influence scar formation and myocardial remodeling (6,7).
  • Furthermore, owing to their size, nanoparticles demonstrate prolonged retention in the infarct area, which is enabled by the presence of leaky vasculature (8,9).
  • The authors studied micelles (diameter approximately 15 nm) and liposomes (diameter approximately 100 nm) to investigate influence of nanoparticle size.
  • Furthermore, contrast-enhanced in vivo MRI was complemented with cine MRI to determine cardiac function.

2.1. Nanoparticle Characterization

  • Micelles and liposomes were first characterized with respect to hydrodynamic size and MRI relaxivity properties at 1.41 and 9.4 T (Table 1).
  • Micelle diameter was approximately 15 nm and the liposome diameter of 100 nm was significantly larger.
  • At 1.41 T, the micelle and liposome longitudinal relaxivity (r1) values were higher than those for Gd–DTPA.
  • Thus, the nanoparticles are powerful MRI contrast agents, which is further amplified by the high payload of Gd–DOTA-carrying lipids incorporated in the lipid membranes.
  • The ratio of transversal and longitudinal relaxivities (r2/r1) of both micelles and liposomes was relatively high at 9.4 T, indicating that the nanoparticles will display a pronounced T2 shortening effect at high field strengths.

2.2. Blood Circulation Half-lives and Biodistribution

  • To investigate the blood circulation half-lives and biodistribution, mice were injected with Gd–DTPA, micelles or liposomes and blood samples were obtained up to 48h after administration.
  • Frommono-exponential fits the blood circulation half-lives were calculated (Fig. 1a).
  • Previously, van Bochove et al. observed longer blood circulation half-lives in mice for micelles (22.5 2.8h) and liposomes (7.0 1.0h) containing neutral Gd–DTPA-carrying lipids (20).
  • The large size of liposomes prohibits renal clearance and therefore it is likely that they are removed from the blood by the reticuloendothelial system.
  • Myocardial IR injury resulted in a similar reduction in cardiac function at all investigated time points (Supporting Information, Fig. S1).

2.4. Acute IR Injury – Day 1

  • For both groups the accumulation of Gd–DTPA and paramagnetic nanoparticles was visualized by T1-weighted short-axis multi-slice MRI at day 1 after the IR injury.
  • In contrast to the observations for Gd–DTPA, administration of nanoparticles at day 1 resulted in hyperenhancement of remote cardiac tissue at 0.1h after injection, while the infarct area remained isointense and, therefore, appeared as a dark rim (Fig. 3a).
  • Accumulation was high in the infarct border zones and in the core of the infarcted myocardium.
  • For NIR visualization after staining, this laser intensity was always set to 50%.
  • Liposomes had extravasated after 24 h of circulation and were massively associated with the infarcted myocardium, although the accumulation pattern appeared more scattered compared with micelles.

2.5. Chronic IR Injury – Weeks 1 and 2

  • LGE MRI with Gd–DTPA resulted in hyperenhancement of chronic infarcts at 0.1 h after injection (Fig. 5a, c).
  • Owing to fast washout, Gd–DTPA enhancement was absent at later time points.
  • After short circulation of the nanoparticles (3 h), CLSM revealed diffuse accumulation of micelles in the infarcted myocardium, which sometimes co-localized with inflammatory cells (Figs 6 and 7).

2.6. Implications

  • Micelles and particularly liposomes have extensively been studied and applied as drug carriers, mainly for oncological Figure 6.
  • Autofluorescence is less intense in the infarcted myocardium.
  • All images were obtained after 3h circulation of the nanoparticles.
  • Cardiotoxicity, a well-known side effect of several cytotoxic anti-tumor drugs, for example, doxorubicin, can be diminished by encapsulation of the therapeutics (29,30).
  • Importantly, in their study little to no accumulation of micelles and liposomes was observed in the healthy remote myocardium, indicating specific delivery of the nanoparticles to infarcted myocardium.

3. CONCLUSIONS

  • In this study the extravasation and accumulation properties of paramagnetic micelles and liposomes in mouse myocardial IR injury were studied with MRI and CLSM.
  • Micelles and liposomes accumulated massively and specifically in the acute infarcted myocardium.
  • Micelles displayed faster accumulation kinetics compared with liposomes, presumably owing to their smaller size.
  • Because the nanoparticles generated significant contrast in MRI they are suitable for combined imaging and therapy.
  • Altogether, the authors conclude that the presented lipid-based nanoparticles are promising vehicles for drug targeting purposes in myocardial infarction.

Did you find this useful? Give us your feedback

...read more

Content maybe subject to copyright    Report

PDF hosted at the Radboud Repository of the Radboud University
Nijmegen
The following full text is a publisher's version.
For additional information about this publication click this link.
http://hdl.handle.net/2066/118930
Please be advised that this information was generated on 2022-05-30 and may be subject to
change.

Passive targeting of lipid-based nanoparticles
to mouse cardiac ischemiareperfusion injury
Tessa Geelen, Leonie E. Paulis, Bram F. Coolen, Klaas Nicolay and
Gustav J. Strijkers*
Reperfusion therapy is commonly applied after a myocardial infarction. Reperfusion, however, causes secondary
damage. An emerging approach for treatment of ischemiareperfusion (IR) injury involves the delivery of therapeutic
nanoparticles to the myocardium to promote cell survival and constructively inuence scar formation and myocardial
remodeling. The aim of this study was to provide detailed understanding of the in vivo accumulation and distribution
kinetics of lipid-based nanoparticles (micelles and liposomes) in a mouse model of acute and chronic IR injury. Both
micelles and liposomes contained paramagnetic and uorescent lipids and could therefore be visualized with magnetic
resonance imaging (MRI) and confocal laser scanning microscopy (CLSM). In acute IR injury both types of nanoparticles
accumulated massively and specically in the infarcted myocardium as revealed by MRI and CLSM. Micelles displayed
faster accumulation kinetics, probably owing to their smaller size. Liposomes occasionally co-localized with vessels
and inammatory cells. In chronic IR injury only minor accumulation of micelles was observed with MRI. Nevertheless,
CLSM revealed specic accumulation of both micelles and liposomes in the infarct area 3 h after administration. Owing
to their specic accumulation in the infarcted myocardium, lipid-based micelles and liposomes are promising vehicles
for (visualization of) drug delivery in myocardial infarction. Copyright © 2012 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper
Keywords: liposomes; micelles; myocardial infarction; drug delivery; MRI
1. INTRODUCTION
The best treatment option for acute myocardial infarction is
currently early reperfusion of the affected myocardium. The aim
of restoring blood ow is to limit the extent of myocardial necrosis
and scarring, which are important factors in the development of
systolic heart failure and determine prognosis. The downside
of reperfusion treatment is that it causes adverse secondary
ischemiareperfusion (IR) injury by the generation of cytotoxic
reactive oxygen species, resulting in additional apoptosis (1). After
the initial IR event a dynamic cascade of events is initiated to
promote myocardial infarct healing. In the acute phase, early after
the ischemic event, infarct healing is characterized by cell death
and inammation. At later time points, in the chronic phase, the
affected myocardium remodels into scar tissue (25).
An emerging approach for further treatment of IR injury
involves the delivery of therapeutic compounds to the myocar-
dium to promote cell survival and constructively inuence scar
formation and myocardial remodeling (6,7). The effectiveness
of intravenously injected therapeutics may be hampered by fast
clearance from the blood circulation and by lack of retention in
the infarcted myocardium. To improve drug delivery to the
infarct, nanoparticles offer a suitable vehicle as they can be
designed to display long blood circulation half-lives and are able
to encapsulate a large amount of drug molecules. Furthermore,
owing to their size, nanoparticles demonstrate prolonged
retention in the infarct area, which is enabled by the presence
of leaky vasculature (8,9). Previously, liposomal nanoparticles
were exploited for such purposes. Injection of ATP-, coenzyme
Q10-, PGE
1
- or adenosine-loaded liposomes resulted in a
reduction of the extent of irreversibly damaged myocardium
within the area at risk (1015). Furthermore, accumulation of
pegylated micelles in the infarcted myocardium has been
demonstrated in a rabbit model of myocardial infarction (16).
Therefore, micelles were proposed for delivery of lipophilic drugs
(16,17). The above studies have in common that information on
accumulation kinetics in the heart was lacking and the exact
location of the lipid-based nanoparticles at cellular scale was
not visualized. Obviously, these need to be determined for
optimization of drug delivery. Furthermore, only acute IR injury
(up to 3 h reperfusion time) was considered, which is clinically
less relevant, and therefore later time points after IR injury
should be studied as well.
Therefore, the aim of this study was to provide detailed under-
standing of the in vivo accumulation and distribution kinetics of
long-circulating lipid-based nanoparticles in a mouse model of
acute (1 day old) as well as chronic (up to 2 weeks) myocardial
IR injury. We studied micelles (diameter approximately 15 nm)
and liposomes (diameter approximately 100 nm) to investigate
inuence of nanoparticle size. Both micelles and liposomes were
equipped with paramagnetic Gd-containing lipids and with
uorescent lipids. Importantly, this enabled us to study the
distribution of the nanoparticles in the infarcted myocardium
in vivo using MRI, as well as to localize the nanoparticles at the
* Correspondence to: G. Strijkers, Biomedical NMR, Department of Biomedical
Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB,
Eindhoven, The Netherlands. E-mail: g.j.strijkers@tue.nl
T. Geelen, L.E. Paulis, B.F. Coolen, K. Nicolay, G.J. Strijkers
Biomedical NMR, Department of Biomedical Engineering, Eindhoven University
of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands
Full Paper
Received: 17 May 2012, Revised: 12 July 2012, Accepted: 21 August 2012, Published online in Wiley Online Library:
(wileyonlinelibrary.com) DOI: 10.1002/cmmi.1501
Contrast Media Mol. Imaging 2013, 8 117126 Copyright © 2012 John Wiley & Sons, Ltd.
117

cellular level ex vivo with confocal laser scanning microscopy
(CLSM). As a control late gadolinium enhancement (LGE) MRI
was performed after administration of GdDTPA. Furthermore,
contrast-enhanced in vivo MRI was complemented with cine
MRI to determine cardiac function.
2. RESULTS AND DISCUSSION
2.1. Nanoparticle Characterization
Micelles and liposomes were rst characterized with respect to
hydrodynamic size and MRI relaxivity properties at 1.41 and
9.4 T (Table 1). GdDTPA was included as a reference. Micelle
diameter was approximately 15 nm and the liposome diameter
of 100 nm was signicantly larger. At 1.41 T, the micelle and
liposome longitudinal relaxivity (r
1
) values were higher than
those for GdDTPA. Thus, the nanoparticles are powerful MRI
contrast agents, which is further amplied by the high payload
of GdDOTA-carrying lipids incorporated in the lipid membranes.
As expected, at 9.4 T, r
1
values were considerably lower compared
with 1.41 T (18). Nevertheless, the r
1
of micelles was still higher
than the r
1
of GdDTPA. The ratio of transversal and longitudinal
relaxivities (r
2
/r
1
) of both micelles and liposomes was relatively
high at 9.4 T, indicating that the nanoparticles will display a
pronounced T
2
shortening effect at high eld strengths. From
the relaxivity data we concluded that the nanoparticles possessed
ample sensitivity for in vivo MR imaging of nanoparticle accumula-
tion in cardiac IR injury.
2.2. Blood Circulation Half-lives and Biodistribution
To investigate the blood circulation half-lives and biodistribution,
mice were injected with GdDTPA, micelles or liposomes and
blood samples were obtained up to 48 h after administration.
Blood ΔR
1
values (= 1/T
1,post
1/T
1,pre
) determined at 9.4 T served
as a measure of the concentration of nanoparticles in the circula-
tion (Fig. 1a) (19). From mono-exponential ts the blood circulation
half-lives were calculated (Fig. 1a). As expected, GdDTPA had a
short blood circulation half-life of 0.30 0.05 h owing to fast renal
clearance enabled by its small size. Micelles and liposomes
displayed relatively long blood circulation half-lives of 3.90 0.44
and 2.31 0.40 h, respectively. Previously, van Bochove et al.
observed longer blood circulation half-lives in mice for micelles
(22.5 2.8 h) and liposomes (7.0 1.0 h) containing neutral
GdDTPA-carrying lipids (20). The GdDOTA-conjugated lipids
used in this study have a charge of 1, which could induce faster
blood clearance via ingestion by phagocytic cells (21).
To determine the in vivo fate of micelles and liposomes, animals
were killed 48 h after administration of the nanoparticles. Organs
were excised and the biodistribution was studied with CLSM
(Fig. 1b). Micelles accumulated mainly in the kidney, suggesting
a clearance pathway that partly involved renal elimination.
Liposomes were mainly detected in the spleen and in smaller
amounts in the liver, lungs and kidneys. The large size of liposomes
prohibits renal clearance and therefore it is likely that they are
removed from the blood by the reticuloendothelial system.
2.3. In Vivo MRI
Mice underwent transient occlusion (30 min) of the left anterior
descending (LAD) coronary artery to induce cardiac IR injury.
Contrast-enhanced in vivo MRI was performed at day 1 (acute), or
at week 1 or week 2 (chronic) after IR injury to visualize the
distribution and extravasation kinetics of GdDTPA, micelles and
liposomes. The MRI protocol is depicted schematically in Fig. 2.
Table 1. Characterization of GdDTPA, micelles and liposomes
Hydro-dynamic
diameter (nm)
r
1
(mM
1
s
1
)at
1.41 T, 37
C
r
2
(mM
1
s
1
)at
1.41 T, 37
C
r
2
/r
1
at
1.41 T, 37
C
r
1
(mM
1
s
1
)at
9.4 T, 20
C
r
2
(mM
1
s
1
)at
9.4 T, 20
C
r
2
/r
1
at
9.4 T, 20
C
GdDTPA ND 3.3 0.2 3.7 0.3 1.14 0.01 3.9
a
4.2
a
1.1
a
Micelles 15.6 0.2 29.7 1.4 45.9 1.0 1.55 0.05 6.3 0.3 51.5 2.2 8.1 0.1
Liposomes 100.1 3.6* 14.1 0.7* 22.2 1.0* 1.58 0.01 3.2 0.1* 56.7 3.0 17.9 0.3*
Mean standard error of the mean (n = 3), except:
a
n =1. *p < 0.05 vs micelles.
Figure 1. Blood circulation half-lives and biodistribution. (a) ΔR
1
(=1/T
1,post
1/T
1,pre
) of all blood samples, as measured at 9.4 T, plotted vs time after
injection. Blood circulation half-lives were determined by tting with a mono-exponential decay function (solid lines), leading to the blood circulation
half-lives (t
1/2
) as shown in the table (Mean SD). (b) Biodistribution of nanoparticles in several organs. The red color originates from the near-infrared
(NIR) signal of micelles and liposomes. As a non-uorescent negative control, organs from mice injected with GdDTPA are shown. Scale bar = 100 mm.
T. GEELEN ET AL.
wileyonlinelibrary.com/journal/cmmi Copyright © 2012 John Wiley & Sons, Ltd. Contrast Media Mol. Imaging 2013, 8 117126
118

In addition, cine MRI was performed to determine cardiac
function. Myocardial IR injury resulted in a similar reduction in
cardiac function at all investigated time points (Supporting
Information, Fig. S1). Ejection fractions (EF) were 52 2, 54 3
and 59 4% at day 1, week 1 and week 2, respectively, which
are lower than EF values reported for healthy mice (7080%),
conrming the presence of myocardial infarction (22,23). Relatively
high standard deviations in EF suggested heterogeneous infarct
sizes within groups. Cardiac output (CO) and the left ventricular
mass were signicantly higher at week 1 and week 2 as compared
with day 1, which can be explained by left ventricular remodeling
after IR injury.
2.4. Acute IR Injury Day 1
GdDTPA, micelles or liposomes were injected immediately or at
day 1 after induction of IR injury. For both groups the accumula-
tion of GdDTPA and paramagnetic nanoparticles was visualized
by T
1
-weighted short-axis multi-slice MRI at day 1 after the IR
injury. Injection of GdDTPA at day 1 resulted in immediate
hyperenhancement of the infarcted myocardium (Fig. 3a). The
hyperenhancement slowly disappeared within the next 30 min,
in agreement with the extensively described LGE effect used to
measure infarct size (24). The contrast-to-noise ratio (CNR) of
infarct versus remote tissue at 0.1 h after administration (Fig. 3b)
was signicantly enhanced compared with CNRs pre injection
and at later time points (46.9 3.7, p < 0.05 vs all time points).
No residual contrast enhancement was observed at day 1 when
GdDTPA was injected directly after IR injury and circulated for
24 h. As a negative control for the uorescence microscopy
analysis of hearts from nanoparticle-injected mice, CLSM of mouse
hearts injected with GdDTPA was performed. As expected, no
near-infrared (NIR) autouorescence was observed (Fig. 4).
In contrast to the observations for GdDTPA, administration of
nanoparticles at day 1 resulted in hyperenhancement of remote
cardiac tissue at 0.1 h after injection, while the infarct area
remained isointense and, therefore, appeared as a dark rim (Fig. 3a).
Consequently, the CNR of infarct versus remote tissue at 0.1 h was
negative, amounting to 11.7 1.4 and 9.3 3.1 for micelles
and liposomes, respectively (Fig. 3b). At this early time point after
administration micelles and liposomes were still circulating in the
blood, while accumulation into infarcted myocardium might not
be present yet. We propose that the absence of signal intensity
changes in the infarct reected the impaired perfusion of the
infarct. Often the dark rim of infarct tissue was present in the
subendocardium. Indeed, the subendocardium is most prone
to IR injury as it is located most distal from the coronary
arteries (25,26). These observations suggest that the lipid-based
Figure 2. In vivo MRI protocol. T
1
-weighted scans were acquired in all sessions to investigate accumulation of GdDTPA, micelles or liposomes in
myocardial tissue up to 48 h after injection. During the last imaging session of a series cine MRI scans were recorded as well, to evaluate cardiac function.
Arrows indicate the time point of injection of GdDTPA, micelles or liposomes. In the chronic ischemiareperfusion (IR) injury groups, one mouse was killed
after 3 h of circulation of micelles or liposomes (day 6/13) for histology, while the other mice were followed up to 48 h after injection. IR, Ischemiareperfusion
surgery; &, cine MRI; and ,sacrice and tissue harvesting for histological validation.
Figure 3. In vivo MRI of acute IR injury. (a) Short-axis T
1
-weighted MR images obtained before and after injection of GdDTPA (row 1), micelles (row 2)
or liposomes (row 3). In columns 13, the agents were injected on day 1 after IR injury, while in column 4 the agents were administered at the start of
reperfusion and circulated for 24 h. Arrows indicate the areas of contrast enhancement. (b) Group-averaged CNRs between infarct and remote tissue at
different time points after injection. * p < 0.05 vs all time points; ** p < 0.05 vs pre; p < 0.05 vs 0.1 h after injection; †† p < 0.05 vs all contrast agents at
1.4 h after injection; and { p < 0.05 vs GdDTPA at 24 h after injection.
LIPIDASED NANOPARTICLES IN MYOCARDIAL IR INJURY
Contrast Media Mol. Imaging 2013, 8 117126 Copyright © 2012 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/cmmi
119

nanoparticles may offer a surrogate diagnostic readout, as a
blood-pool agent, of the viable and perfused myocardium.
Nevertheless, for the determination of myocardial infarct size
traditional LGE MRI with GdDTPA is still the method of choice.
After 1.4 h, micelle accumulation in the infarct area became
apparent resulting in disappearance of the dark rim in the infarct
area (Fig. 3). The CNR increased signicantly to a positive value
of 6.9 5.4 (p < 0.05 vs 0.1 h). For the larger liposomes, the
T
1
-weighted signal increase proceeded more slowly. The suben-
docardial infarct remained hypoenhanced at this time point and
this resulted in a persistent negative CNR of 4.0 2.4. CLSM
was used to detect the NIR lipid present in the micelles and
liposomes to determine nanoparticle localization at the cellular
level. For this purpose, short-axis histological sections of multiple
mice at multiple longitudinal positions and multiple locations
in the infarct, in the border zone and in the remote myocardium
were studied. CLSM of hearts at 3 h after injection conrmed
extensive accumulation of micelles in the infarcted myocar-
dium (Fig. 4, Table 2). Accumulation was high in the infarct
border zones and in the core of the infarcted myocardium. NIR
signal of micelles did not co-localize with inammatory cells or
vessels. Staining of laminin (extracellular matrix) revealed that
micelles were primarily associated with infarcted cardiomyocytes.
Liposomes, on the other hand, were present in distinct spots in
the infarct border zone area and occasionally co-localized with
macrophages, indicating phagocytosis.
After 24 h of circulation (Fig. 3), both micelles and liposomes
had accumulated in the infarcted myocardium and caused
Figure 4. Confocal laser scanning microscopy (CLSM) of infarcted myocardium and border zones at day 1 after IR injury. Images were acquired after short
(3 h) or after long (24 h) circulation of the nanoparticles. In all images the uorescence of NIR lipids incorporated in micelles and liposomes is shown in red. As
a uorescence-negative control, mice injected with GdDTPA are shown. Scale bar = 100 mm. Row 1: green corresponds to autouorescence of the heart.
Autouorescence is less intense in the infarcted myocardium. Laser intensities for NIR visualization are given as percentages of the maximal laser intensity.
For NIR visualization after staining, this laser intensity was always set to 50%. Row 2: leukocytes (CD18
+
) in blue; row 3: macrophages (CD68
+
)ingreen;row4:
vessels (CD31
+
)inblue;androw5:lamininingreen.
Table 2. Visual scoring of confocal laser scanning microscopy
images for intensity of near-infrared uorescence signal
intensities after acute ischemiareperfusion injury
Time after
administration nanoparticle Remote Border zone Infarct
3h GdDTPA   
Micelles +++
Liposomes +
24 h GdDTPA   
Micelles  ++
Liposomes  +++
 = No; = low; = moderate; + = high; and ++ = very high
near-infrared uorescence signal intensity.
T. GEELEN ET AL.
wileyonlinelibrary.com/journal/cmmi Copyright © 2012 John Wiley & Sons, Ltd. Contrast Media Mol. Imaging 2013, 8 117126
120

Figures (4)
Citations
More filters

Journal ArticleDOI
TL;DR: Enzyme-responsive peptide-polymer amphiphiles are assembled as spherical micellar nanoparticles, and undergo a morphological transition from spherical-shaped, discrete materials to network-like assemblies when acted upon by matrix metalloproteinases.
Abstract: A method for targeting to and retaining intravenously injected nanoparticles at the site of acute myocardial infarction in a rat model is described. Enzyme-responsive peptide-polymer amphiphiles are assembled as spherical micellar nanoparticles, and undergo a morphological transition from spherical-shaped, discrete materials to network-like assemblies when acted upon by matrix metalloproteinases (MMP-2 and MMP-9), which are up-regulated in heart tissue post-myocardial infarction.

137 citations


Journal ArticleDOI
TL;DR: The in vivo use of targeted paramagnetic liposomes has facilitated the specific imaging of pathophysiological processes, such as angiogenesis and inflammation, and MR image‐guided drug delivery using such liposome allows the visualization and quantification of local drug delivery.
Abstract: Liposomes are a versatile class of nanoparticles with tunable properties, and multiple liposomal drug formulations have been clinically approved for cancer treatment. In recent years, an extensive library of gadolinium (Gd)containing liposomal MRI contrast agents has been developed for molecular and cellular imaging of disease-specific markers and for image-guided drug delivery. This review discusses the advances in the development and novel applications of paramagnetic liposomes in molecular and cellular imaging, and in image-guided drug delivery. A high targeting specificity has been achieved in vitro using ligand-conjugated paramagnetic liposomes. On targeting of internalizing cell receptors, the effective longitudinal relaxivity r1 of paramagnetic liposomes is modulated by compartmentalization effects. This provides unique opportunities to monitor the biological fate of liposomes. In vivo contrast-enhanced MRI studies with nontargeted liposomes have shown the extravasation of liposomes in diseases associated with endothelial dysfunction, such as tumors and myocardial infarction. The in vivo use of targeted paramagnetic liposomes has facilitated the specific imaging of pathophysiological processes, such as angiogenesis and inflammation. Paramagnetic liposomes loaded with drugs have been utilized for therapeutic interventions. MR image-guided drug delivery using such liposomes allows the visualization and quantification of local drug delivery. Copyright © 2013 John Wiley & Sons, Ltd.

80 citations


Cites background from "Passive targeting of lipid-based na..."

  • ...The majority of clinically approved MRI contrast agents are based on paramagnetic gadolinium (Gd)-chelates, such as Gd-DTPA, Gd-DOTA and Gd-HPDO3A [DTPA, diethylenetriaminepentaacetic acid; DOTA, 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid; HPDO3A, 10-(2- hydroxypropyl)-1,4,7-tetraazacyclododecane-1,4,7-triacetic acid] (5)....

    [...]

  • ...41 T, the r1 value of Gd-DOTADSPE-based liposomes is 14–15mM 1 s 1 (57,77,78)....

    [...]

  • ...For instance, for Gd-DOTADSPE liposomes, the r1 value is around 3mM 1 s 1 at 9.4 T, whereas this is 3.9mM 1 s 1 for clinically approved Gd-DTPA (77,78)....

    [...]

  • ...Moreover, the in vitro cytotoxicity of Gd-DTPA-bis(stearylamide)-containing liposomes in cultures of HUVEC has been examined....

    [...]

  • ...In a similar study, antibodies against CD105 were conjugated to liposomes loaded with Gd-DTPA in the lumen and were employed for MRI of tumor angiogenesis (127)....

    [...]


Journal ArticleDOI
TL;DR: The focus of this progress report is to provide a survey of NP strategies employed in cerebral ischemia and brain trauma and provide insights for improved NP‐based diagnostic/treatment approaches.
Abstract: Brain injuries affect a large patient population with major physical and emotional suffering for patients and their relatives; at a significant cost to the society. Effective diagnostic and therapeutic options available for brain injuries are limited by the complex brain injury pathology involving blood–brain barrier (BBB). Brain injuries, including ischemic stroke and brain trauma, initiate BBB opening for a short period of time, which is followed by a second reopening for an extended time. The leaky BBB and/or the alterations in the receptor expression on BBB may provide opportunities for therapeutic delivery via nanoparticles (NPs). The approaches for therapeutic interventions via NP delivery are aimed at salvaging the pericontusional/penumbra area for possible neuroprotection and neurovascular unit preservation. The focus of this progress report is to provide a survey of NP strategies employed in cerebral ischemia and brain trauma and finally provide insights for improved NP-based diagnostic/treatment approaches.

59 citations


Journal ArticleDOI
17 Jul 2017-Small
TL;DR: In vivo single-photon emission computed tomography and autoradiography demonstrate increased accumulation of ANP-PSi nanoparticles in the ischemic heart, particularly in the endocardial layer of the left ventricle, demonstrating cardioprotective potential.
Abstract: Ischemic heart disease is the leading cause of death globally. Severe myocardial ischemia results in a massive loss of myocytes and acute myocardial infarction, the endocardium being the most vulnerable region. At present, current therapeutic lines only ameliorate modestly the quality of life of these patients. Here, an engineered nanocarrier is reported for targeted drug delivery into the endocardial layer of the left ventricle for cardiac repair. Biodegradable porous silicon (PSi) nanoparticles are functionalized with atrial natriuretic peptide (ANP), which is known to be expressed predominantly in the endocardium of the failing heart. The ANP-PSi nanoparticles exhibit improved colloidal stability and enhanced cellular interactions with cardiomyocytes and non-myocytes with minimal toxicity. After confirmation of good retention of the radioisotope 111-Indium in relevant physiological buffers over 4 h, in vivo single-photon emission computed tomography (SPECT/CT) imaging and autoradiography demonstrate increased accumulation of ANP-PSi nanoparticles in the ischemic heart, particularly in the endocardial layer of the left ventricle. Moreover, ANP-PSi nanoparticles loaded with a novel cardioprotective small molecule attenuate hypertrophic signaling in the endocardium, demonstrating cardioprotective potential. These results provide unique insights into the development of nanotherapies targeted to the injured region of the myocardium.

52 citations


Journal ArticleDOI
Zhaoqiang Dong1, Jing Guo1, Xiaowei Xing1, Xuguang Zhang1, Yimeng Du1, Qing-Hua Lu1 
TL;DR: RGD modified and PEGylated solid lipid nanoparticles loaded with puerarin are developed to improve bioavailability of PUE, to prolong retention time in vivo and to enhance its protective effect on acute myocardial ischemia model.
Abstract: Context Puerarin has been widely used as a therapeutic agent for the treatment of cardiovascular diseases. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy. Objective RGD modified and PEGylated solid lipid nanoparticles loaded with puerarin (RGD/PEG-PUE-SLN) were developed to improve bioavailability of PUE, to prolong retention time in vivo and to enhance its protective effect on acute myocardial ischemia model. Methods In the present study, RGD-PEG-DSPE was synthesized. RGD/PEG-PUE-SLN were prepared by the solvent evaporation method with some modifications. The physicochemical properties of NPs were characterized, the pharmacokinetics, biodistribution, pharmacodynamic behavior of RGD/PEG-PUE-SLN were evaluated in acute MI rats. Results The mean diameter, zeta potential, entrapment efficiency and drug loading capacity for RGD/PEG-PUE-SLN were observed as 110.5 nm, −26.2 mV, 85.7% and 16.5% respectively. PUE from RGD/PEG-PUE-SLN exhibited sustained drug release with a burst release during the initial 12 h and a followed sustained release. Pharmacokinetics results indicated that AUC increased from 52.93 (μg/mL h) for free PUE to 176.5 (μg/mL h) for RGD/PEG-PUE-SLN. Similarly, T 1/2 increased from 0.73 h for free PUE to 2.62 h for RGD/PEG-PUE-SLN. RGD/PEG-PUE-SLN exhibited higher drug concentration in the heart and plasma compared with other PUE formulations. It can be clearly seen that the infarct size of RGD/PEG-PUE-SLN is the lowest among all the formulation. Conclusion We conclude that RGD modified and PEGylated SLN are promising candidate delivery vehicles for cardioprotective drugs in treatment of myocardial infarction.

47 citations


References
More filters

Journal ArticleDOI
01 May 1970-Lipids
TL;DR: Separation of polar lipids by two-dimensional thin layer chromatography providing resolution of all the lipid classes commonly encountered in animal cells and a sensitive, rapid, reproducible procedure for determination of phospholipids by phosphorus analysis of spots are described.
Abstract: Separation of polar lipids by two-dimensional thin layer chromatography providing resolution of all the lipid classes commonly encountered in animal cells and a sensitive, rapid, reproducible procedure for determination of phospholipids by phosphorus analysis of spots are described. Values obtained for brain and mitochondrial inner membrane phospholipids are presented.

3,111 citations


"Passive targeting of lipid-based na..." refers methods in this paper

  • ...The final lipid concentrations of micelles and liposomes were measured by a phosphate determination according to Rouser (39)....

    [...]


Journal ArticleDOI
TL;DR: This article will review postinfarction remodeling, pathophysiological mechanisms, and therapeutic intervention in left ventricular remodeling and provide important insights into the remodeling process and a rationale for future therapeutic strategies.
Abstract: Left ventricular remodeling is the process by which ventricular size, shape, and function are regulated by mechanical, neurohormonal, and genetic factors.1 2 Remodeling may be physiological and adaptive during normal growth or pathological due to myocardial infarction, cardiomyopathy, hypertension, or valvular heart disease (Figure 1⇓). This article will review postinfarction remodeling, pathophysiological mechanisms, and therapeutic intervention. Figure 1. Diagrammatic representation of the many factors involved in the pathophysiology of ventricular remodeling. ECM indicates extracellular matrix; RAAS, renin-angiotensin-aldosterone system; CO, cardiac output; SVR, systemic vascular resistance; LV, left ventricular; and AII, angiotensin II. ### Postinfarction Left Ventricular Remodeling The acute loss of myocardium results in an abrupt increase in loading conditions that induces a unique pattern of remodeling involving the infarcted border zone and remote noninfarcted myocardium. Myocyte necrosis and the resultant increase in load trigger a cascade of biochemical intracellular signaling processes that initiates and subsequently modulates reparative changes, which include dilatation, hypertrophy, and the formation of a discrete collagen scar. Ventricular remodeling may continue for weeks or months until the distending forces are counterbalanced by the tensile strength of the collagen scar. This balance is determined by the size, location, and transmurality of the infarct, the extent of myocardial stunning, the patency of the infarct-related artery, and local tropic factors.1 3 The myocardium consists of 3 integrated components: myocytes, extracellular matrix, and the capillary microcirculation that services the contractile unit assembly. Consideration of all 3 components provides important insights into the remodeling process and a rationale for future therapeutic strategies. The cardiomyocyte is terminally differentiated and develops tension by shortening. The extracellular matrix provides a stress-tolerant, viscoelastic scaffold consisting of type I and type III collagen that couples myocytes and maintains the spatial relations between the myofilaments and their capillary microcirculation.4 5 The collagen framework couples adjacent myocytes by intercellular struts that …

1,588 citations


"Passive targeting of lipid-based na..." refers background in this paper

  • ...An emerging approach for further treatment of IR injury involves the delivery of therapeutic compounds to the myocardium to promote cell survival and constructively influence scar formation and myocardial remodeling (6,7)....

    [...]


Journal ArticleDOI
TL;DR: This review will discuss some recent trends in using micelles as pharmaceutical carriers, including lipid-core micells, which may become the imaging agents of choice in different imaging modalities.
Abstract: Micelles, self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell are currently successfully used as pharmaceutical carriers for water-insoluble drugs and demonstrate a series of attractive properties as drug carriers. Among the micelle-forming compounds, amphiphilic copolymers, i.e., polymers consisting of hydrophobic block and hydrophilic block, are gaining an increasing attention. Polymeric micelles possess high stability both in vitro and in vivo and good biocompatibility, and can solubilize a broad variety of poorly soluble pharmaceuticals many of these drug-loaded micelles are currently at different stages of preclinical and clinical trials. Among polymeric micelles, a special group is formed by lipid-core micelles, i.e., micelles formed by conjugates of soluble copolymers with lipids (such as polyethylene glycol-phosphatidyl ethanolamine conjugate, PEG-PE). Polymeric micelles, including lipid-core micelles, carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities. All these micelles can also be used as targeted drug delivery systems. The targeting can be achieved via the enhanced permeability and retention (EPR) effect (into the areas with the compromised vasculature), by making micelles of stimuli-responsive amphiphilic block-copolymers, or by attaching specific targeting ligand molecules to the micelle surface. Immunomicelles prepared by coupling monoclonal antibody molecules to p-nitrophenylcarbonyl groups on the water-exposed termini of the micelle corona-forming blocks demonstrate high binding specificity and targetability. This review will discuss some recent trends in using micelles as pharmaceutical carriers.

1,563 citations


"Passive targeting of lipid-based na..." refers background in this paper

  • ...Therefore, micelles were proposed for delivery of lipophilic drugs (16,17)....

    [...]


Journal ArticleDOI
TL;DR: The ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients.
Abstract: Pegylated liposomal doxorubicin (doxorubicin HCl liposome injection; Doxil® or Caelyx®) is a liposomal formulation of doxorubicin, reducing uptake by the reticulo-endothelial system due to the attachment of polyethylene glycol polymers to a lipid anchor and stably retaining drug as a result of liposomal entrapment via an ammonium sulfate chemical gradient. These features result in a pharmacokinetic profile characterised by an extended circulation time and a reduced volume of distribution, thereby promoting tumour uptake. Preclinical studies demonstrated one- or two-phase plasma concentration-time profiles. Most of the drug is cleared with an elimination half-life of 20–30 hours. The volume of distribution is close to the blood volume, and the area under the concentration-time curve (AUC) is increased at least 60-fold compared with free doxorubicin. Studies of tissue distribution indicated preferential accumulation into various implanted tumours and human tumour xenografts, with an enhancement of drug concentrations in the tumour when compared with free drug. Clinical studies of pegylated liposomal doxorubicin in humans have included patients with AIDS-related Kaposi’s sarcoma (ARKS) and with a variety of solid tumours, including ovarian, breast and prostate carcinomas. The pharmacokinetic profile in humans at doses between 10 and 80 mg/m2 is similar to that in animals, with one or two distribution phases: an initial phase with a half-life of 1–3 hours and a second phase with a half-life of 30–90 hours. The AUC after a dose of 50 mg/m2 is approximately 300-fold greater than that with free drug. Clearance and volume of distribution are drastically reduced (at least 250-fold and 60-fold, respectively). Preliminary observations indicate that utilising the distinct pharmacokinetic parameters of pegylated liposomal doxorubicin in dose scheduling is an attractive possibility. In agreement with the preclinical findings, the ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients. There is evidence of selective tumour uptake in malignant effusions, ARKS skin lesions and a variety of solid tumours. The toxicity profile of pegylated liposomal doxorubicin is characterised by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression, decreased cardiotoxicity compared with free doxorubicin and minimal alopecia. The mucocutaneous toxicities are dose-limiting per injection; however, the reduced cardiotoxicity allows a larger cumulative dose than that acceptable for free doxorubicin. Thus, pegylated liposomal doxorubicin represents a new class of chemotherapy delivery system that may significantly improve the therapeutic index of doxorubicin.

1,254 citations


"Passive targeting of lipid-based na..." refers background in this paper

  • ...be diminished by encapsulation of the therapeutics (29,30)....

    [...]


Journal ArticleDOI
TL;DR: This review attempts to summarize currently available information regarding targeted pharmaceutical nanocarriers for cancer therapy and imaging, as well as different ways to target tumors via specific ligands and via the stimuli sensitivity of the carriers.
Abstract: The use of various pharmaceutical nanocarriers has become one of the most important areas of nanomedicine. Ideally, such carriers should be specifically delivered (targeted) to the pathological area to provide the maximum therapeutic efficacy. Among the many potential targets for such nanocarriers, tumors have been most often investigated. This review attempts to summarize currently available information regarding targeted pharmaceutical nanocarriers for cancer therapy and imaging. Certain issues related to some popular pharmaceutical nanocarriers, such as liposomes and polymeric micelles, are addressed, as are different ways to target tumors via specific ligands and via the stimuli sensitivity of the carriers. The importance of intracellular targeting of drug- and DNA-loaded pharmaceutical nanocarriers is specifically discussed, including intracellular delivery with cell-penetrating peptides.

656 citations


Related Papers (5)
Frequently Asked Questions (1)
Q1. What have the authors contributed in "Passive targeting of lipid-based nanoparticles to mouse cardiac ischemia–reperfusion injury" ?

Strijkers et al. this paper investigated the in vivo accumulation and distribution kinetics of long-circulating lipid-based nanoparticles in a mouse model of acute ( 1 day old ) as well as chronic ( up to 2 weeks ) myocardial IR injury.