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Liposomal cerasome a nanohybrid of liposome and silica.

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ASIA-PACIFIC JOURNAL OF CHEMICAL ENGINEERING
Asia-Pac. J. Chem. Eng. 2011; 6: 569–574
Published online 28 April 2011 in Wiley Online Library
(wileyonlinelibrary.com) DOI:10.1002/apj.592
Commentary
Liposomal cerasome: a nanohybrid of liposome
and silica
Xiuli Yue, Yuanmiao Jing and Zhifei Dai*
Nanomedicine and Biosensor Laboratory, School of Sciences, State Key Laboratory of Urban Water Resources and Environment, Harbin Institute of
Technology, Harbin 150080, P. R. China
Received 20 December 2010; Revised 30 March 2011; Accepted 31 March 2011
INTRODUCTION
The rapid development of nanotechnology has created a
myriad of engineered nanomaterials, which have found
extensive applications in various industries. Especially,
a tremendous expansion of research and potential applications of nanotechnology has been seen in medicine,
including the exploitation of nanomaterials as carriers
of active pharmaceutical drugs in delivery and targeting
applications, and for medical imaging purposes. However, before nanoparticles (NPs) can be widely implemented in the field of medicine, numerous questions
need be addressed and their toxicity has to be carefully evaluated[1] . For instance, what is the relationship
between the size, shape, and surface chemistry of NPs
and their in vivo behavior? What is the propensity of
NPs to cross cell barriers, enter cells and interact with
subcellular structures? Are NPs themselves degraded or
metabolized, and are NPs and/or their degradation products effectively excreted from the body? Do NPs cause
new types of effects not previously seen with larger
particles or bulk chemicals?
It is known that the immune system serves as a primary defense against foreign invasion. Nano–immuno
interactions are therefore important to consider when
engineered NPs are devised for in vivo administration[2] .
However, NPs may not freely or indiscriminately cross
all biological barriers but these processes may instead
be governed by the specific physico-chemical properties of NPs themselves as well as the identity of the
functional molecules added to their surfaces. Cellular
uptake may occur through several different pathways,
depending on the properties of the NPs (such as primary
particle size, shape, surface charge, etc.) but also on the
specific cell type in question. Therefore, it is essential to
understand the mechanisms that dictate the behavior and
*Correspondence to: Zhifei Dai, Nanomedicine and Biosensor Laboratory, School of Sciences, State Key Laboratory of Urban Water
Resources and Environment, Harbin Institute of Technology, Harbin
150 080, P. R. China. E-mail: zhifei.dai@hit.edu.cn
 2011 Curtin University of Technology and John Wiley & Sons, Ltd.
Curtin University is a trademark of Curtin University of Technology
fate of NPs upon introduction into the body, not only
for the development of NPs for targeted drug delivery,
but also for the prediction of the potential toxicological
responses to such NPs[3] .
Both liposomes and silica NPs have been widely used
for drug delivery. Despite excellent biocompatibility,
liposomes still have not attained their full potential
as drug and gene delivery vehicles because of their
insufficient stability. The serious drawbacks of silica
NPs are their inherently non-biodegradability, high
rigidity and low biocompatibility. Recently, biomimetic
cerasome (partially silica-coated liposome) has drawn
much attention as a novel drug delivery system because
its atomic layer of polyorganosiloxane surface imparts
higher stability than conventional liposomes and its
liposomal bilayer structure reduces the overall rigidity
and density greatly compared with silica NPs. The
rapid expansion of cerasomes promises to have potential
applications in medicine but there is increasing concern
that human and environmental exposure to cerasomes
may result in significant adverse effects. Herein, we
will have a brief comment on the toxicity of cerasomes
compared with conventional liposomes and silica NPs.
MESOPOROUS SILICA NPs
The potential applications of mesoporous silica nanoparticle (MSN), comprised of a honeycomb-like porous
structure with empty channels (pores) of nanosized
dimensions, have encompassed areas such as diagnostics, bioanalysis and imaging, drug delivery, and gene
transfer[4] . As a consequence, it is conceivable that
MSN may someday be administered into the human
body through all possible routes of entry, including
oral ingestion, inhalation, intra-venous injection, and
transdermal delivery. Information regarding the absorption, biodistribution, retention, degradation, clearance,
and safety of MSN in different tissues and organs is
therefore of vital importance to the future of MSN as a
biomaterial.
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X. YUE, Y. JING AND Z. DAI
Cellular uptake of MSN
Cellular uptake of MSN is dependent on particle size,
shape and surface charge, and has also been reported
to be cell type-specific[5] . The effect of the shape of
MSN on cellular uptake and found that rod-shaped MSN
showed increased cellular uptake and consequently a
greater effect on apoptosis, migration and disturbed
organization of the cytoskeleton, which could have
important implications for the design of efficient and
safe drug delivery systems. The suggested uptake mechanism is through endocytosis and slightly charged MSN
were reported to be taken up by clathrin-dependent
mechanisms whereas the uptake of highly positively
charged particles could not be repressed by different
endocytosis inhibitors, suggesting other mechanisms of
uptake[6] . MSN with a primary particle size 50 nm was
shown to accumulate in the perinuclear region of HeLa
cervical carcinoma cells. It was found that AMS-6 and
AMS-8 particles were effectively taken up by primary
human monocyte-derived macrophages via an active
process and this cellular uptake was independent on the
presence of serum in the cell culture medium. Moreover, internalization of MSN did not interfere with the
ability of macrophages to engulf apoptotic target cells
or IgG-opsonized red blood cells nor did the particles
affect macrophage secretion of cytokines.
Asia-Pacific Journal of Chemical Engineering
doses of amorphous silica or composite NPs of silica
and chitosan. A cell proliferation assay indicates that silica NPs are nontoxic at low dosages but that cell viability decreases at high dosages. A lactate dehydrogenase
assay indicates that high dosages of silica induce cell
membrane damage. In contrast, silica–chitosan composite NPs induce less inhibition in cell proliferation
and less membrane damage. This study suggests that the
cytotoxicity of silica to human cells depends strongly
on their metabolic activities but that it could be significantly reduced by synthesizing silica with chitosan[10] .
The biocompatibility of NPs is the prerequisite for
their applications in biomedicine but can be misleading because of the absence of criteria for evaluating the
safety and toxicity of those nanomaterials. Recent studies indicate that MSN can easily internalize into human
mesenchymal stem cells (hMSCs) without apparent
deleterious effects on cellular growth or differentiation, and hence are emerging as an ideal stem cell
labeling agent. Although cell viability, cell proliferation, and regular osteogenic differentiation of hMSCs
are not affected by the internalized MSN, the actin
polymerization, RhoA activity, and induced expression
of the osteocyte-specific marker gene, alkaline phosphatase, are significantly upregulated fleetingly. These
findings suggested that the effects of NPs on diverse
aspects of cellular activities should be carefully evaluated even though the NPs are generally considered as
biocompatible[11] .
In vitro cytotoxicity of MSN
Some in vitro cytotoxicity studies have been performed on MSN. It was reported that MCM-41 (2Dhexagonal) particles prepared with cationic surfactants
displayed low toxicity when introduced into HeLa cell
cultures[7] . But, Hudson et al . showed the so-called
MCM-41 particles were highly cytotoxic to all three
cell lines tested, presumably because of residual cationic
surfactant present in its pores whereas particle size
appeared to have no bearing on the cytotoxicity of
MSN, within the range of the particle sizes examined
(150–4000 nm)[8] . AMS-6 and AMS-8 (3D-cubic) particles with surface areas above 500 m2 /g, which were
prepared with anionic surfactants, were efficiently internalized in human dendritic cells, a key cell of the
immune system which plays a central role in the initiation of both primary and secondary immune responses.
Low cytotoxicity was observed, but a weak immunestimulatory effect was evident with elevated levels of
co-stimulatory molecule CD86 and an induction of the
T-cell stimulating factor, IL-12. It was shown that coating MSN with soft organic macromolecules such as
poly(ethylene glycol) (PEG) increased the water solubility and the biocompatibility, and reduced undesired
interactions between the biological environment and the
nanocarriers[9] . Chang et al . investigated the response
of several normal fibroblast and tumor cells to varying
 2011 Curtin University of Technology and John Wiley & Sons, Ltd.
Structural effects of silica particles
on hemolysis
It is well known that amorphous silica materials can
cause hemolysis (or rupture) of red blood cells and this
has raised safety concerns over their use in drug delivery. Many explanations for this phenomenon exist, but
it is widely agreed that hemolytic activity is because
of silanol groups on the surface of the materials. Slowing et al . reported that in contrast to amorphous silica,
the MSN did not show any hemolysis at concentrations between 20 and 100 g/cm3 , even though it contained more silanol groups, indicating that the extent
of hemolytic activity is not proportional to the number
of silanol groups, as proposed previously. The honeycomb structure of the MSN is thought to distribute the
silanol groups on the surface and inside the pores in
such a way that only a small fraction is accessible to the
cell membrane for hemolysis. It suggests that the structural effects of certain silica particles may help lower
hemolysis[12] .
In vivo toxicity of MSN
Although MSN are widely considered as a potential
drug delivery vehicle, there are few in vivo studies on
Asia-Pac. J. Chem. Eng. 2011; 6: 569–574
DOI: 10.1002/apj
Asia-Pacific Journal of Chemical Engineering
the toxicity to date. Hudson et al .[8] recently examined
the in vivo biocompatibility of MSN with particle sizes
of 150 nm, 800 nm and 4 µm and pore sizes of 3, 7
and 16 nm. Following subcutaneous injection of high
doses of particles in rats (30 mg particles/animal), the
amount of residual material decreased progressively
over 3 months and good biocompatibility was observed
at all time points. In contrast, intra-peritoneal and intravenous injections in mice resulted in death or euthanasia as a result of distress at high doses. However,
intra-peritoneal doses of 1 mg of particles per animal (corresponding to 40 mg/kg) were non-fatal. Thus,
although the local tissue reaction was benign, the materials caused severe systemic toxicity, at least upon
administration at very high doses (30 mg per mouse).
It is speculated that the higher death rate in animals
injected in the peritoneum compared with the subcutaneous route could be because of the faster rate of
clearance of the silica particles from the former site,
resulting in a higher systemic dose of particles[8] . Wu
et al .[13] published the first in vivo study of superparamagnetic iron oxide NPs with mesoporous silica shells
(SPION-MSN). When injected into mice, these particles were shown to be cleared from the kidney within
2 h followed by accumulation in the liver and spleen.
A comprehensive toxicological assessment was not performed but the authors reported that no statistical differences in the body weight changes between controls
and SPION-MSN-treated mice were detected during a
4-week study period[13] . Overall, these studies suggest
that biomedical applications of MSN should be explored
in the context of synthetic modifications to reduce systemic toxicity, especially if large quantities of particles
are to be used.
LIPOSOMES
Liposomes are highly biocompatible
Liposomes are the most clinically established nanometer
scale systems capable of transporting drug molecules to
specific target site with enhanced efficacy and safety[14] .
Liposomes consist of a single or multiple concentric
lipid bilayers that encapsulate an aqueous compartment.
Biocompatibility, biodegradability, reduced toxicity and
capacity for size and surface manipulations comprise the
outstanding profile that liposomes offer compared with
other delivery systems. The versatility of the liposomal
structure lies in its capacity to cargo drug molecules
and biological macromolecules that are hydrophilic
(therefore entrapped in the liposome inner aqueous core)
or hydrophobic (therefore incorporated within the lipid
bilayer). Drug encapsulation into liposomes can alter a
drug’s in vivo pharmacokinetic and pharmacodynamic
profile, leading to all increase in the therapeutic index,
reduction in tissue toxicity and other side effects,
 2011 Curtin University of Technology and John Wiley & Sons, Ltd.
LIPOSOMAL CERASOME
an increase in drug stability or the emergence of a
sustained release profile formulation. Nanometer sized
particles, such as SPION and quantum dots, possess
novel magnetic and optical properties that can be used
as imaging probes. Encapsulation of these NPs within
liposomes can lead to enhanced NP hydrophilicity,
stability in plasma and an overall improvement in their
biocompatibility[14] .
Insufficient stability limits the widespread
application of liposomes
Up to now, liposome-based drug formulations have not
entered the market in great numbers. One of the major
problems limiting the widespread use of liposomes is
insufficient stability. Liposomes cause aggregation in
the blood by their mutual reaction with various blood
plasma proteins and are captured by the reticuloendothelial system. Also, the liposomes are subject to
electrostatic, hydrophobic, and Van der Waals interactions with high-density lipoproteins and low-density
lipoproteins in plasma, resulting in destabilization of
the liposomes leading to rapid clearance of the vesicles
from circulation. In addition, difficulties have arisen in
producing liposome encapsulating certain drugs because
of the drugs’ interactions with the phospholipids of the
liposomes. For example, anthracyclines have exhibited
a surfactant- or detergent-like effect on the phospholipid vesicle bilayer that causes leakage and creates
liposome vesicle instability. Thus, liposomes unstable
to the circulation environment and/or its content will
leak the antineoplastic agent prematurely before reaching the tumor site. As a result of the ‘leaky’ liposomes
and the resulting devastating toxicities, scientists have
tried to develop long-circulating liposomes that are able
to extravasate to tumor sites.
Pegylation increases the stability of liposomes
but leads to skin toxicity
Hydrophilic polymers, such as PEG, have been widely
used as polymeric steric stabilizer because of many useful properties, such as biocompatibility, solubility in
aqueous and organic media, lack of toxicity, very low
immunogenicity and antigenicity, and good excretion
kinetics. The most significant advantages of PEGylated
vesicles are their strongly reduced mononuclear phagocyte system (MPS) uptake and their prolonged blood
circulation and thus improved distribution in perfused
tissues. Moreover, the PEG chains on the liposome surface avoid the vesicle aggregation, improving stability
of formulations. The pegylated liposomes appeared to
reduce some of the toxic effects caused by the release
of their contents, but, unfortunately, new toxic effects
appeared because of the presence of the polyethylene
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DOI: 10.1002/apj
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Asia-Pacific Journal of Chemical Engineering
Figure 1. Chemical structure of cerasomes and schematic diagram of
their interactions with cells. This figure is available in colour online at
www.apjChemEng.com.
glycol (PEG)[15] . For example, the liposomal preparations containing pegylated phospholipids have lead
to skin toxicity generally known as ‘Hand–Foot syndrome’, which results in skin eruptions/ulcers on the
palms of the hands and soles of the feet. Another disadvantage with pegylated liposomes is the presence of
PEG large molecules on the liposomal surface may
reduce the interactions of liposomes with cells and hinder entry of liposomes into the tumor tissue, thereby
possibly reducing the accumulation of liposomal drug in
the tumor tissue. Thus, there remains a need for stable,
long circulating liposomes that do not cause such deleterious effects such as the ‘Hand–Foot syndrome’[16] .
LIPOSOMAL NANOHYBRID CERASOMES
Cellular uptake of cerasomes
Cerasome with a liposomal bilayer structure and an
atomic layer of inorganic polyorganosiloxane networks on its surface has been fabricated by molecularly designed lipidic organoalkoxysilane (Fig. 1)[17] .
Such unique structure gives wide applicability to
the cerasomes in roles as gene carriers[18] , drug
delivery systems[19] , other biomedical applications[20]
and biological energy transfer[17] . Thus, the increased
applications of cerasomes have compelled researchers
to investigate their potential biological effects[21] .
 2011 Curtin University of Technology and John Wiley & Sons, Ltd.
The zeta potentials of cerasomes and silica NPs were
−24.2 ± 1.0 and −26.3 ± 2.1 mV, respectively, indicating cerasomes possessed similar surface properties
with silica NPs. The cellular uptake of cerasomes is
a concentration-, time-, and energy-dependent process
and occurred through a process of clathrin-mediated
endocytosis[21] . It was observed that the uptake of cerasomes by Human Umbilical Vein Endothelial Cells
(HUVECs) increased notably with increasing concentrations of cerasomes (0–400 µg/mL) after 4 h incubation. When the concentration reached 400 µg/mL, little
increased internalization suggested that the uptake of
cerasomes got saturated. The kinetics of cell association with NPs revealed that the uptake of cerasomes
by HUVECs increased as the incubation time during
the first 6 h. But the uptake amount reached maximum
at 6 h and no more uptake was observed even after
19 h incubation, which appeared to derive from saturation of the uptake system. Fluorescent cerasomes
were clearly observed inside the cells as green spots and
showed a cytosolic localization, indicating that the cerasomes were indeed endocytosed (Fig. 1). The uptake
of cerasomes was obviously inhibited after treatment
at 4 ◦ C with respect to the same experiment carried
out at 37 ◦ C, indicating that the cellular internalization of cerasomes follows an energy-dependent or independent pathway. After HUVECs were treated by
sucrose and K+ -free buffer, the uptake of cerasomes
Asia-Pac. J. Chem. Eng. 2011; 6: 569–574
DOI: 10.1002/apj
Asia-Pacific Journal of Chemical Engineering
by cells decreased to 73 and 75%, respectively, suggesting that the uptake of cerasomes occurred possibly through a clathrin-dependent endocytosis pathway.
NPs are usually transported into the cell by specific or
non-specific cellular uptake mechanisms depending on
the surface properties of NPs. Cerasomes were negatively charged and did not possess any specific ligands
on their surfaces so a non-specific cellular uptake would
participate in the process of cerasome uptake.
Cytotoxicity of cerasomes
Cell viability studies showed that cerasomes had lower
cytotoxicity than silica NPs[21] . Both cerasomes and silica NPs exhibited growth inhibition in a concentration-,
time-, and cell type-dependent manner in both HUVECs
and HeLa cells. Cell viability decreased with increased
NP concentrations. However, cerasome-treated cells
showed higher viability than cells incubated with silica
NPs at the same concentration at 24 h. The difference in
cell viability between cells incubated with cerasome or
silica NPs seemed to be more significant when the incubation time was prolonged to 72 h. At 0.2 mg/mL, cell
viability of HUVECs treated with cerasomes and silica NPs for 24 h was 76 and 70%, respectively. After
72 h incubation, only 43% of the cells treated with silica NPs survived while cell viability for cerasomes was
68% (p < 0.01). Furthermore, the effects of NPs on
cell viability are cell type dependent. HeLa cells are
less sensitive than HUVECs when exposing to NPs of
the same concentration. The differences suggested that
cancerous cells presented several features different from
healthy cells to promote their survival and may also
attribute to the differences in uptake levels in cancer
cells. Cell proliferation study showed that cerasomes
had similar cytotoxicity as low as liposomes. Nevertheless, the biocompatibility of cerasomes is much better
than silica NPs. It is reported that large amount of silicic
acid released by the silica NPs would probably increase
the cytotoxicity by reducing local extracellular or intracellular pH. Silica NPs were significantly more toxic
than cerasomes by inducing G0/G1 arrest in HUVECs.
Both cerasomes and silica NPs produced cell death via
necrosis not apoptosis after 24 h incubation. But, silica NPs induced a higher percentage of necrosis cells,
leading to increased percentage of cell lysis into large
nuclear fragments. It was found that more endogenous
reactive oxygen species (ROS) of cells was stimulated
in response to the treatment with silica NPs. In contrast, cerasomes induced lower cytotoxicity probably
because of less intracellular ROS production. Previous studies indicated that the changes of ROS generation strongly influenced cell proliferation and gave
rise to necrosis in cells incubated with NPs. Therefore,
the lower cell viability and higher percent of necrotic
cells may be attributed to the higher endogenous ROS
 2011 Curtin University of Technology and John Wiley & Sons, Ltd.
LIPOSOMAL CERASOME
level caused by silica NPs than cerasomes. Compared
with cerasomes, silica NPs caused increased adhesiveness shown by induction of Inter-Cellular Adhesion
Molecule 1 (ICAM-1). It is reported that silica-induced
inflammation is believed to occur after cell necrosis
rather than after apoptosis. The contents released by
necrotic cells are highly inflammatory and therefore
necrotic cells invariably cause inflammation in the body.
Thus the higher expression of ICAM-1 would probably
arise from the induction of more necrotic cells treated
with silica NPs. Exposure to silica NPs may be a significant risk for the development of inflammatory disease.
In contrast, cerasome is a less potent activator of inflammatory reaction than silica NPs for ICAM-1 expression.
DISCUSSION
Both liposomes and silica NPs have been widely investigated in the field of medicine. However, the serious drawbacks of silica NPs are their inherently nonbiodegradability, high rigidity and low biocompatibility.
Large amount of silicic acid released by silica NPs
would probably increase the cytotoxicity by reducing
local extracellular or intracellular pH. Despite the excellent biocompatibility, liposomes still have not attained
their full potential as drug and gene delivery vehicles
because of the insufficient morphological stability.
Compared with conventional liposomes and silica
NPs, cerasomes take a number of advantages: (1) The
siloxane surface adds remarkably high mechanical stability and heat resistance[17] ; (2) The silica surface can
facilitate the stabilization of cerasomes in an environment with a slightly alkaline pH or a significant salt
concentration; (3) The presence of a liposomal bilayer
structure reduces the overall rigidity and density of
cerasomes greatly compared with silica NPs, which is
expected to enhance the stability of such particles in
aqueous systems against precipitation; (4) Cerasomes
can be loaded with hydrophilic, hydrophobic as well
as amphiphilic drugs without destroying their morphological stability; (5) Like silica NPs, the silanol
groups located on the exterior surface of cerasome can
be functionalized to allow the easy bioconjugation of
biomolecules with silane-coupler chemistry.
A comprehensive toxicological assessment has not
performed but the preliminary studies have shown that
cerasomes exhibit higher biosafety than silica NPs
because of the incorporation of the liposomal architecture into cerasomes. Cerasomes are internalized via
non-specific or clathrin-related endocytosis. Cerasomes
affect different aspects of cell functions to a smaller
extent than silica NPs of the similar size, including
cell proliferation, cell cycle, cell apoptosis, endogenous ROS level and ICAM-1 expression. This makes
such cerasome technology very attractive for biomedical applications, including the exploitation of cerasomes
Asia-Pac. J. Chem. Eng. 2011; 6: 569–574
DOI: 10.1002/apj
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X. YUE, Y. JING AND Z. DAI
as carriers of active pharmaceutical drugs in delivery
and targeting applications, and for medical imaging purposes. Nevertheless, a further evaluation of the toxicity
of cerasomes will make a major contribution to the
risk assessment that is urgently needed to ensure that
cerasomes are made safely, are exploited to their full
potential and then disposed of safely.
Acknowledgements
This research was financially supported by National
Natural Science Foundation of China (NSFC-20977021
and 30970829) and State Key Lab of Urban Water
Resource and Environment (HIT-2010TS07).
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DOI: 10.1002/apj
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