-
Surface Modification and Local Orientations of Surface Molecules
in Nanoth-erapeutics
Md. Lutful Amin, Jae Yeon Joo, Dong Kee Yi, Seong Soo A. An
PII: S0168-3659(15)00235-7DOI: doi:
10.1016/j.jconrel.2015.04.017Reference: COREL 7638
To appear in: Journal of Controlled Release
Received date: 25 December 2014Revised date: 9 April
2015Accepted date: 12 April 2015
Please cite this article as: Md. Lutful Amin, Jae Yeon Joo, Dong
Kee Yi, Seong Soo A.An, Surface Modication and Local Orientations
of Surface Molecules in Nanotherapeu-tics, Journal of Controlled
Release (2015), doi: 10.1016/j.jconrel.2015.04.017
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Surface Modification and Local Orientations of Surface
Molecules in Nanotherapeutics
(REVISED VERSION II)
Ms. Ref. No.: JCR-D-14-01819
Md. Lutful Aminad, Jae Yeon Jooa, Dong Kee Yibc*, Seong Soo A.
Ana**
aDepartment of BioNano Technology, Gachon University,
Gyeonggi-do, Republic of Korea.
bDepartment of Chemistry, Myongji University, Yongin,
Gyeonggi-do, Republic of Korea.
cDepartment of Energy and Biotechnology, Myongji University
dDepartment of Pharmacy, Stamford University Bangladesh
* Corresponding author at: Department of Chemistry, Myongji
University, 116 Myongji-ro,
Cheoin-gu, Yongin, Gyeonggi-do 449 728, Republic of Korea, Tel:
+82 31 330 6178, Email:
[email protected]; [email protected]
** Corresponding author at: Department of BioNano Technology,
Gachon University, 1342
Seongnamdaero, Sujeong-gu, Seongnam, Gyeonggi-do 461 701;
Republic of Korea, Tel: +82
31 750 8981, Email: [email protected];
[email protected]
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ABSTRACT
Nanotechnology has emerged as a powerful tool for various
therapeutic applications, solving
many difficulties in both diagnosis and treatment. However, many
obstacles in complex
biological systems have impeded the successful application of
therapeutic nanoparticles, and
fine-tuning nanoparticle properties has become extremely
important in developing highly
effective nanomedicines. To this end, particles have been
engineered in various ways, with a
special emphasis on surface modifications. The nanoparticle
surface contacts the biological
environment, and is a crucial determinant of the response. Thus,
surface coating, surface charge,
conjugated molecules, shape, and topography have enormous
impacts on the total behavior of
nanoparticles, including their biodistribution, stability,
target localization, cellular interaction,
uptake, drug release, and toxicity. Hence, engineering of the
particle surface would provide
wider dimensions of control for the specific and precise
functions in the development of smart
nanomedicines. Moreover, local orientation of nanoparticles in
vivo and orientations of surface
molecules are critical for their efficacy. Herein, we analyze
surface functionalities, focusing on
their mechanisms and respective advantages, and summarize
results of surface engineering and
renovating applications of nanoparticles.
Keywords: targeting strategy, surface engineering, surface
orientation, surface topography, drug
delivery, nanotoxicity.
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1. INTRODUCTION
The emergence of nanotechnology in medical science has improved
drug delivery systems in
terms of solubility, membrane permeability, drug targeting, and
controlled release [1,2]. Over the
last few decades, development of therapeutic nanocarriers has
become an important area of
research, as they can improve the delivery of active molecules
to the target site and overcome
biological barriers [1,3]. In complex biological systems,
nanomedicines have faced obstacles
such as rapid clearance, lack of proper interaction, nonspecific
targeting, inability to enter
targeted cells and the core of tissues, and uncontrolled drug
release [4,5]. Several investigations
have found that nanoparticle surfaces greatly impact their
performance [6,7]. Because
nanoparticle surfaces come in contact with biological systems,
surface characteristics determine
how the nanoparticles will behave in vivo and the overall
effectiveness of the particles, including
stability, cellular interaction, uptake, drug delivery, and
toxicity [4,6,8,9]. Therefore, engineering
of the particle surface provides another dimension of control
for specifically tailoring the
functions and developing smart nanoparticles.
Nanoparticle surfaces have been engineered in various ways for
specific functions depending on
the intended therapeutic use. Surface modifications such as
attachment of bioactive and
penetrating molecules, use of stimulus-responsive materials,
surface coating, and modification of
surface charge, texture, and shape allow nanoparticles to serve
as smart devices that interact
selectively with targeted cells, enter the core of tissues, and
release drugs at a controlled rate,
escaping from body clearance [4,10]. Surface modification with
hydrophilic biocompatible
polymers increases the circulation time and delays the removal
of nanoparticles by the
mononuclear phagocyte system (MPS), preventing rapid clearance
prior to reaching the targeted
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tissue and delivering drugs [11,12]. The surface charge of
nanoparticles has been modified
according to the charge of the target cells or tissues to
increase cellular interaction and
internalization [13]. Conjugating active molecules on the
surface of nanoparticles converts them
into guided vehicles that exhibit cell-specific targeted
interactions and penetrate to the core of
the target tissue [1,14,15]. Attachment of specific penetrating
peptides to nanoparticles is also
effective for enhancing cellular uptake [16]. Nanoparticle
surfaces have been decorated with
stimulus-responsive materials to release drugs in response to
various stimuli [17]. Importantly,
the orientation and alignment of surface molecules affect their
functions and the overall
efficiency of nanomedicines [15,16]. In addition, modification
of surface roughness and
nanoparticle shapes significantly affect cellular interactions
and drug release [18], and
nanoparticle toxicity is related to surface properties, as
variation in surface characteristics has
significantly lowered the level of toxicity [19,20]. Combining
these properties has allowed
development of intelligent nanoparticles to meet delivery and
therapeutic objectives [21].
Surface engineering thus has become a major tool to address the
particular challenges of
nanotherapeutics. Studies have shown how surface engineered
nanoparticles can efficiently
overcome the limitations of other delivery systems [22].
Nowadays, proper surface
functionalization has become a prerequisite for effective
application of nanoparticles [23]. In this
review, we focus on different surface characteristics of
nanoparticles and discuss conventional
and newer functionalities that have been discovered to increase
the efficiency of nanoparticles.
We further review the effect of surface molecule and
nanoparticle orientations on function.
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2. SURFACE MODIFICATION FOR ENHANCED STABILITY OF
NANOPARTICLES
Surface properties play the most important role for nanoparticle
stability in blood circulation.
Conventional nanoparticles with unmodified surfaces are unstable
and rapidly cleared by the
MPS before reaching the target tissue. Nanoparticles are
recognized by the immune system
through opsonization, a process by which a particle becomes
covered with opsonin proteins,
making it more visible to the MPS (liver, spleen, lungs, and
bone marrow), and thereby
increasing clearance [24]. Different functional groups on
nanoparticle surfaces are the primary
determinants of stability [24,25]. Usually, the degree of
hydrophobicity determines the extent of
opsonin binding: a high level of hydrophilicity is associated
with lower opsonin binding and
higher stability of nanoparticles in blood circulation, whereas
hydrophobic surfaces induce
nanoparticle aggregation through hydrophobic interactions and
minimize surface energy, which
can trigger opsonization and rapid elimination [26].
The stability of nanoparticles in blood has been increased by
surface modification. The surface
has been coated with biocompatible hydrophilic
polymers/surfactants or copolymers with
hydrophilic properties. Hydrophilic polymers on the surface of
the nanoparticles repel other
molecules by steric effects. Thus, nanoparticles are not covered
with opsonin proteins and are
protected from rapid clearance [27]. Widely used surface-coating
materials for prolonging the
circulation time include polyethylene glycol (PEG), polyethylene
oxide (PEO),
polyvinylpyrrolidone (PVP), polyacrylic acid, dextran,
poloxamer, poloxamine, and polysorbate
(Tween-80). PEG is the most widely used material and has
efficiently enhanced the stability of
nanoparticles in many studies [26,27,28].
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In addition to the density of the polymer on the nanoparticle
surface, polymer conformation
plays a significant role in determining stability [27]. PEG
molecules with brush-like
configurations on the surface of nanoparticles reduce
phagocytosis and complement activation,
whereas mushroom-like structures of PEG are potent complement
activators and favor
phagocytosis [11,29]. Polymer conformation is described using
the Flory radius, F (Eq. 1), which
is determined by the number of monomers per polymer chain, n,
and the length of one monomer,
, in Angstroms ( = 3.5 for PEG). Hence, F increases with
increasing molecular weight of
PEG. Polymers that are less densely grafted to the nanoparticle
surface form mushroom-like
structures wherein the mean distance between each grafting site
is larger than the polymer size
(Flory radius); thus, the individual polymer chains remain
separated without interacting. When
the mean distance is decreased and F is increased, each polymer
chain overlaps, resulting in
higher grafting density and polymer interaction. It forms a
brush like conformation PEG,
extending from the NP surface [30]. Brush-like PEG chains on the
surface establish a
hydrophilic lining that prevents attachment of molecules to the
nanoparticles [31]. PEG densities
below 9% on the surface of nanoparticles form a mushroom-like
structure, and those above 9%
form a more rigid, brush-like morphology [32]. Larger
nanoparticles can be coated with smaller
lengths of PEG (3,40010,000 monomers) because increases in
hydrodynamic radius can shorten
the half-life [33].
Equation 1:
F = n3/5
--------------------------------------------------------------------------------------------------
(1)
Superparamagnetic iron oxide nanoparticles (45 nm) were coated
with 2030 dextran chains in
a brush-like conformation, which reduced the rapid clearance of
the nanoparticles from the
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bloodstream with a prolonged half-life (t1/2) of 34 h [34].
Figure 1 illustrates the effect of PEG
density on serum exposure and macrophage uptake. Neutral
functional groups on nanoparticle
surfaces provide excellent protection from opsonization, whereas
charged functional groups are
responsible for active nanoparticle interaction with target
cells [35,36]. A zwitterionic copolymer
showed excellent shielding of nanoparticles in blood circulation
and maximized their interactions
with target tissue. Yuan et al. developed a zwitterionic
polymer-based nanoparticle for enhanced
drug delivery to tumors. The nanoparticles were neutrally
charged at physiological conditions
and thus showed a prolonged circulation time (t1/2 24.05 h in a
three-compartment
pharmacokinetic model). After leaking into the tumor, the
nanoparticles became positively
charged in the acidic extracellular environment, and were
efficiently taken up by tumor cells
[35]. In our previous study, we modified silica nanoparticles
with a PEG-conjugated
polyethyleneimine copolymer, and studied the biodistribution
profile by ICP-MS and
fluorescence imaging. The observed biodistribution indicated
that the particles were retained for
a long time, and efficiently entered A549 lung cancer cells
[37].
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Figure 1. Influence of PEG density on serum protein adsorption
to gold nanoparticles and their
subsequent uptake by macrophages. (Adapted with permission from
C.D. Walkey, J.B. Olsen, H.
Guo, A. Emili, W.C. Chan. Nanoparticle size and surface
chemistry determine serum protein
adsorption and macrophage uptake. J. Am. Chem. Soc. 134 (2012)
2139-2147. Copyright (2012)
American Chemical Society.)
Although hydrophilic materials on the surface of nanoparticles
prevent them from being
opsonized, hydrophobic characteristics are often required for
purposes such as controlled release
and increasing membrane permeability and cellular uptake [38].
Amphiphilic copolymers with
both hydrophilic and hydrophobic residues have shown promising
results addressing these
issues. The hydrophobic part interacts with the hydrophobic
core, whereas the hydrophilic part
remains outside to protect the nanoparticles from opsonization.
Subtle Change in the degree of
surface hydrophilicity and hydrophobicity has also shown
substantial effect on circulation and
uptake. [38,39]. Block copolymers have been popular for
designing nanomaterials, incorporating
desired properties of several polymers [40]. Novel amphiphilic
triblock copolymers consisting of
PEG as the hydrophilic segment and poly(-caprolactone) as the
hydrophobic block were used
successfully to encapsulate the poorly water-soluble anticancer
drug 4 -demethyl-
epipodophyllotoxin via hydrophobic interactions, resulting in
controlled drug release [41].
3. SURFACE CHARGE AND CELLULAR INTERACTIONS
Because cell membranes are charged, nanoparticle surface charge
plays a major role in active
cell interaction and cellular uptake. Neutral and negatively
charged nanoparticles show lower
levels of internalization than positively charged particles
because of the negative charge of the
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cell membrane [35]. Several cationic polymers such as
poly(L-lysine) (PLL), poly(ethylenimine)
(PEI), chitosan, and diethylaminoethyl-dextran (DEAE-DEX) have
been used successfully for
cellular uptake. PEI bears the highest density of charged groups
on its surface and greatly
increases membrane permeability, as reported in several studies
[42-46].
Cationic particles bind to negatively charged groups on the cell
surface (e.g., sialic acid) and
translocate across the plasma membrane [43]. The amount of
positive charge is correlated with
cellular internalization. Clathrin-dependent endocytosis occurs
at lower charge density, whereas
strongly charged surface coatings bypass typical uptake
mechanisms in certain cells [13]. When
the endocytic pathway is inhibited, compensatory endocytosis
causes higher internalization of
cationic particles [47]. Among cationic polymers that do not
possess fusogenic activity, some
can disrupt endosomal membranes through their buffering capacity
[48]. Moreover, plasma
proteins can bind to the cationic surface of nanoparticles and
increase cellular uptake [49].
Depolarization of the plasma membrane and formation of holes in
lipid bilayers by cationic
nanoparticles is common regardless of the shape, chemical
composition, deformability, charge
density, or size of the particles [50]. Positively charged
nanoparticles are also effective in
mucosal drug delivery. Nanoparticles coated with chitosan or
hyaluronic acid showed increased
in vivo association to gastrointestinal tract mucosae, nasal
mucosae, and the cornea [48].
Efficient uptake of cross-linked chitosan nanoparticles (e.g.,
particles having a zeta potential of
+15 to +30 mV) by Caco-2 cells has been reported in several
studies [51]. Positively charged
nanoparticles have also shown increased penetration through the
skin [52,53].
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Despite these findings showing greater interactions, a
positively charged surface is not a
prerequisite for efficient endocytosis. Neutral or negatively
charged nanoparticles also show
efficient cellular uptake, especially when conjugated with
targeting ligands. There is also
evidence of internalization of negatively charged particles
without targeting ligand. Nonspecific
binding and clustering of the particles on the few cationic
sites on the plasma membrane are
believed to be responsible for their internalization [47,54,55].
Oligonucleotide-modified gold
nanoparticles were examined for cellular uptake and were readily
taken up by mouse endothelial
cells even with negative surface charge [56]. Further study
revealed the adsorption of serum
proteins on the surface of the nanoparticles through
electrostatic and hydrophobic interactions,
which allowed them to interface with the cell membrane [56,57].
The possible role of
nanoparticle surface charge on entry through the apical plasma
membrane (facing the external
environment) was investigated. Both cationic and anionic
nanoparticles were targeted mainly to
the clathrin endocytic pathway. A few nanoparticles (both
positive and negative) were thought to
be internalized through a macropinocytosis-dependent pathway.
Many nanoparticles
transcytosed and accumulated at the basolateral membrane, and
some anionic nanoparticles
transited through the degradative lysosomal pathway. It was
therefore suggested that cationic
nanoparticles may be promising carriers for transcytosing drugs
[58].
Cationic nanoparticles have been found to cross the blood-brain
barrier (BBB) to a greater
extent, resulting in increased brain penetration [59]. However,
highly cationic and anionic
nanoparticles were found to cause charge mediated disruption of
the BBB. Neutral and slightly
negative NPs were more effective in delivering therapeutics in
brain, maintaining the integrity of
BBB [60].
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4. CELL TARGETING LIGAND ON THE SURFACE OF
NANOPARTICLE
Targeting molecules are the major components in active tissue
targeting. Specific targeting
moieties can be conjugated to the surface of a core particle
that recognizes the unique surface
properties of the targeted cells. Molecular interactions between
nanoparticle and cell surfaces are
based on ligand-receptor binding theory [61]. Targeting
agent-linked nanoparticles are
internalized through the pathway utilized by the unconjugated
ligand, and the higher
concentrations of targeting agents on nanoparticle surfaces
cause stronger cell interactions
compared to those observed with the ligand alone [40]. Figure 2
depicts a comparison of cellular
uptake among nanoparticles conjugated to a targeting moiety,
PEGylated nanoparticles, and
unconjugated nanoparticles. It shows a high cellular uptake of
folate-conjugated nanoparticles
and greater internalization of PEGylated particles than that
observed with unmodified
nanoparticles because of increased circulation time. Various
molecules such as folic acid, biotin,
transferrin, peptides, enzyme substrates, mono- or
oligosaccharides (which specifically interact
with the membrane protein lectin), and antibodies have been
successfully used as the targeting
moiety [62]. Table 1 summarizes some investigations of
ligand-conjugated nanocarriers and their
extent of cellular uptake. In most of these studies,
nanoparticles were successfully internalized
despite bearing negative surface charges. The uptake of
particles was associated with the
targeting moiety rather than with the effect of surface charge.
Successful uptake was also shown
for positively charged particles. These findings suggest that
the surface charge of nanoparticles is
not significant when targeting moieties are conjugated.
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Figure 2. Confocal microscopic images of KB cells treated with
(A) PLGA nanoparticles, (B)
functional PLGA nanoparticles (PLL-PEG coated), and (C)
folate-conjugated nanoparticles.
(Adapted with permission from S.H. Kim, J.H. Jeong, K.W. Chun,
T.G. Park. Target-specific
cellular uptake of PLGA nanoparticles coated with
poly(l-lysine)-poly(ethylene glycol)-folate
conjugate. Langmuir 21 (2005) 88528857. Copyright (2012)
American Chemical Society.)
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Table 1.
Different targeting moieties on nanoparticle surfaces and extent
of their internalization.
Targeting
Moiety
Nanoparti
cle
Size
(nm)
Surface
Charge
(mV)
Targeted
Tissue
Result Conjugation
Method
Referen
ces
Folate
PLGA
Nanoparti
cles
108.9 -18.4 KB 6.7-fold
higher uptake
Covalent
Binding
(amide
linkage)
[63]
Iron
Oxide
Nanoparti
cles
60-80 -12.5 HeLa >3-fold
higher uptake
Covalent
Binding
(amide
linkage)
[64]
Transferri
n
PLGA
Nanoparti
cles
220 -8 PC3 3-fold higher
uptake
Linker
Chemistry
[65]
Biotin Gold
Nanoparti
cles
20-40 - HeLa,
A549,
MG63
>2-fold
higher uptake
Covalent
Binding
(amide
linkage)
[66]
Chitosan
Nanoparti
cles
165.3 +16.5 MCF-7
cells
>2-fold
higher uptake
Covalent
Binding
(amide
linkage)
[67]
Monoclo
nal
Antibody
PLGA
Nanoparti
cles
124.2 +12.0 MDA-
MB-231
cells
>2-fold
higher uptake
Covalent
Binding
(amide
[68]
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linkage)
RGD
Peptide
Albumin
Nanoparti
cles
130 -30.77 BxPC-3 >2-fold
higher uptake
(after 24 h)
Linker
Chemistry
[69]
Galactose Gold
Nanoparti
cles
50 -30 Hepatocy
te
16-fold
higher uptake
Au-S Binding [70]
Targeting moieties are attached to nanoparticles with longer
chains so that they extend outside of
the dense polymer brush, thereby avoiding steric hindrance and
enabling binding to the targeted
receptors [61,71]. However, increased ligand concentrations on
nanoparticle surfaces can
enhance rapid clearance due to adsorption of opsonin. Gu et al.
used aptamers as a targeting
ligand for prostate cancer-specific antigens (PSMA) and found
greater accumulation of
nanoparticles in the liver and the spleen with higher surface
ligand density. The nanoparticles
also showed lower tumor localization compared to the particles
functionalized with lower
densities of aptamers [72]. These findings were supported by
Kirpotin et al., who used an HER-2
antibody and observed higher clearance rates with dense ligand
loading. High targeting moiety
surface density makes the stealth polymer layer ineffective,
resulting in serum protein binding
[73], which can diminish the ability of the ligands to interact
with the target receptors [74].
Therefore, the number, density, and orientation of targeting
ligands on the surface of
nanoparticles are important for effective targeting.
The active site of the ligand must be available in the correct
three-dimensional arrangement to
bind to the receptor [75]. Particular consideration is required
to ensure that serum proteins do not
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cover the targeting moiety. As previously discussed, the
addition of targeting moieties may
compromise the stealth feature of nanoparticles and can
accelerate their clearance [76]. Salvati et
al. developed transferrin-modified PEGylated silica
nanoparticles (86 nm) and observed that the
accumulation and uptake of transferrin-modified particles was
lower than that of the unmodified
particles. The number of transferrin molecules per nanoparticle
was high (~250), and a protein
corona formed on the nanoparticles [74]. McNeeley et al.
observed a similar effect for
doxorubicin-loaded, folate-modified PEGylated liposomal
formulations: the incorporation of
0.15% (of total lipid formulation) folate conjugates resulted in
a 41.8% smaller area under the
curve (AUC), whereas formulations containing 0.2% folate
conjugates demonstrated a 61.9%
reduction in AUC compared to that observed with non-targeted
liposomes [77]. These results
imply that low ligand concentration can increase half-life and
improve biodistribution of
nanoparticles.
Lee et al. developed folate-modified tetrahedron-shaped
oligonucleotide nanoparticles (28.6 nm)
for siRNA delivery and showed that at least three folate
molecules per nanoparticle are required
for optimal delivery to cancer cells. Increasing the number of
folate molecules did not increase
the cellular uptake. The nanoparticles showed a longer
circulation time in vivo (t1/2 24.2 min).
They found that gene silencing occurred only when the ligands
were in the appropriate spatial
orientation. The density and location of folate on the
tetrahedron were varied, and greater gene
silencing was observed when the local density of three folic
acids on the tetrahedron was
maximized (encompassing a face of the tetrahedron). However,
when the density of the three
folic acid molecules was decreased (greater distance from each
other), no gene silencing was
observed. They speculated that higher local ligand density might
influence the intracellular
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trafficking pathway of nanoparticles through the cells and
affect gene silencing [78]. Elias et al.
developed ligand conjugated magnetic nanoparticle and showed
that an intermediate ligand
density can provide greater cellular association compared with
higher and lower ligand densities.
Even though multivalency increases binding avidity,
over-crowding can prevent ligands from
obtaining the correct orientation. Furthermore, higher ligand
density can saturate receptor
binding [79]. The receptor density reaches an entropic limit at
critically large ligand density,
resulting in insufficient adhesion to overcome membrane
deformation cost [80].
These investigations indicate that the number and orientation of
the targeting ligand should be
considered for proper biodistribution and cellular uptake.
Optimizing the number of ligands and
their orientations is critical for nanotherapeutics and is not
equivalent to increasing the number of
ligands per nanoparticle.
4.1 METHODS CURRENTLY BEING DEVELOPED FOR TARGETING
Methods for increasing target specificity are currently being
developed, and some show
increased efficiency over conventional targeting strategies.
These methods are based on surface
engineering and involve two steps. In the first step, signaling
molecules or surface labels are
delivered to the target cells; in the second step, therapeutic
nanoparticles with complimentary
surface functionality target those molecules. This has been
described by two approaches called
communication control system and chemical targeting system; both
effectively amplify the
location of a tumor and subsequently target the amplified tumor
with therapeutic particles [81].
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Von Maltzahn et al. reported the communication control system
where tumor-targeted tissue
factor (tTF-RGD) was delivered as a signaling module to activate
the coagulation cascade in
tumors. Coagulation transglutaminase factor XIII (FXIII)-binding
peptides were conjugated on
the surface of doxorubicin loaded liposomes which acted as the
receiving module to target the
coagulation. This autonomous communication system improved the
tumor targeting efficiency
by up to 40-fold relative to particles without a communication
system [82].
The chemical targeting system involves in vivo metabolic
labeling with artificial chemical
groups. Unnatural azide-functionalized glycans are delivered to
cells and become incorporated
by glycosylation. These azide functional groups are nonreactive
and compatible with endogenous
biological molecules. Cells effectively "tag" glycoproteins with
the azide group by using an
intrinsic glycan synthesis process and express azide-modified
sialic acids on their surface. This
azide group then can be specifically targeted by an
alkyne-activated compound, using copper-
free "click" chemistry. Various cancer cell lines including
A549, U87MG, MCF-7, and KB cells
have been shown to express azide groups homogeneously on the
cytoplasmic membrane [83,84].
Lee et al. reported tumor targeting using a chemical targeting
system (Figure 3). In the first step,
an unnatural glycan, tetraacetylated N-azidoacetyl-D-mannosamine
(Ac4ManNAz), was used to
introduce azide groups on the cell surface. Ac4ManNAz was
delivered to cells by using chitosan
nanoparticles, which accumulated in tumor cells by enhanced
permeability and retention effect.
Cells expressed azide-containing glycoproteins in a
dose-dependent manner. In the second step,
Ce6-loaded bicyclo[6.1.0]-nonyne-modified nanoparticles were
delivered to A549 human lung
cancer cells for effective photodynamic therapy. The
nanoparticles showed significantly higher
tumor accumulation than did unmodified particles [84].
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Figure 3. Tumor targeting strategy via metabolic
glycoengineering and click chemistry.
(Adapted with permission from S. Lee, H. Koo, J.H. Na, S.J. Han,
H.S. Min, S.J. Lee, S.H. Kim,
S.H. Yun, S.Y. Jeong, I.C. Kwon, K. Choi, K. Kim. Chemical
tumor-targeting of nanoparticles
based on metabolic glycoengineering and click chemistry. ACS
Nano 8 (2014) 20482063.
Copyright (2012) American Chemical Society.)
5. PENETRATING AGENTS
Cell-penetrating peptides (CPPs) are short peptide sequences
that can assist nanoparticle entry
into the cell and have delivered drugs 200 times larger than
their established size limit for
bioavailability. Surface modification with CPPs enhances the
cell permeability of nanoparticle-
based drug delivery systems [85,86]. Unlike targeting ligands,
CPPs can assist nanoparticle
internalization to various types of cells (not specific for a
particular cell type) and are especially
useful for internalizing nanoparticles by passive targeting
[87,88]. Trans-activating
transcriptional activator (TAT) has been widely tested and has
shown potential for enhancing
cellular uptake. Other CPPs include penetratin, transportan,
VP-22, MPG, Pep-1, MAP, SAP,
PPTG1, hCT (932), RGD, and SynB [89].
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TAT moieties were attached to the surface of long-circulating
PEGylated liposomes and PEG-
phosphatidylethanolamine (PEG-PE)-based micelles by using
TATp-short PEG-PE derivatives
and showed high level of internalization [90]. Superparamagnetic
iron oxide particles,
conjugated to the TAT peptide sowed approximately 100-fold
higher cell penetration than non-
modified particles [91]. Zhao et al. developed paclitaxel-loaded
polymeric liposomes with
surface-conjugated TAT peptide and folic acid (size: 6070 nm;
zeta potential: 28.69 mV). A
cellular internalization study showed that TAT peptide-modified
particles, and folate-TAT
peptide-modified particles had 2.63-fold and 3.38-fold higher
uptakes, respectively, than
unmodified particles in A549 cells, and 6.67-fold and 24.27-fold
higher uptakes, respectively,
compared to unmodified particles in KB cells [88].
Todorova et al. studied the effects of TAT peptide concentration
and surface arrangement on
membrane permeation capacity using 3-nm gold nanoparticles. They
found that maximal
penetration occurred with 5.4% TAT (Figure 4). A high TAT
concentration could reduce the
stability of nanoparticles in solution and result in lower cell
penetration ability. Dense
arrangement of TAT peptides resulted in like-charge repulsion,
which changed the solution
conformations to disfavor membrane interactions [92]. Therefore,
it is necessary to control and
maintain appropriate surface coverage of CPPs to produce stable
and cell-permeating
nanoparticles.
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Figure 4. TEM images of nanoparticles in the cytosol showing the
effect of CALNNTAT
concentrations on the internalization of gold nanoparticles by
HeLa cells. (a) 1.8%; (b) 3.6%; (c)
5.4%; and (d) 9.0%. (Adapted with permission from N. Todorova,
C. Chiappini, M. Mager, B.
Simona, I.I. Patel, M.M. Stevens, I. Yarovsky. Surface
presentation of functional peptides in
solution determines cell internalization efficiency of tat
conjugated nanoparticles. Nano Lett 14
(2014) 5229-5237. Copyright (2012) American Chemical
Society.)
Petersen et al. developed penetratin-conjugated gold
nanoparticles and demonstrated up to 100%
uptake within 2 h in a preliminary biological study [93]. Most
CPPs are positively charged, and
zeta potential is thought to play a major role in cellular
uptake; however, CPP-conjugated
nanoparticles with negative zeta potentials also show effective
cellular uptake. PEG-poly(lactic
acid) nanoparticles were functionalized by penetratin for
efficient biodistribution and brain drug
delivery. The particles (100 nm) with a zeta potential of -4.42
mV showed enhanced cellular
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uptake in MDCK-MDR cells via both lipid raft-mediated
endocytosis and direct translocation
processes. They also exhibited significantly enhanced brain
uptake and reduced interactions with
non-targeted tissues in in vivo pharmacokinetic and
biodistribution studies [94].
Although the exact mechanism by which CPPs enter cells remains
unclear, two general
mechanisms, direct penetration and endocytosis, have been
described for their internalization.
Direct penetration occurs through various mechanisms including
inverted micelle formation,
pore formation, the carpet-like model, and the membrane thinning
model. The first step in all of
these pathways is interaction between the positively charged CPP
and negatively charged
elements of the cell membrane (e.g., heparan sulfate and the
phospholipid bilayer), which results
in stable or transient destabilization of the membrane. In
contrast, endocytic pathways include
phagocytosis for large particles and pinocytosis for smaller
particles. In pinocytosis, vesicles are
formed after the inward folding of the outer surface of the cell
membrane. Clathrin or caveolin
pits are involved in receptor-mediated endocytosis [95].
6. EFFECT OF SHAPE
In addition to other surface properties, the shape of
nanoparticles was found to be useful for their
interaction with cells, cellular uptake, biodistribution, and
subsequent fate [96]. For drug
delivery, zero-order release was achieved with a hemi-spherical
particle that degraded at its face
[97]. Transferrin-coated rod-shaped nanoparticles were developed
with much lower
internalization efficiency than transferrin-coated spherical
nanoparticles. The uptake of the rod-
shaped nanoparticles was speculated to be more dependent on
their width than length [98].
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Internalization kinetics and efficacy can be affected by local
surface curvature, which determines
the interactions between cell and particle surfaces. Spherical
gold particles with diameters of 14
or 75 nm showed 375500% greater uptake in HeLa cells than 74 14
nm rod-shaped particles.
Chan et al. hypothesized that the differences in particle
curvature were responsible for the
differences in cellular uptake, which was affected by particle
contact area with the cell
membrane [18]. Florez et al. evaluated particle shape and
demonstrated that ellipsoidal
nanoparticles had higher cell surface binding but lower uptake
compared to spherical particles.
The negative correlation between aspect ratio and uptake rate
was related to the lower uptake of
non-spherical nanoparticles, which was further explained by the
larger radius of curvature for
non-spherical particles adsorbed on the cells [99]. A similar
effect was observed for polystyrene
nanoparticles upon change from a three-dimensional spherical
particle to a two-dimensional disk,
which enhanced cell surface binding but reduced cellular uptake.
The surface charges of the
spherical and disk-shaped particles were 13.6 and 16.8 mV,
respectively, which suggests the
role of shape in cellular uptake irrespective of surface charge
[100,101].
The effect of nanoparticle shape and orientation on the pattern
of cell penetration was examined.
Rod-shaped nanoparticles were most rapidly internalized among
all shapes when they were
longitudinally perpendicular to the cell membrane. When the rod
was oriented tangentially to the
cell membrane, the internalization rate significantly decreased.
This was explained by greater
difficulty enclosing the particles in their tangential
orientation. In contrast, the penetration of
spherical nanoparticles was independent of contact angle because
of their symmetric shape
(Figure 5) [102].
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Figure 5. Effect of shape and nanoparticle orientation on
cellular uptake.
Xu et al. reported the effects of the shape of layered double
hydroxide (LDH) particles (rods with
width 3060 nm and length 100200 nm and hexagonal sheets with
width 50150 nm and
thickness 1020 nm) on cellular internalization. Both shapes were
readily taken up by CHO-K1,
NIH 3T3, and HEK 293T cells. The rod-like particles specifically
targeted the nucleus, whereas
the sheet-like particles were retained in the cytoplasm. The
uptake of the differently shaped
particles was primarily associated with strong positive charge.
Both types possessed high zeta
potential (around +40 mV), which interacted with the negatively
charged cell membrane
irrespective of shape. Further investigation revealed that the
LDH particles were internalized
through clathrin-mediated endocytosis [103]. Gratton et al.
demonstrated uptake of PRINT-
fabricated nanoparticles of different sizes and aspect ratios in
HeLa cells and found that
cylindrical nanoparticles had the highest percentage of cellular
internalization over time. Cubic
particles showed similar internalization profiles to those of
cylindrical particles. However,
internalization depended on positive surface charge. When the
charge was reversed, uptake of
particles decreased dramatically [104].
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In blood circulation, nanoparticle motion encounters different
forces. Hemodynamic forces are
fluid resistant forces that oppose the motion of nanoparticles
in blood and are proportional to the
shape of the nanoparticle in a fluid with a moderate to high
Reynolds number. An investigation
of fluid resistant forces demonstrated that the force increased
with the radius of spherical
particles. Additionally, non-spherical particles experience
tumbling and rolling because of
unequal moments resulting from these forces [105,106].
Self-assembled filamentous micelles
with very high aspect ratios (2260 nm diameter, 28 m length)
were found circulate ten times
longer (~ 1 week) than spherical particles [107]. Polystyrene
particles of different geometric
shapes but otherwise identical properties (dimensions, surface
area, volume, and chemistry) were
fabricated, and their engulfment by macrophages was monitored.
The local particle shape at the
point of initial contact determined their phagocytic fate.
Macrophages that attached to elliptical
disks along the major axis internalized them very quickly (
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1.6% of the injected disk-shaped particles remained in the blood
at 1 and 30 min, respectively
[110]. Although more investigation is needed to fully determine
the role of particle shape in
clearance, these investigations imply that non-spherical
particles can be retained longer in blood
circulation and suggest a relationship between particle movement
in blood and clearance. As the
spherical particles maintain stable orientations during
movement, the complex tumbling and
rolling motions of non-spherical particles (with high aspect
ratios) might interfere with the
macrophage attachment and phagocytosis.
From these experiments, we conclude that, in blood circulation,
non-spherical particles with high
aspect ratios are phagocytosed less than spherical particles
are. However, spherical particles
show better performance in entering target cells than do the
non-spherical particles.
7. SURFACE TEXTURE OF NANOCARRIERS
The surface texture of nanoparticles can significantly affect
their cell attachment, interaction,
uptake, and drug delivery [111,112]. Although smoothness is
important for controlled drug
release, roughness also has beneficial effects. Surface
roughness promotes cell binding through
nonspecific binding forces that enhance cellular uptake. Direct
penetration into the cell
membrane may occur through a combination of nonspecific
attractive forces (e.g., roughness and
charge) on the surface of spiked particles without the need for
ligand-receptor interactions [111].
Niu et al. developed silica nanoparticles with a viral
capsid-like rough structure on the surface.
These particles were very effective in penetrating the membrane,
disrupting the endosome, and
delivering siRNA (Figure 6) [113]. Nanoscale surface roughness
greatly minimizes repulsive
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interactions (e.g., electrostatic and hydrophilic interactions)
between cells and nanoparticles,
thereby promoting adhesion and possibly facilitating engulfment
by cells [111].
Figure 6. Silica nanoparticles with capsid like rough surface
and their cellular uptake. (Adapted
with permission from Y. Niu, M. Yu, S.B. Hartono, J. Yang, H.
Xu, H. Zhang, J. Zhang, J. Zou,
A. Dexter, W. Gu, C. Yu. Nanoparticles mimicking viral surface
topography for enhanced
cellular delivery. Adv. Mater. 25 (2013) 6233-6237. Copyright
John Wiley and Sons)
Particles can be fabricated with different surface textures such
as ridges on the sides, with a
variation in surface areas and surface roughness. These surface
properties can be used to alter the
drug release pattern of nanoparticles or to affect their
movement in the bloodstream [114]. The
performance of aerosols was enhanced by increasing the surface
roughness in several studies.
Particles tend to become cohesive, partially amorphous, and
physically unstable in aerosols,
making powder deagglomeration and precise delivery to the lungs
difficult because of their
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cohesion forces. A small variation in the surface roughness was
important for reducing the
cohesion and performance variability of powdered BSA [115].
Rough surfaces were also useful
for mucoadhesion of nanoparticles for mucoadhesive drug
delivery. Ageros et al. developed
cyclodextrinpoly(anhydride) nanoparticles for bioadhesion within
the gut, where high
bioadhesive capacity was observed for nanoparticles with a rough
surface morphology [116]. In
contrast, surface smoothness is needed to minimize the variation
in drug release and can be an
important factor in the biodistribution of nanoparticles
[112,113]. Proteins and biomolecules tend
to bind more to the rough surfaces of nanoparticles than to
smoother surfaces [113]; therefore,
nanoparticles with smoother surfaces are more stable in
biological systems [24].
8. STIMULI RESPONSIVE DELIVERY
Drug release can be triggered by internal and external stimuli.
The carrier system can be
designed with materials to control the release of drug in the
targeted area [117]. Materials or
chemical groups sensitive to various stimuli are conjugated to
the surface of nanoparticles and,
upon exposure to the stimulus, undergo a conformational change,
cleavage, or other chemical
changes that result in drug release [18].
8.1 SURFACE SWITCHING
Recently, surface switching has been investigated for stimuli
responsive delivery. In this
technique, surface molecules or chemical groups can toggle
activity upon exposure to different
stimuli. This method includes changing wettability
(hydrophilicity-hydrophobicity), surface
charge, or shape in response to temperature, pH, electric field,
light, and ionic strength
[118,119].
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Yoo et al. reported low-molecular-weight PLGA nanoparticles
(160310 nm) that were able to
switch their shape from elliptical disk to spherical in a
stimulus-responsive manner. Elliptical
disk-shaped particles show prolonged circulation and increased
tumor accumulation but exhibit
slower cellular uptake compared to spherical particles. The
disk-shaped particles could become
spherical in the targeted area for efficient internalization.
The shape-switching characteristics
were achieved by a subtle balance between polymer viscosity and
interfacial tension. The PLGA
molecules possess a carboxylic acid end group, and the
interfacial tension of PLGA particles was
controlled through ionization of these carboxylic acid groups.
At physiological pH, the end
carboxyl groups are charged, causing low hydrophobicity and low
interfacial tension. When the
pH was lowered, carboxylate groups were protonated, thus
increasing hydrophobicity and
inducing the shape switch with an exponential response, where
interfacial tension provided the
main driving force for shape change [120].
Rotello et al. recently reported surface charge-based DNA
uncaging from the surface of
photolabile gold nanoparticles. The surface was designed with a
photocleavable o-nitrobenzyl
ester linker and a quaternary ammonium salt to switch the
surface from cationic to anionic upon
irradiation. DNA was complexed with the nanoparticles. After
irradiation with near-UV light, the
nitrobenzyl linkage was cleaved to produce an anionic
carboxylate group, resulting in DNA
release. In vitro studies were conducted using a T7 RNA
polymerase assay, which revealed
restored DNA transcription upon UV irradiation [121].
Lahann et al. developed a smart surface that changes its
wettability in response to an electrical
potential. Gold nanoparticles with a self-assembled
16-mercaptohexadecanoic acid (MHA)
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monolayer were fabricated to possess a hydrophobic chain capped
by a hydrophilic carboxylate
group. Upon applying the electrical potential, the negatively
charged carboxylate groups were
attracted towards the positive gold surface, resulting in a
conformational change of the MHA
hydrophobic chains. Because of this chain bending, the aliphatic
MHA chains were changed
from an all-trans conformation to a mixture of trans and gauche
conformations. This mixed
conformation increased intermolecular van der Waals contacts and
exposed hydrophobic chains
to the surface, converting the hydrophilic surface to a
moderately hydrophobic state [122].
8.2 ENZYME RESPONSIVE SURFACE DESIGN
Enzymes have also been targeted for responsive drug delivery. In
some diseases, abnormal
production of enzymes differentiates diseased cells from normal
healthy cells. Nanomaterials
have been designed with appropriate substrates, mostly peptides,
attached to the surface of the
nanoparticle, that are cleaved by the respective enzyme, causing
release of the drug [119]. For
example, matrix metalloproteinase (MMP) is overexpressed by many
cancer cells and is needed
for their metabolism. Specific peptide sequences attached to the
surface of nanoparticles are
cleaved between Leu and Gly residues by MMP [119,123]. We
previously reported the
development of MMP-sensitive gold nanorods using a peptide
sequence Gly-Pro-Leu-Gly-Val-
Arg-Gly-Cys conjugated to a fluorescent probe (Cy5.5) for
simultaneous imaging and treatment
of cancer by hyperthermia. The enzyme-sensitive nanorods were
studied in HeLa cells, and the
Cy5.5 activated by MMP enzymes in the cell culture media was
successfully visualized [123].
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9. EFFECT OF SURFACE PROPERTIES ON NANOPARTICLE
TOXICITY
The toxicity of nanomedicines has become a major issue impeding
their effective application.
Several toxic effects of nanoparticles such as endocrine
disruption and neurotoxicity have been
reported [124,125]. The abundance of macrophages and
accumulation of nanoparticles cause
organs such as the liver and spleen to be highly affected by
toxicity. Organs with high blood flow
(e.g., kidney and lung) are also prone to nanoparticle-induced
toxicity. Inside cells, nanoparticles
may interact with cellular components, alter cell function,
damage DNA, arrest the cell cycle,
cause mutagenesis, create reactive oxygen species (ROS), and
induce apoptosis. As nanoparticles
have a large surface area, various transition metals, chemicals,
and proteins can be attached to
their surface and produce ROS [126-128]. The main molecular
mechanism underlying
nanotoxicity is free radical formation and induction of
oxidative stress by ROS, which can be
formed by several mechanisms including the phagocytic cell
response to nanoparticles, presence
of transition metals, and environmental factors [126].
Different nanoparticle surface properties such as charge and
functional groups can affect toxicity
[127]. Surface protection plays a critical role in preventing
toxicity by reducing deposition of
transition metals, chemicals, and proteins and the generation of
ROS [129]. Gold nanoparticles
without surface modifications have shown in vivo toxicity in
many studies. However, surface-
modified gold nanoparticles exhibit lower toxicity over long
exposure [130,131].
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9.1 ROLE OF DIFFERENT SURFACE MOLECULES IN NANOTOXICITY
Various reports indicate that nanoparticle toxicity is highly
dependent on the type of particle,
surface material and their molecular weights, and particle
concentrations [132]. Drug carriers can
be inorganic functional materials that impart unique
physicochemical properties such as
photothermal activity (gold nanorod), magnetic moment (iron
oxide nanoparticles), porous
structure (mesoporous silica nanoparticles), and fluorescence
(quantum dots [QDs]). However,
inorganic materials usually show toxicity [133]. Similarly,
organic materials such as different
synthetic polymers also show toxicity in vivo. Cationic polymers
appear to be especially toxic to
different organs. Interestingly, lower toxicity was observed for
a lower molecular weight cationic
polymer (PEI) [134]. Low-molecular-weight dextran on
nanoparticle surfaces also showed lower
toxicity than did high-molecular-weight dextran [135].
Furthermore, when toxic polymers are
linked to hydrophilic polymers such as PEG, the combined
amphiphilic polymers can reduce
toxicity [136].
Hoshino et al. developed carboxylic acid, polyalcohol, and
amine-modified QDs and evaluated
their cytotoxicity. The cytotoxicity of QDs was related to the
surface-conjugated molecules but
not the nanocrystalline particle itself. Among all the
particles, hydroxyl-modified QD was the
least toxic [137]. Our group developed silica-coated gold
nanorods, minimized the size of the
silica layer to sub-nanometer thickness, and performed
cytotoxicity studies. In our investigation,
a very thin layer of silica effectively reduced the toxicity of
gold nanorods with a half-maximal
inhibitory concentration >400 g/mL. The optothermal
efficiency of bare rods was maintained
even after coating with silica [138]. These results suggest that
hydrophilic nanoparticle surfaces
are important for preventing toxicity due to the protection of
surface from binding of different
molecules.
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Cetyltrimethylammonium bromide (CTAB) is a cationic surfactant
commonly used to stabilize
gold nanorods during synthesis. CTAB is highly toxic, causing
mitochondrial damage and
generating ROS. Displacement of CTAB with safe materials such as
PEG and citric acid or
conjugation with biocompatible hydrophilic materials can
significantly reduce gold-induced
toxicity [129,139]. Wang et al. reported that CTAB -containing
nanorods showed no toxicity in
vivo when conjugated to poly(styrenesulfonate) [129]. Boca et
al. examined the toxicity of
chitosan-capped gold nanoparticles in Chinese hamster ovary
cells and found that more than
85% of the cells were viable even after a long period of
exposure [130].
9.2 SURFACE CHARGE AND GEOMETRY IN NANOTOXICITY
Positively charged nanoparticles were reported to be toxic in
many studies because of their
ability to destabilize the negatively charged cell membrane
through electrostatic interactions
[127]. Positively charged particles can further damage the outer
membrane of mitochondria,
which is slightly negatively charged and has an electrochemical
gradient very similar to that of
the plasma membrane, which is very sensitive to charge. If
positively charged nanoparticles
accumulate outside the mitochondria, the mitochondrial membrane
potential is imbalanced,
resulting in membrane damage and release of pro-apoptotic
proteins into the cytosol [140].
Goodman et al. fabricated cationic and anionic nanoparticles
functionalized with quaternary
ammonium and carboxylate groups, respectively. Their results
demonstrated that cationic
nanoparticles were moderately toxic, whereas anionic
nanoparticles were non-toxic to cells
[141]. The toxicity of poly(amidoamine) PAMAM dendrimers was
evaluated in mice. Positively
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charged particles showed toxicity, whereas negatively charged
particles from the same materials
were non-toxic [127,142].
Yu et al. evaluated the toxicity of silica nanoparticles in
animal model. Nonporous silica
nanoparticles (120 nm) exhibited low systemic toxicity and the
highest maximum tolerated dose
(MTD) (450 mg/kg) compared to mesoporous silica nanoparticles
(MTDs: 3065 mg/kg).
However, toxicity decreased when mesoporous silica nanoparticles
were modified with primary
amine groups (MTDs: 100150 mg/kg) [143]. It suggests the
protection of large porous surface
for reducing toxicity. Although the surface was modified with
amines, toxicity depends on
charge density. Yu et al. showed increased cellular association
of silica nanoparticles with higher
zeta potentials (+17 mV versus +32 mV), which they explained by
a surface charge threshold
(> +30 mV) above which the amine functionalities facilitated
nanoparticle-cell interaction
through electrostatic interactions [144]. Adsorption of serum
proteins on the nanoparticle surface
can also decrease the overall charge and toxicity [145].
Different particle shapes and aspect ratios did not
significantly affect particle toxicity. However,
gold nanorods were shown to be more toxic than their spherical
counterparts [145]. Further
studies revealed that the toxicity was associated with surface
CTAB molecules and was
attenuated when CTAB molecules were replaced by other molecules
as discussed above.
10. PERSPECTIVE
Although the effects of different surface characteristics have
been discovered and various
methods of surface modification have evolved, control of
conjugation at specific sites with
ordered individual components will require optimization to
achieve reproducible and effective
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surface modifications [146]. Particle aggregation must be
carefully considered as it can diminish
the success of particle engineering [147]. Our current
observation suggests that nanomedicine
will be based on smart surface functionalities and will rely on
development of drug carriers as a
platform for prolonged blood circulation, interaction with
specific sites, and accurate drug
delivery in addition to addressing toxicity concerns during and
after drug delivery [146, 148].
Surface engineering will supplement existing techniques and will
be valuable for newer
applications. Since understanding of the interactions between
nanoparticle surface features and
the biological milieu is increasing, future particle design will
enable precise behavioral control of
nanomedicines, which may be applied as real-time monitoring
tools for biodistribution and drug
delivery [146, 147]. Functionalized moieties on the nanohybrid
structure will reform adjuvant
cancer therapy with selective and precise targeting and
destruction of cancer cells, which will
improve long-term survival.
Smart surfaces of nanoparticles may be utilized for
ultrasensitive biorecognition through the
interaction of biomarkers and the nanoparticle surface, which
will accelerate treatment of
complicated disorders [146]. As present targeting strategies
involve cellular internalization only,
there is a high probability that surface chemistry can be
designed to direct and localize
nanoparticles to a particular area [149,150]. In addition to
intracellular delivery, surface
functionalization will play a key role for delivery of
therapeutics to various sites. As several
studies have already shown that surface modification of
nanoparticles can enhance their cell
attachment, future formulations for drug delivery to the
extracellular matrix, which strongly
affects cell growth and death, will be based on engineered
surfaces. Hence, design of smart
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surfaces will be the most critical ground to improve cell
responses of nanomedicines for
particular applications.
Conclusion
Herein, we analyzed how various functionalities on nanoparticle
surfaces affect their desired
behavior. Several studies have successfully engineered
nanoparticle surfaces to overcome the
limitations of conventional nanoparticles where surface
modification was deemed the most
efficient technique to increase the efficacy of nanomedicines.
This review demonstrated how
surface modification and local orientations of surface molecules
are important for the efficiency
and utility of nanotherapeutics. Based on our current
understanding of nanoparticle surfaces, we
predict that surface functionalization will change and
revolutionize the therapeutic applications
of nanoparticles and treatment patterns of different diseases in
the near future.
Acknowledgment
This work was supported by the grant of National Research
Foundation of Korea (NRF), funded
by Korean government (MEST) (2012R1A2A2A03046819), and
(2013R1A1A2005329).
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