intracellular delivery barriers. In this review, we discuss the role of stimuli-responsive nanocarrier systems for drug and gene delivery. The
2.1. pH differences for stimuli-responsive delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Available online at www.sciencedirect.com
Journal of Controlled Release 126 (2008) 187–204
www.elsevier.com/locate/jconrel
2.2. Temperature differences for stimuli-responsive delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
2.3. Changes in the redox status at the disease site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
3. Illustrative examples of pH-responsive nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
3.1. pH-responsive polymeric nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
3.2. pH-responsive polymer–drug conjugates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
3.3. pH-responsive liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
3.4. pH-responsive micellar delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
3.5. pH-responsive dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
4. llustrative examples of temperature-responsive nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
4.1. Temperature-responsive polymeric nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
© 2008 Elsevier B.V. All rights reserved.
Keywords: Nanotechnology; Targeted delivery; Stimuli-responsive nanocarriers; pH; Temperature; Redox potential
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
1.1. Target-specific pharmacotherapy: need for nanocarrier delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
1.2. Passive and active targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
1.3. Intracellular delivery and sub-cellular distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
2. Stimuli-responsive delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
in material design, there is a highly promising role of stimuli-responsi
advancement in material science has led to design of a variety of materials, which are used for development of nanocarrier systems that can
respond to biological stimuli. Temperature, pH, and hypoxia are examples of “triggers” at the diseased site that could be exploited with stimuli-
responsive nanocarriers. With greater understanding of the difference between normal and pathological tissues and cells and parallel developments
ve nanocarriers for drug and gene delivery in the future.
Review
A review of stimuli-responsive nanocarriers for drug and gene delivery
Srinivas Ganta, Harikrishna Devalapally, Aliasgar Shahiwala, Mansoor Amiji ⁎
Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 110 Mugar Life Sciences Building, Boston, MA 02115, United States
Received 15 September 2007; accepted 3 December 2007
Available online 11 January 2008
Abstract
Nanotechnology has shown tremendous promise in target-specific delivery of drugs and genes in the body. Although passive and active
targeted-drug delivery has addressed a number of important issues, additional properties that can be included in nanocarrier systems to enhance the
bioavailability of drugs at the disease site, and especially upon cellular internalization, are very important. A nanocarrier system incorporated with
stimuli-responsive property (e.g., pH, temperature, or redox potential), for instance, would be amenable to address some of the systemic and
4.2. Temperature-responsive liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
⁎ Corresponding author. Tel.: +1 617 373 3137; fax: +1 617 373 8886.
E-mail address: m.amiji@neu.edu (M. Amiji).
0168-3659/$ - see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2007.12.017
5. Illustrative examples of redox-responsive nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
5.1. Disulfide cross-linked polymeric nanocarriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
5.2. Disulfide cross-linked liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
1. Introduction
1.1. Target-specific pharmacotherapy: need for nanocarrier
delivery systems
With parallel recent breakthroughs in molecular under-
standing of diseases and controlled manipulations of material at
the nanometric length scale, nanotechnology offers tremendous
delivered to desired sub-cellular compartments in an efficient
and reproducible manner [2].
Nanoparticulate carriers can be made from a variety of organic
and inorganic materials including non-degradable and biodegrad-
able polymers, lipids (liposomes, nanoemulsions, and solid-lipid
nanoparticles) self-assembling amphiphilic molecules, dendri-
mers, metal, and inorganic semiconductor nanocrystals (quantum
dots) [1,3]. The selection of material for development of
188 S. Ganta et al. / Journal of Controlled Release 126 (2008) 187–204
promise in disease prevention, diagnosis, and therapy [1].
Among the various approaches for exploiting developments in
nanotechnology for biomedical applications, nanoparticulate
carriers offer some unique advantages as delivery, sensing and
image enhancement agents [2]. Many bioactives used for
pharmacotherapy, while have a beneficial action, can also
exhibit side-effects that may limit their clinical application.
There has long been the desire to achieve selective delivery of
bioactives to target areas in the body in order to maximize
therapeutic potential and minimize side-effects. For example,
cytotoxic compounds used in cancer therapy can kill target
cells, but also normal cells in the body resulting in undesired
side-effects. For achieving better therapeutic application,
nanocarriers are considered for target-specific delivery of
drugs and gene to various sites in the body in order to improve
the therapeutic efficacy, while minimizing undesirable side-
effects. Improvements in target-to-non-target concentration
ratios, increased drug residence at the target site, and improved
cellular uptake and intracellular stability are some of the major
reasons for greater emphasis on the use of nanoparticulate
delivery systems. With nucleic acid-based therapeutic modal-
ities, there is substantial need for the therapeutic molecules to be
Fig. 1. Different types of stimu
nanoparticulate carriers is mainly dictated by the desired
diagnostic or therapeutic goal, type of payload, material safety
profile, and the route of administration. Preponderance of
literature on nanocarrier systems is based on the use of polymeric,
lipid, self-assembling, and a variety of inorganic nanoparticulate
carriers [1,3,4].
The use of stimuli-responsive nanocarriers offers an interesting
opportunity for drug and gene delivery where the delivery system
becomes an active participant, rather than passive vehicle, in the
optimization of therapy. Several families of molecular assemblies
are employed as stimuli-responsive nanocarriers for either passive
or active targeting. Liposomes, polymeric nanoparticles, block
copolymer micelles and dendrimers are colloidal molecular
assemblies (Fig. 1). The composition of each class of these
molecular assemblies can be manipulated to obtain nanocarrier
of desired stimuli-responsive property. The benefit of stimuli-
responsive nanocarriers is especially important when the stimuli
are unique to disease pathology, allowing the nanocarrier to
respond specifically to the pathological “triggers”. Select
examples of biological stimuli that can be exploited for targeted-
drug and gene delivery include pH, temperature, and redox
microenvironment [2,5–8]. The extracellular and intracellular pH
li-responsive nanocarriers.
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profile of biological system is greatly affected by diseases. For
instance, in solid tumors, the extracellular pH tends to be
significantly more acidic (∼6.5) than the pH of the blood (7.4) at
37 °C [9]. In addition, the pH values of endosomal and lysosomal
vesicles inside the cells are also significantly lower that the
cytosolic pH. By selecting the right material composition, it is
possible to engineer nanocarriers that can exploit these pH
differences and allow for delivery of the encapsulated payload to
specifically occur in select extracellular or intracellular sites.
Temperature is another variable that can be exploited in
specifically releasing the nanocarrier-delivered drugs or genes to
a select target site [10]. For instance, using temperature-sensitive
nanocarriers one could envision a delivery system that will only
release the payload at temperatures above 37 °C. Such a system
would keep the toxic drug encapsulated in the systemic circulation
or upon contact with non-targeted tissue. However, on application
drug throughout the tumor tissue [17]. Light-responsive
nanocarriers have also gained recent attention. Designing of
light sensitive polymeric systems that undergo reverse micelli-
zation/disruption under the action of light is an attractive idea
that would allow external control of drug release [18].
Discussion of extensive current literature on the external stimuli
is beyond the scope of the present review. Several examples
illustrating approaches to designing external stimuli are
available for further reading from the references [12–16].
1.2. Passive and active targeting
For systemic therapy, passive and active targeting strategies
are utilized. Passive targeting relies on the properties of the
delivery system and the disease pathology in order to
preferentially accumulate the drug at the site of interest and
189S. Ganta et al. / Journal of Controlled Release 126 (2008) 187–204
of hyperthermic stimuli to the disease area, the drug would be
readily available in a localized region [10]. Lastly, intracellular
glutathione (GSH) levels in tumor cells are 100–1000 fold higher
than the extracellular levels [11]. This concentration gradient can
be exploited using disulfide cross-linked nanocarriers that will
release the payload inside the cell. Such a system is especially
relevant in delivery of nucleic acid-based therapies, such as
plasmid DNA, small interference RNA, or oligonucleotide, since
these molecules have to reach intracellular targets in a stable form
for efficient therapeutic effect.
Another possible strategy is physical targeting of drugs and
genes by external stimuli (magnetic field, ultrasound, light and
heat) [12–16]. An interesting example is targeted delivery of
iron oxide nanoparticles using magnetic field. Upon the
administration, the drug immobilized magnetite carrier can
accumulate at targeted site under the direction of external
magnetic field [14]. During the last decade, ultrasound has
attracted growing attention in the targeted-drug delivery.
Ultrasound has been used to achieve the targeted delivery to
the tumor by local sonication after the injection of micellar
encapsulated drugs [15,16]. In addition to tumor uptake, this
technique also allows the uniform distribution of micelles and
Fig. 2. Schematic illustration for passive targeting using t
avoid non-specific distribution. For instance, poly(ethylene
glycol) (PEG)- or poly(ethylene oxide) (PEO)-modified nano-
carrier systems can preferentially accumulate in the vicinity of
the tumor mass upon intravenous administration based on the
hyper-permeability of the newly-formed blood vessels by a
process known as enhanced permeability and retention (EPR)
effect, schematically illustrated in Fig. 2. Maeda and colleagues
[19,20] first described the EPR effect in murine solid tumor
models and this phenomenon has been confirmed by others.
When polymer–drug conjugates are administered, 10–100 fold
higher concentrations can be achieved in the tumor due to EPR
effect as compared to administration of free drug [21]. The EPR
effect has been also present in other diseases such as chronic
inflammation and infection. Thus, the application of nanocar-
riers is expected to have therapeutic benefits for treating these
diseases as well [22]. The tendency of nanocarriers to localize in
the reticuloendothelial system also presents an opportunity for
passive targeting of bioactives to the macrophages present in the
liver and spleen. For example therapies can be used to treat
intracellular infections such as candidiasis, leishmaniasis and
listeria; where macrophages are directly involved in the disease
process [23]. Other approaches for passive targeting involve the
he enhanced permeability and retention (EPR) effect.
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use of specific stimuli-sensitive delivery system that can release
the encapsulated payload only when such a stimuli is present.
For instance, the pH around tumor and other hypoxic disease
tissues in the body tends to be more acidic (i.e., ∼5.5 to 6.5)
relative to physiological pH (i.e., 7.4). Using pH-sensitive poly
(beta-amino ester) (PbAE) nanoparticles, we have found
significant enhancement in drug delivery and accumulation in
the tumor mass as compared to drug administration in PCL
nanoparticles, a non-pH-sensitive polymer, and in aqueous
solution [5–7]. Further approaches for passive targeting involve
size of the nanocarriers and surface charge modulation.
Nanoparticles of b200 nm in diameter and those with positive
surface charge are known to preferentially accumulate and reside
in the tumor mass for longer duration than either neutral or
negatively charged nanoparticles [21]. Recently, we have
examined the role of combination paclitaxel and the apoptotic
second messenger, C6-ceramide, when administered concur-
rently in PEO-modified PCL nanoparticles to overcome multi-
drug resistance in cancer [21,24].
Furthermore, we have shown that passively-targeted delivery of
type B gelatin-based nanoparticles has been very effective in
systemic gene delivery to solid tumor [25]. TypeBgelatin (pI∼4.5)
transfect tumor cells in response to higher intracellular glutathione
levels [8,29]. When PEG-modified thiolated gelatin nanoparticles
encapsulated with plasmid DNA encoding for soluble vascular
endothelial growth factor receptor 1 (sVEGFR-1 or sFlt-1), highly
efficient transgene expressionwas observed in human breast cancer
cells and in vivo in an orthotopic tumor model. In addition, the
expressed sFlt-1 was very effective in suppressing tumor growth
and angiogenesis [29].
Active targeting to the disease site relies, in addition to PEG
modification of nanocarriers to enhance circulation time and
achieve passive targeting, coupling of a specific ligand on the
surface that will be recognized by the cells present at the disease
site [30]. Using solid tumor as an example again, there are
several strategies that can be adopted for surface modification of
nanocarrier systems for effective targeted delivery to the tumor
cells or to endothelial cells of the tumor blood vessels. Since
tumor cells are rapidly proliferating, they over-express certain
receptors for enhanced uptake of nutrients, including folic acid,
vitamins, and sugars. When the surface of nanocarriers is
modified with folic acid, they can be targeted to the tumor cells
that over-express folate receptors (Fig. 3). In addition, Fig. 3
also illustrates the intracellular delivery of folate anchored
190 S. Ganta et al. / Journal of Controlled Release 126 (2008) 187–204
in nanoparticulate formulations is able to physically encapsulate
plasmid DNA at neutral pH [26]. The physically encapsulated
DNA in PEG-modified gelatin nanoparticles was found to be more
effective in vitro and in vivo in transfection of reporter plasmid
DNA expressing green fluorescent protein and beta-galactosidase
[27,28]. Upon systemic administration in C57/BL6J mice bearing
Lewis lung carcinoma, the PEG-modified gelatin nanoparticle
afforded long-lasting transfection (up to 96 h) upon intravenous and
intratumoral delivery. Recently, we have shown that PEG-modified
thiolated gelatin nanoparticles could also encapsulate DNA and
Fig. 3. Schematic illustration of active drug t
nanocarrier through endocytosis process and releasing its
contents in response to internal stimuli. Tumor and capillary
endothelial cells also express specific integrin receptors, such as
αvβ5 or αvβ3 that can bind to arginine–glycine–aspartic acid
(RGD) tripeptide sequence. RGD-modification, therefore, has
been used to direct nanocarriers to tumor cells and capillary
endothelial cells of the angiogenic blood vessels. The phage
display method has been used to identify specific peptide
sequences that can be used for targeting tumors and other
disease areas in the body [31]. For example, Schluesener et al.
argeting with surface-modified micelles.
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[32] used in vivo phase display of recombinant M13 phages as a
tool to select peptides targeting pathological endothelium of
experimental rat brain tumors. One of the FDA approved
targeted therapeutics is Adalimumab® antibody; a human anti-
TNF IgG1 used against rheumatoid arthritis is generated by
phage display technique [33]. Recently, Farokhzad et al. [34]
have elegantly described the use of aptamers, nucleic acid
constructs that specifically recognize prostate membrane
antigen on prostate cancer cells. The aptamer technology
provides an additional strategy for active targeting of tumor
cells in the body. Development of monoclonal antibodies
against specific epitopes present only on tumor cells allows for
other targeting strategies. For instance, HER2 specific antibody
(Trastuzumab® or Herceptin®) modified nanoparticles were
able to localize and deliver the therapeutic payload specifically
in HER2 expressing tumor cells [35]. Using a monoclonal
antibody 2C5 that specifically recognizes anti-nuclear histones,
Torchilin's group has developed various strategies for active
targeted delivery of drugs to the tumor mass using liposomes
and micellar delivery systems [36,37]. Other groups have used
1.3. Intracellular delivery and sub-cellular distribution
Once the nanocarriers are delivered to the specific diseased
organ or tissue, they may need to enter the cells of interest and
ferry the payload to sub-cellular organelles (Fig. 4). In this case,
non-specific or specific cell penetrating strategies need to be
adopted [42]. Non-specific cell uptake of nanocarriers occurs by
endocytotic process, where the membrane envelops the
nanocarriers to form a vesicle in the cell called an endosome.
The endosome then shuttles the content in the cell can fuse with
lyososomes, which are highly acidic organelles rich in degrading
enzymes. Endocytosed nanocarriers usually travel in a specific
direction and converge at the nuclear membrane. Endosomal
acidic condition is deterrent to therapeutic molecules present in
the nanocarrier. This bottleneck in gene delivery can be
responsible for the degradation of N99% of the
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