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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5610_Библиотеки_им_академика_М_И_Перельмана
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402 N. Nomikou et al.
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Fig. 15.4 Polymitoxantrone (PolyMTO)-based DSPE-PEG NPs for targeted and deeply penetrating cancer treatment. PEG coating allows for better blood circulation and the iRGD peptide
facilitates the tumour penetration and cellular uptake. Subsequently, elevated levels of intracellular
ROS led to cleavage of the thioketal bonds in the polyMTO chain, releasing intact MTO drug
molecules (Xu et al. 2017a, b)
15.2.6 Hypoxia-Responsive Nanoparticles
Hypoxia, defined as the suppression of physiological levels of oxygen pressure, is a
characteristic feature of various diseases, including most types of cancer, and is
associated with poor therapeutic outcomes of the traditional forms of treatment, such
as chemotherapy and radiotherapy (Muz et al. 2015
linkages form hydrophilic functional groups and enhance the hydrophilicity of the
nanocarriers in response to the reducing microenvironment of hypoxia, leading to
efficient drug release under hypoxic conditions. Metabolism in cancer cells is
primarily through aerobic and anaerobic glycolysis, as distinct from the oxidative
phosphorylation pathway, resulting in the accumulation of reducing agents, such as
NADPH or NADH, and oxidoreductases, such as nitroreductase. The
overexpression of such bioreductive enzymes may be exploited by hypoxiaresponsive nanoparticles and pro-drugs (Kumari et al.
responsive nanoparticles have been developed for the targeted treatment of different
types of cancer by incorporating hypoxia sensitive groups such as nitroimidazoles
(Khatoon et al.
derivatives (Zhang et al. 2020a, b), and azobenzene derivatives (Dong et al. 2020;
). The hypoxia-responsive
2020). Several hypoxia-
2018; Thambi et al. 2014; Yang et al. 2021), nitrobenzyl alcohol
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Fig. 15.5 Schematic illustration of a cross-section of “hypoxic” tumour mass. Hypoxia within the
tumour exists as a gradient, with normoxic cancer cells near the blood vessels and hypoxic cancer
cells closer to and within the centre of the tumour mass
Yan et al. 2019). For example, Zhang et al. describe the synthesis of a hypoxiasensitive co-polymer by conjugating the nitrobenzyl alcohol derivative 4-nitrobenzyl
(3-azidopropyl) carbamate to the side chains of methoxy PEG-b-poly(γ-propargylglutamate). The deriv atized polymer was then used to form doxorubicin-containing
micelles with drug-release properties under hypoxic conditions.
MSNs have also been functionalized to yield hypoxia-responsive drug delivery
systems for targeted delivery. A number of hypoxia-sensitive MSNs have been
reported in the literature that are used to carry different types of therapeutic agents,
such as doxorubicin (Khatoon et al. 2018) and the photosensitizer, chlorin e6 (Ce6)
(Yan et al. 2019). A 4-nitroimidazole-β-CD complex has been used as a hypoxiaresponsive “gatekeeper” in the pores of doxorubicin-containing silica nanoparticles.
In a hypoxic environment, the nitroimidazole gatekeeper moieties are disintegrated
through bioreduction of the hydrophobic nitroimidazole state to its hydrophilic state,
leading to doxorubicin release. Importantly, doxorubicin release at normoxic conditions was impaired (Khatoon et al. 2018).
The levels of hypoxia within a diseased site can vary. Even within the same
tumour, hypoxia exists as a gradient (Fig.
15.5), with lower oxygen levels in its
L-
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centre, compared to the outer, well-vascularized, parts. The expression of
bioreductive enzymes also varies and tumour-targeting nanoparticle formulations
based on hypoxia-specific stimuli will have to overcome these challenges in order to
improve the therapeutic properties of the payload and reduce off-target effects.
15.3 Nanoparticles That Are Responsive to Externally
Applied Stimuli
15.3.1 Temperature-Responsive Nanoparticles
Temperature-responsive or thermoresponsive nanoparticles are amongst the most
common stimulus-responsive systems developed and used for improving the sitespecific and/or controlled delivery of therapeutic agents. The thermoresponsive
nanoparticulate systems designed for this purpose are stable at temperatures lower
than or equal to 37 °C, for remaining intact in blood circulation, and lose their
integrity releasing their payload at temperature fluctuations of ±2 °C magnitude. At
least one component of the nanoparticulate structure must alter its properties upon
temperature change, leading to total or partial disintegration or perforation of the
structure for releasing the therapeutic agent. The majority of the temperatureresponsive systems have been developed to respond to temperature increase up to
40–42 °C. Mild hyperthermia in a site-specific manner can be achieved using a
simple water bag (e.g. for superficial tumours or local inflammation), microwaves,
ultrasound, radiofrequency, or infrared illumination. Temperature in human tissues
can be raised up to 43 °C for a prolonged period of time, without heat-induced
irreversible effects.
The clinically relevant mild hyperthermia-triggered therapeutic nanosystems that
have been developed thus far are liposomes, polymeric nanocapsules, or polymeric
nanospheres, and usually their structural sensitivity is based on the temperature
increase-induced phase transition of one or more lipid or polymeric components.
ThermoDox
system, that has been successfully used for the treatment of liver and breast cancer
and has been under evaluation for the treatment of other types of cancer, has resulted
in higher tumour drug levels, compared to those achieved with conventional
doxorubicin-carrying liposomal formulations (e.g. Doxil
bicin. The liposome shell in the formulation contains dipalmitoyl phosphatidylcholine (DPPC) that undergoes phase change at 42 °C, as well as myristoylstearoyl
phosphatidylcholine, which reduces the transition temperature of DPPC and accelerates the drug release process (Bulbake et al.
“leucine zipper peptide–lipid hybrid” nanoliposome, has been developed by incorporating a temperature-sensitive peptide in the lipid bilayer in order to facilitate lipid
shell rupture and subsequent drug release at 42 °C (Fig.
2012). Chen and colleagues developed thermoresponsive bubble-generating
®
(Celsion Corporation), a clinically applied thermosensitive liposomal
®
, Janssen) or free doxoru-
2017). An innovative system, called
15.6a) (Al-Ahmady et al.
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Fig. 15.6 (a) Drug release from liposomes containing a heat-responsive peptide in their shell. (b)
Heat-responsive liposomes containing ammonium bicarbonate (NH
leading to liposome collapse upon temperature increase
HCO3) that produces CO
4
liposomes, by encapsulating ammonium bicarbonate in the liposomal core, together
with the therapeutic agent (Fig. 15.6b). Decomposition of ammonium bicarbonate at
42 °C generates CO
leading to drug release. Additionally, the generated CO
bubbles, which destabilize the lipid bilayer, subsequently
2
bubbles serve as a contrast
2
agent during ultrasound imaging and allow monitoring of the temperature-controlled
drug delivery course (Chen et al.
2013a,
b).
The temperature-controlled drug release from polymer-based nanoparticles is
afforded with the inclusion of thermoresponsive polymers with transition temperatures around 40 °C (Fig. 15.7a), such as poly(N-isopropylacrylamide) (PNIPAM), its
copolymers, elastin-like polypeptides or poly(γ-2-(2-(2-methoxyethoxy)-ethoxy)
ethoxy-ε-caprolactone)-b-poly(γ-octyloxy-ε-caprolactone), in the nanoparticle
structure (He et al. 2020; Bordat et al.
2019; Rodríguez-Cabello et al.
2016; Cheng
et al. 2012). Interestingly, certain combinations of thermoresponsive polymers can
be used for the formation of nanoparticles with tuneable respon se temperatures
and/or the functionality to release different therapeutic agents at different times. In
addition, thermoresponsive polymers can be combined with phospholipids for the
formation of thermally tuneable liposomes for controlled drug release (Han et al.
2006; Chen et al.
2013a, b). An innovative approach utilizes thermoresponsive
2
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Fig. 15.7 (a) Drug release from nanoparticles that are based on heat-responsive polymers, (b) Drug
release from nanoparticles based on heat-responsive polymer that contracts upon temperature
reduction
polymers for shielding cancer-targeting ligands, such as folic acid, that functionalize
the surface of nanoparticles. Upon temperature increase, in a site-specific manner,
the polymer retracts and exposes the targeting moiety within the cancerous tissue,
facilitating improved interaction with tumour cells and increased cellular uptake
(Chen et al. 2013a, b).
Equivalent nanosystems have also been designed for the spatiotemporal control
of drug release upon temperature decrease. In these systems, cooling can cause
reversible swelling or contraction of the nanoparticles that can lead to increased
porosity and subsequently, the free diffusion of the entrapped drugs (Fig. 15.7b).
One example is the use of nanoparticles formed with Pluronic F127–
polyethyleneimine for the delivery of small interfering RNA in the cytoplasm and
the induction of gene silencing (Lee et al. 2008).
The diversity of thermoresponsive nanoparticles that have been developed up to
date can find potential applications in the treatment of different diseases and some
are already clinically exploited. Those developed for cancer therapy are loaded with
chemotherapeutic agents for augmenting the release, cellular uptake, and accumulation of the latter within tumours, improving the therapeutic efficacy of cytotoxic
agents and somewhat reducing off-target toxicity (Amin et al.
2020).
Thermoresponsive nanosystems have also been developed for intra-articular
15 Stimulus-Responsive Nanoparticles for Drug Delivery 407
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injection to allow controlled release of anti-inflammatory peptides, triamcinolone
acetate or hyaluronic acid, and prevent or alleviate the effects of osteoarthritis
(Deloney et al. 2020; Seo et al. 2022; Maudens et al. 2018). Moreover, Seo et al.
(2015) fabricated polymeric thermoresponsive nanocomplexes with bone morp hogenic protein 2 (BMP-2) that transformed to a hydrogel upon injection and at body
temperature, for stably releasing BMP-2 to induce site-specific bone regeneration.
15.3.2 Light-Responsive Nanoparticles
The photoresponsive and photosensitive nanosystems developed for drug delivery
are based on the use/inclusion of materials with the capability to change their
properties/conformation upon light irradiation or to absorb light and convert the
electromagnetic energy to heat, both of which can trigger drug release. The design
and components of the photoresponsive nanoparticles define the energy of light that
the latter respond to.
Photosensitive nanosystems for drug delivery can exploit the reversible photoinduced isomerization of the azobenzene group and its derivatives—from trans to
cis, and from cis to trans—using ultraviolet (UV) light at 300–380 nm, and visible
light, respectively (Lu et al. 2008; Yuan et al. 2012). For instance, the drugcontaining pores of MSNs can be blocked with a CD ring functionalized with
azobenzene-containing embedded molecules to allow photoswitchable drug release
15.8a) (Yan et al. 2012). Alternatively, the pores of drug-containing MSNs can
(Fig.
be blocked with a cyclobutane dimer, which is formed by the irradiation of thymine
at 365 nm. When irradiated with light at 240 nm, the cyclobutane dimer is
photocleaved, unblocking the pores and allowing the release of the drug (He et al.
2012). In addition, micelles that include an azobenzene-containing surfactant can
afford photoactivatable intracellular nucleic acid release upon UV irradiation (Liu
et al. 2009). Photocleavable o-nitro benzyl groups mediating the conjugation of
drugs on gold nanoparticles (Fig. 15.8b), offering gatekeeping in MSNs and
crosslinking polymers for the formation of nanoparticles, are also among the chemical groups used in photo-induced controlled drug release (Agasti et al. 2009;
Vivero-Escoto et al. 2009; Azagarsamy et al. 2012). An innovative approach has
enabled the UV-activated in situ protein synthesis using photo-releasable caged
DNA, co-carried with the factors and enzymatic components required for transcription and translation, in liposomal vehicles (Schroeder et al. 2012).
Despite the advanced level of innovation characterizing the design of
nanosystems that respond to light irradiation in the UV and visible regions of the
electromagnetic spectrum, their applicability is limited to lesions/defects in superficial sites in the body (e.g. eye, skin, luminal surface) due to the poor tissue
penetration of light at these wavelengths, which can afford irradiation of only 2–3 millimetres in dep th. Light in the near-infrared (NIR) region of the spectrum, i.e. at
wavelengths higher that 700 nm, however, can provide deeper irradiation, due to
decreased photon scattering through tissue. NIR-absorbing plasmonic materials that
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Fig. 15.8 (a) Light-triggered drug release from MSN, when the drug-containing mesopores are
shielded with a polymer that contains light-cleavable bonds, (b) Light-induced release of drug
conjugated on gold nanoparticles via light-sensitive bond, (c) Light-triggered release of drug
incorporated in the double strands of DNA molecules that are bound on gold nanorods
can convert the energy absorbed during irradiation into heat have been exploited in
nanosystems to facilitate light-induced drug release. One example is the release of
doxorubicin from hollow gold nanospheres or gold nanorods upon irradiation at
808 nm (You et al. 2012; Awan et al. 2021). In general, gold nanorods are preferred
as light-activatable drug release systems due to their improved photothermal conversion efficiency compared to other gold-based nanomaterials (Awan et al.
The temperature increase caused by the surface plasmon resonance of gold upon
NIR irradiation can also be exploited in order to trigger the release of agents
incorporated in heat-responsive materials included in the nanoparticulate structure.
2021)
.
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Fig. 15.9 (a) Gold-coated thermoresponsive polymeric nanoparticles for light-induced drug
release, (b) Gold-coated thermoresponsive micelles for light-triggered drug release
For instance, drug molecules incorporated in DNA helices that are conjugated on the
surface of gold nanorods can be released when the nanoparticles are exposed to NIR,
due to the heat-induced DNA dehybridization (Fig.
15.8c) (Xiao et al. 2012).
Similarly, the NIR-induced heat in gold-containing nanoparticles can facilitate the
release of agents incorporated in phase transition polymers or lipids included in the
nanoparticulate structure (Kumar and Lim
2021; Xu et al. 2017a, b). A wide
range of
phase-changing materials in combination with NIR-absorbing photothermal agents
have been used in nanoparticulate platforms to achieve on-demand drug release. Wu
et al. developed NIR-shrinkable doxorubicin-containing micelles based on poly
(acrylamide-acrylonitrile)-PEG-lipoic acid, encapsulating gold nanorods (Wu et al.
2021). Upon laser irradiation, the heat produced from the nanorods causes splitting
of large micelles into ultrasmall ones that can potentially distribute efficiently
throughout a tumour mass and can facilitate improved cellular uptake for the
delivery of doxorubicin. Alternative systems are gold-coated polymeric
nanoparticles (Fig.
atures (Yang
15.9a) based on polymers with relatively low transition temper-
2009; Lee et al. 2011) and gold-coated nanosized micelles
et al.
(Fig. 15.9b) (Ma et al. 2012) for NIR-triggered drug release. When the pores of a
silver-gold coated mesoporous silica hollow nanoplatform containing 5-fluorouracil
were capped with the thermosensitive lauric acid, spatiotemporally controlled
release of the chemotherapeutic agent became possible upon NIR irradiation, in a
2018)
system developed for prostate cancer treatment (Poudel et al.
approac
h,
NIR-respon
sive and rod-based urchin-like Bi
2S3
. In an innovative
hollow nanoparticles
were designed for the laser-triggered release of chemotherapeutic agents (Zhang
et al. 2020a, b). The nanoparticles were loaded with doxorubicin and coated with
1-tetradecanol, with a melting point at approx. 38 °C, which served as the
“gatekeeper”.
The co-administration of thermosensitive nanoparticles, such as liposomes, with
gold nanorods, as two separate entities, has also been successful in vivo, for the
spatiotemporal control of drug release within tumours using NIR (Agarwal et al.
2011). In addition, pulsed NIR has been applied to trigger the sit e-specific formation
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of plasmonic nanobubbles from gold nanoparticles for enhancing the cytoplasmic
release of liposomal doxorubicin in tumours (Lukianova-Hleb et al. 2012). The latter
two approaches would require co-localization of the gold-based NIR-responsive
nanosystems with the co-administered drug-containing thermoresponsive
nanoparticles within the tumour mass.
Apart from plasmonic materials, such as gold nanoparticles, heptam ethine cyanine dyes (e.g. the FDA-approved indocy anine green) absorb NIR and convert it to
heat, resulting in photothermal effects. Essentially, the incorporation of these dyes in
thermoresponsive nanocarriers can facilitate heat-induced drug release upon NIR
irradiation (Zhu et al. 2017; Zangabad et al. 2018; Yuan et al. 2018; Xiong et al.
2020).
15.3.3 Magnetic Field-Responsive Nanoparticles
A diversity of nanocarriers for drug delivery have been developed to respond to an
extracorporeally applied magnetic field. The mode of magnetic field defines the
nature of response, and it varies among different applications. A permanent magnetic
field can be applied to guide the accumulation of systemically administered drugcarrying magnetic nanoparticles to a defective/diseased site within the body, usually
a tumour. Conversely, an alternating magnetic field can be applied to induce
oscillation of drug-carrying magnetic nanoparticles with subsequent temperature
increase, which can trigger drug release and/or cause ablative hyperthermia. The
heating effect upon application of a magnetic field is associated with the Néel and
Brownian relaxation of the particle magnetic moments, due to the delay of the
magnetic particle relaxation time compared to the oscillating magnetic field.
The nanosystems developed for magnetic guidance can be magnetic core shell
nanoparticles that are made of a highly magnetic core material, usually iron oxide or
magnetite (Fe
drug delivery. Due to their high surface reactivity, magne tite nanoparticles can
induce reactive oxygen species formation, cause tissue inflammation, and even
become genotoxic (Kawanishi et al. 2013). These effects can be minimized by
coating the surface of the nanoparticles with a polymer, gold, and/or silicon dioxide
). In addition, the therapeutic agent(s) to be delivered can be incorporated and
(SiO
2
carried within the polymer coating (Fig. 15.10a), by being chemically conjugated on
the polymer chains or gold coating (Fig. 15.10b), or by being absorbed in the SiO
coating. The coated surface of the Fe3O4 nanoparticles can also afford
functionalization with targeting moieties, such as folic acid, for improving cellular
uptake at the site of guided accumulation (Ak et al. 2018; Hiremath et al. 2019).
A widely used approach with applications in cancer therapy is based on the
incorporation of hydrophobic chemotherapeutic agents, such as paclitaxel, in the
polymeric shell (Fig.
common polymers used as coatings are chitosan, dextran, polyethyleneimine, and
Pluronics (Khan et al. 2021). Although the majority of these systems have been
), and have a wide range of applications in biomedical imaging and
3O4
15.10a) (Hiremath et al. 2019; Mdlovu et al. 2019). The most
2
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Fig. 15.10 (a) Polymer-coated magnetic nanoparticles, (b) Gold-coated magnetic nanoparticles,
(c) Magnetoliposomes with (i) a single magnetic nanoparticle in the core, (ii) a cluster of magnetic
nanoparticles in the core, (iii) magnetic nanoparticles embedded in the lipid bilayer, and
(iv) magnetic nanoparticles attached on the surface
designed for guided drug delivery in the treatment of different cancers, they can also
offer therapeutic benefits in a wider variety of site-specific defects. For instance,
core-shell magnetic nanoparticles coated with dextran and loaded with
protocatechuic acid have been developed, for the treatment of vascular inflammation
(Anghelache et al. 2021). A magne tic nanoformulation for the delivery of antioxidant enzymes (e.g., catalase) with the aim of increasing resistance to oxidative stress
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