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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5346_Библиотеки_им_академика_М_И_Перельмана
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Fig. 6 Applications of MNRs for precision medicine applications. (Reprinted from Soto F, Wang J, Ahmed
R, Demirci U. Medical micro/nanorobots in precision medicine. Adv Sci 7 2020:2002203. 2020 Open-access,
Wiley Online Library.)
bacterium that uses the urease enzymes in its body to change the pH of the surrounding
environment to increase the viscosity of the fluid, thus facilitating its penetration [84].
These are just a few examples to describe how natural-occurring strategies are used
for efficient locomotion at small scales.
From a technological perspective, propulsion mechanisms have high relevance to
each specific task performed. In fact, MNRs have been considered as dynamic platforms
to deliver a large array of cargoes (e.g., pharmaceutical, biologic) by exploiting the same
mechanisms that propel their structures, often in combination with other external stimuli. In order to carry and release agents, MNRs take advantage of electrostatic or covalent
interactions to hold them on their surfaces, or they are equipped with multistable structures that are triggered by external stimuli (e.g., polarized light) or the variation in the
environmental conditions (e.g., pH, temperature) [85–88].
After a description of the main propulsion mechanisms currently employed in
MNRs, we describe the main drug delivery applications of synthetic MNRs for precision
medicine. Many of the strategies reported above using NPs, could also comply with the
MNR philosophy, once they are provided with a locomotion system.
115Biomaterials and devices for immunotherapy
5. Propulsion engines for MNRs
Locomotion in MNRs is mainly achieved by exploiting either the interaction with
an external source (exogenous-driven devices) or exploiting the results of an internal
116 Emily M. Jordan et al.
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chemical or biological reaction (endogenous engines) [89]. Specifically, the first group
includes propulsion devices triggered by magnetic or electric fields [90,91] or solutions
based on the exploitation of light or ultrasounds [92–94] (Fig. 7). The common requirement for a propulsion engine is the ability to have sufficient autonomy to guide the device
to its target with the lowest positioning error achievable, to efficiently perform the
envisioned task (e.g., drug delivery) [95].
Magnetism is undoubtedly the most employed trigger to propel MNRs. Scientists
have successfully employed magnetic fields to enable a helical or undulated motion to
penetrate fluids [90,96]. Interestingly, it has been demonstrated that magnetic fielddriven microengines can perform precise movements, even in living cells [97], with fields
that are 1000 times weaker than a traditional magnetic resonance imaging (MRI) procedure [98]. This approach originated from the solution developed by nature in billions
of years of evolution that is still observable in bacteria or microorganisms that take advantage of flagella or flexible bundles. Synthetic applications usually combine helicoidal
shapes with magnetic fields, whose directions and amplitudes ensure precise locomotion
of the device [99,100] (Fig. 8). In contrast, Au-Ag-Ni nanowires have been used to create
flexible bodies able to perform undulatory locomotion leading to a traveling wave. In this
case, the different polarization of Au and Ni gives an asymmetry in the rotational amplitudes, creating a rototranslational motion de facto [101]. Authors have studied the locomotion differences between one-, two-, and three-link magnetic structures, achieving a
complete S-like movement only with the three-link device [102]. The last propulsion
mechanism activated by magnetic fields is the so-called surface walking. Rotating Ni
nanowires of colloidal microwheels are positioned onto MNRs to enable movements
on top of surfaces [103,104].
Electricity is an energy source that is strictly connected with magnetic field since they
can mutually influence each other. Rotational electrical nanomotors have been designed
Fig. 7 Propulsion for MNRs: a classification.
Fig. 8 Magnetic MNRs. Panel A. Helicoidal MNR and in vitro tests to assess movements upon variable
magnetic fields. (Reprinted with permission Zhang L, Abbott JJ, Dong L, Kratochvil BE, Bell D, Nelson BJ.
Artificial bacterial flagella: fabrication and magnetic control. Appl Phys Lett 2009;94:64107. © 2009 AIP
Publishing.)
and employed in a large number of applications since electricity is easily accessible and can
be manipulated to prevent damage to living tissues. As occurs for magnetic-field-driven
engines, MNRs propelled by electricity have metallic components that may lead to
health issues, while the main disadvantage consists in its weak penetration in tissues [105].
Light is an energy source that has been used more as a trigger for specific tasks rather
than as a source to activate propulsion. Movement directionality depends on light frequency, polarization, intensity, and propagation direction [92]. However, within the
light spectrum, visible light cannot penetrate tissues [105] while UV light allows good
locomotion but causes harmful effects [106]. Only NIR light can penetrate tissues
without causing health problems and therefore is the most promising in terms of both
locomotion and task triggers [107,108].
The last exogenous source for MNRs is the energy given by ultrasounds that are usually carried by gold nanowires [93]. The working principle is based on the exploitation of
the pressure gradient generated by ultrasounds conveyed in a concave cavity of the MNR
[109]. Due to the impossibility of steering an MNR with ultrasounds, magnetic fields are
usually employed to change the directionality of the movement [110]. However, in contrast to other propulsion systems, ultrasound stimulation provides a fast and highamplitude thrust that allows an efficient penetration of MNR into tissues and even cells
[105]. As the main disadvantage, oxidative stress has been observed in cells penetrated by
ultrasounds, a phenomenon that might damage the functionality of healthy tissues [111].
Endogenous-powered MNRs are designed as asymmetric structures that are coated
with catalyzers in order to properly interact with the surrounding environment. As anticipated above, propulsion is achieved by converting the energy from a chemical reaction
117Biomaterials and devices for immunotherapy
118 Emily M. Jordan et al.
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(e.g., redox activity) into a driving force. The most employed method in vitro is the
exploitation of the decomposition of hydrogen peroxide into water and oxygen through
catalysts (e.g., enzymes, metals). However, from a clinical standpoint, the exploitation of
hydrogen peroxide for in vivo applications is limited due to its nonneglectable toxicity and
the nonbiodegradation of many MNRs [105]. Practicable alternatives are the employ-
ment of magnesium that produces propelling bubbles when in contact with water
[112,113], or the use of biocompatible enzyme catalysis [114]. Endogenous-driven
MNRs have a great potential for drug delivery applications [115,116] but the main disadvantages are the potential discontinuity of the movement ( e.g., the propulsion is not
sufficient to propel the MNR up to its target), and the difficulty in controlling the directionality of the movement that can be disturbed by ionic media [105].
6. Applications of MNRs
Among the wide range of applications in which MNRs have been employed, we
focus on drug delivery for targeted immunotherapy and chemotherapy tasks. Applications of MNRs are, thus, here reported using the propulsion system as a clustering
method. Table 2 summarizes the main applications, advantages and disadvantages of each
class of MNR.
6.1 Magnetic-driven MNRs
One of the first magnetic MNRs was developed a decade ago by using a catalytic nanowire to release PLGA liposomes charged with Dox and iron oxide. Cargo release was
achieved by a rapid change of direction of the magnetic field and passively helped by
the induced drag forces [117]. Similar structures have been employed to carry and deliver
liposomes with calcein that were adsorbed onto the surfaces of the material with electrostatic forces [118,119]. A magnetic MNR was developed by Qiu et al. that uses a
temperature-sensitive liposome coating on a magnetism-driven titanium structure, to
deliver drugs upon temperature regulation. With this MNR, the authors achieved a
73% 15% correct release of calcein at 41°C [98]. In another application, the same
authors designed and fabricated a metallic structure with flagella that were loaded with
lipoplexes containing pDNA. The results of the in vitro study revealed good delivery of
the plasmids in human embryonic kidney cells. However, when translating this approach
to an in vivo study, the potential cytotoxic issues due to the accumulated metals in nontargeted organs have to be taken into account [120]. Flexible magnetic MNR carriers
were designed by Gao et al. to deliver microspheres made of PLGA containing drugs.
The authors assessed the functionality of the MNR by delivering in vitro Dox to HeLa
cancer cells. The main challenge, in this case, was the balance between the amount of
drug and the capability of the engine to carry the load [118,121]. Worm-like MNRs have
been developed by using rigid links connected with flexible joints for delivering drugs in
Table 2 Summary of the applications of MNRs based on the propulsion mechanisms.
Propulsion Advantages Limitations Cargo Reference
119Biomaterials and devices for immunotherapy
Magnetic • Work in
relative
weak magnetic field
• Precise
navigation
• Good
penetration
Electric
• Energetic
source
easily
available
• Precise
navigation
• Structural
materials may
harm living
tissues
• Electric fields
may harm living
tissues
• Weak
penetration
PLGA liposomes
charged with Dox
and iron oxide
PLGA liposomes
charged with
calcein
Liposomes with
calcein triggered by
temperature
variation
Lipoplexes containing
pDNA delivered in
human embryonic
kidney cells
PLGA Microspheres
with Dox for HeLa
cancer cells
6-carboxyfluoresceins
for HeLa cancer
cells
Dox for HeLa/
spheroid cancer cells
Dox triggered with
NIR light
Zeolitic-imidazole
framework-8
released via pH
variation
Tissue plasminogen
activators (rtPA or
tPA) in blood clots
Microvalves with 6-
carboxyfluorescein
Not disclosed [100]
Not disclosed [91,135]
Nile Blue stains [136,1 37]
Hydrophobic layer of
1-dodecanethiol to
absorb a tumor-
necrosis factor
[117]
[118,119]
[98]
[120]
[118,121]
[122]
[123–125]
[126–128]
[129]
[130–134]
[122]
[138]
Continued
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Table 2 Summary of the applications of MNRs based on the propulsion mechanisms—cont’d
Propulsion Advantages Limitations Cargo Reference
Light • Good pen-
etration
with NIR
light
• NIR light
used also as
an effective
trigger
Ultrasounds
• Strong
penetration
• Precise
navigation
Endogenous
• Good
propulsion
• No need of
external
stimuli to
propel
the MNR
• Weak penetra-
tion of tissues of
visible light
• Harmful
penetration of
UV light
• It requires a
magnetic field
to steer MNRs
• Ulltrasounds
may induce
oxidative stress
in living less
• Structural
materials may
harm living
tissues
• Less precision in
navigation than
other
mechanisms
• Energy may be
insufficient for
performing the
envisaged task
• Fuels not always
safe for living
tissues
Not disclosed [139,140]
Macrophage cell
membrane
Dox for HeLa cancers
cells triggered by a
NIR light beam
pH-sensitive drug for
cancer cells
Brilliant green
antiseptic drug
triggered by pH
variation
pH-responsive
nanovalves to
release insulin in
presence of glucose
Not disclosed [147]
Dox [148–150]
Dox triggered by
ultrasounds on
HeLa cancer cells
Fluorescein
isothiocyanate in
body fluids or blood
plasma
Clarithromycin/
ampicillin to treat
bacterial infections
Dox triggered by NIR
light
Thrombin coagulant
for blood vessels
α-toxin to neutralize
the Staphylococcus
aureus
Anti-CTLAA-4
antibodies in a
dermal melanoma
animal model
[141]
[142]
[105,143–145]
[110]
[146]
[151]
[152]
[153–155]
[115,151,156,157]
[158,159]
[160]
[161]
Dox, doxorubicin.
biological fluids. Propulsion was provided, for instance, by coating the links with magnetic CoFe
nanoparticles. Mesoporous silica nanotubes have been used to create
2O4
linked structures for releasing 6-carboxyfluoresceins to HeLa tumor cell in vitro [122].
Surface magnetic walkers propelled by magnetic fields were developed by Sun et al. that
encapsulated Fe
particles to interact with the external field, and Dox drug to be
3O4
delivered to HeLa cells in vitro [123]. The main limitation of magnetic-field-driven
MNRs dwells in the potential immune reaction, which may lead to inflammations or
other undesired effects in vivo, that can arise from the inclusion of metals required for
the locomotion mechanism [162,163].
Superparamagnetic engines were arranged on a snake-like robot to capture cells and
deliver Dox to cancer cells [124]. A 3D-printed biodegradable MNR made of chitosan
and powered by a weak magnetic field was used to deliver tuned dosages of Dox with a
NIR light [126]. Using gelatin methacryloyl as a structural material, other authors delivered drugs exploiting the natural swelling of the polymer [164]. Magnetic propulsion has
also been used for MNR swimmers in bloodstreams capable of finding cancer cells with
specific antibodies. Dox is then release using NIR light [127,128]. Finally, other relevant
applications of magnetic MNRs concern microhelices coated with a zeolitic-imidazole
framework-8 that was released in environments with acidic pH [129], or nanotubes
coated with magnetic particles for delivering Dox to spheroid tumors [125].
Magnetic NPs were driven to release tissue plasminogen activators (rtPA or tPA) in
blood clots [130–132]. Since the presence of metallic MNRs in living bodies is considered a potential issue, scientists have pushed for MNRs endowed with superparamagnetic
materials to carry tPA through covalent bonds. They were tested to target blood clots in
animal brains and activate chemical lyses [133]. MNRs used for kidney diseases were
found easily collectable in urine using an external magnet [134].
121Biomaterials and devices for immunotherapy
6.2 Electric and piezoelectric MNRs
Electric-field driven MNRs have been used mainly for in vitro applications to test the
transportation and releasing of cargos. Examples are catalytic nanomotors propelled by
conditioning circuits [91] or rotational nanomotors made of carbon nanotubes with high
responsiveness and movement speed [135]. Electric nanomotors have been used to carry
Nile Blue stains through electrostatic interaction, which was efficiently released by
exploiting the rotation of the engine itself. This experiment paved the way for future
use in drug delivery based on a controlled rotation of the MNR rotor [136,137].
Electric nanoengines have been used to propel MNRs aimed at delivering tumornecrosis factors. For instance, gold nanowires were coated with a hydrophobic layer
of 1-dodecanethiol to absorb a tumor-necrosis factor. This eventually led to the activation of the nuclear factor (kappa B transcription factor) inside cells, inducing an immune
reaction [138].
122 Emily M. Jordan et al.
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A different approach to deliver drugs is the use of the piezoelectric effect. Polyvinylidene fluoride (PVDF) is an electroactive polymer with excellent piezoelectric
properties compared to other biocompatible polymers and easily shapeable on the
nanoscale, for example as nanofibers [165]. Kapat et al. and Mushtaq et al. used
PVDF-based copolymers in MNRs [166,167]. Mus htaq et al. developed a nanorobot
that mimics an electric eel (namely, nanoeel) able to generate electricity upon movement. The nanoeel was made of a flexible PVDF tail, attached to a polypyrrole (Ppy)
nanowire, finally decorated with a nickel ring for magnetic actuation. The magnetic
head module was Ni-Ppy; it is able to oscillate upon alternating magnetic field application which causes the ferroelectric tail to flex and generate changes in its electrical
polarization due to the piezoelectrical effect. The prepared hybrid nanoeels can be
magnetically actuated and triggered for targeted and on-de mand drug delivery
[167].Chenet al. developed a wired-shaped magnetoelectric nanor obot, provided with
a magnetic core and piezoelectric shell structure [168]. T he authors demonstrated its
wireless motion and release of the PTX drug on-site by using different magnetic fi eld
modalities.
6.3 Light-driven MNRs
Zhan et al. designed a light-driven MNR by exploiting nanowire linear dichroism of
Sb
a nontoxic and highly biocompatible MNR that is activated by visible-light photocatalysis and is able to perform movements in biological environments [140]. Xuan
et al., instead, designed an MNR that changes the directionality of its movement when
exposed to NIR light, exploiting the generated heat gradient to overcome the Brownian
motion. The authors also coated the structure with macrophage cells, making the MNR
able to actively detect and bind cancer cells [141].
and assessed their efficient locomotion [139]. In addition, Wang et al. developed
2Se3
6.4 Ultrasound-propelled MNRs
Victor et al. designed a four-segment MNR endowed with an Au-Ni-Au wire for ultrasound, which can be steered by a directional magnetic field to deliver Dox-loaded NPs to
HeLa cancer cells when triggered by an NIR light beam [142]. Another application consisted of delivering pH-sensitive drugs carried on a multisegment MNR in an acidic environment [105]. Ultrasound-propelled MNR was endowed with a Ppy-polystyrene
sulfonate segment, holding, via electrostatic interactions, a brilliant green antiseptic drug,
stable at pH 7, that was released when the environmental pH reduced to 4 [110].
pH-sensitive polymers have a remarkable efficiency on cancer cells since these cells
are acidic targets [143–145]. Ultrasound was also used to propel a nanowire with
pH-responsive nanovalves upon variation of the environmental pH [146].
6.5 Endogenous engines for MNRs
Microrockets fueled by oxygen peroxide were tested in vitro to carry Dox via π-π interactions induced by graphene oxide. The release of the drug was achieved by triggering an
electrochemical stimulus that decoupled the holding interaction to the drug [147].
MNRs propelled by urea have been tested to deliver Dox [148]. Endogenous-propelled
MNRs were assembled in a multilayer fashion (e.g., positively-charged chitosan over
negatively-charge sodium alginate) in order to internalize Dox that will be eventually
released via ultrasounds to HeLa cancer cells [151]. Alternative structures to perform
the same task have been fabricated using gelatin. In this case, NIR light was used to trigger drug release [151,157]. Hydrogen peroxide was also used as a fuel to propel soft
MNRs charged with platinum nanoparticles and Dox, eventually released by inducing
a rupture of the PEG shell holding the cargo [115,156].
A more biocompatible solution to fuel MNRs is the employment of magnesium-
powered engines that have been usually coated with pH- or temperature-responsive
polymer holding drugs. This approach has been validated in vitro by delivering fluorescein
isothiocyanate in body fluids or blood plasma [152] or targeting in vivo areas of a mouse
stomach with clarithromycin or ampicillin which serve to treat bacterial infections
[153–155]. Moreover, it has been demonstrated how the efficacy of Dox can be improved
with this biofuel due to a synergistic effect that occurs with the generation of hydrogen
molecules on-site [149]. An MNR propelled by the results of the chemical degradation
of carbonate and tranexamic acid was used to deliver a thrombin coagulant through blood
vessels of animal models [158,159]. A self-propelled magnesium-based MNR was injected
with a vaccine to deliver an α-toxin able to neutralize Staphylococcus aureus [160]. Magnesium has also been used to propel MNR aimed at delivering anti-CTLAA-4 antibodies
autonomously in a dermal melanoma animal model. The antibody could penetrate phantom tissues due to the force generated by hydrogen released when magnesium interacts
with interstitial fluids [161]. Another alternative to hydrogen peroxide is a zinc/iron-based
engine that has been used to deliver Dox in the gastrointestinal tract [150].
123Biomaterials and devices for immunotherapy
7. Conclusion and future outlook
In this chapter, nanobiomaterial-based strategies for the delivery of an immuno-
therapy agent with the delivery of a chemotherapy agent by itself (i.e., without biomaterials) or biomaterial-based strategies for the dual delivery of both the immunotherapy
and chemotherapy agents were discussed. The literature available demonstrated that the
utilization of nanosized biomaterials, usually NPs, including nanospheres, nanorods, and
other nanosized shapes, can greatly help to enhance the delivery and efficacy of the drug
by protecting the agents, to increase targeting to the cells of interest, and tumor sites and
to decrease nonspecific side effects and toxicity. There are several nanobiomaterial-based
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strategies that were utilized to deliver a chemotherapy agent in combination with systemic delivery of immunotherapy (i.e., without biomaterials), however, they are beyond
the scope of this chapter, as we focused on nanobiomaterials-based immunotherapies
[169–173]. To increase the antitumor effects of these strategies, both the immunotherapy
and chemotherapy agents should be administrated via biomaterials as they further serve as
an agent to decrease the nontarget cytotoxic effect of the chemotherapy such as those on
immune cells, ultimately avoiding immune suppression, supporting a healthy immune
function and in turn helping to increase the response to the immunotherapy being delivered. Several preclinical models indicate that the sequence of the combination therapy is
critical and the delivery of chemotherapy first followed by immunotherapy appears to be
the most effective way of combining both of these treatments [174,175]. Thus, welldesigned NPs strategies should be developed to deliver these two agents at optimal times
and doses to result in synergistic effects on antitumor activity. Another interesting class of
polymer NPs, not yet widely exploited and potentially interesting in immunotherapy, are
molecularly imprinted NPs, also known as synthetic antibodies [176]. Molecular
imprinting allows NPs to display specific and selective cavities, having form, dimension,
and chemical structure complementary to molecules or receptor sequences in order to
obtain an efficient and selective recognition in vivo with drugs, ligands, or natural receptors involved in inflammation, infection, or altered processes. Major advantages in the use
of molecularly imprinted NPs for coating with biological antibodies include the possibility of avoiding the use of natural proteins that can induce unwanted immunological
responses [177].
We also focused part of this chapter on special biomaterial-based objects provided
with a propulsion system to allow precise local targeting. Such ultra-small size devices
are named MNRs and are becoming very attractive for drug delivery, in particular in
those applications in which precision and noninvasiveness are strict requirements for efficient therapy. Being able to access parts of the body that are hard to reach, by using
MNRs physicians could perform medical treatments on specific targets without affecting
healthy tissues. In contrast to passive devices, such as scaffolds or nonactuating NPs,
MNRs can be guided through living tissues by means of a propulsion system that, in most
cases, is triggered by external stimuli. However, besides the unquestionable advantages of
MNRs, still many challenges have to be faced and solutions have to be found to improve
these devices. A first issue is related to the biocompatibility of MNRs that, being often
made of metals to ensure responsiveness from electromagnetic fields, may induce inflammations or immune reactions [178,179]. In contrast, devices made of biocompatible
polymers are usually triggered by stimuli that cannot penetrate living tissues efficiently
or, worse, may induce excessive stress on cellular structures. However, sometimes,
the driving mechanism used to direct the MNRs to the target organ can be also exploited
to conduct these objects to the excretory systems, thus facilitating their expulsion and
minimizing their toxicity. The abovementioned disadvantages have limited the investigation on the applicability of MNRs in vivo, restricting most of the studies on in vitro
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