//Background//---
The
cell specific delivery system could deliver nanoparticle in which effective
drug is infused at the target lesion by forming the surface protein (complex)
with high affinity specific to the targeted binding site of the target cell like
cancer or neurological diseases. However, passive releases technique, in which
drug releasing from nanoparticles depends on only intrinsic properties (pH, the
density gradient of chemoattractant, enzymes, blood vessel, retention effect,
binding strength, interstitial fluid pressure, temperature, many barriers
(extracellular matrix, blood brain barrier, blood tumor barrier, endothelial
tissue)), predetermines release profile. Given heterogeneity among patients and
longitudinal environmental change by continuous treatment, passive release
technique may be insufficient to control over the spatiotemporal distribution
of the drug.
To
overcome this challenging drug controlling matter, powerful wireless on-demand
drug delivery technique is suggested(1). This approaches take advantage of
arbitrary extrinsic signals including acoustic waves(2-5), electric field(6,7),
magnetic field(8,9) and electromagnetic radiation(10-12). Seyed M. Mirvakili
& Robert Langer et al. reviews about drug delivery systems exploiting
electric field, magnetic field and electromagnetic radiation. I hope to share a
part of these contents with the global important readers partly in line with
the cell-specific delivery system.
//Electric fields(1)//---
(Conductive polymers)
Conducting polymers are ionically and
electronically conductive, which can change volume through expansion and
contraction triggered by applied electric field. Therefore, this polymer is
used as “Depot (See Fig.1a)”,
this volumetric change enables drug release. For example, poly(dimethyl
aminopropyl acrylamide) (PDMAPAA) loaded with insulin drugs have been
demonstrated arbitrary releasing of drug from this cargo through applied
electric field(13).
There are two ways(#1,2) to apply the electric
field in vivo.
(#1): Sharp needle electrodes inserted into
the dermis layer of skin structure(14).
(#2): Applying metal pads on the surface of
the skin(13).
However, when electrode system is formed in
vivo, the electric double layer is generated where electric potential
exponentially decays. Therefore, at only the place a few nanometers from the
electrodes, the electric potential becomes 36% of strength for the interface of
electrodes. Hence, the field where electric stimulus can be efficiently applied
is limited quite near the electrode.
*The cell specific delivery system
Conductive polymer can be used as “Protected material” of nanoparticles.
Nanoparticles with dense surface materials is susceptible to the surrounding
material including corona formation, by which targeted intrinsic properties
vary in vivo. If these nanoparticles can be protected by the depot and be
released from this depot in a controllable manner, precision of drug-mediated
therapy could be improved.
---
(Electroporation)
Electroporation can be efficiently harnessed
to topical and transdermal drug delivery. In this method, high-voltage pluses
and short pulse width (Typically: >100V, μs~ms) are
applied to the surface of the skin through two electrodes, by which the
electric field emerges in stratum corneum region and this potential enables the
drug delivery (See Fig.1d). This process has been shown to reversibly (able to
recover) disrupt the cell membrane and the lipid bilayer structures in the skin(15,16).
Kinetics of drug including DNA, vaccines, peptides and small-molecule drug is
accordance with electrophoretic migration, which enhances efficiency of
transport by orders of magnitude(17,18). However, the electrical resistance of
the skin near surface (stratum corneum layer) is significantly higher than that
of deeper tissues.
---
(Iontophoresis)
Electroporation can be efficiently harnessed
to topical and transdermal drug delivery. Low-voltage (<10V) galvanostatic
excitation of electrode set on the surface of skin transports drug through
surface to deep region. The main driving force is electrophoresis /
electromigration / electroosmotic flow of surface-charged small-molecule drugs(19).
Previously this method enables only small molecule transport, but currently, delivery
of molecules up to a few kilodalton succeed(20). Concrete application is
following(#).
(#): Lidocaine for local anaesthesia(22),
Tap water for hyperhidrosis treatment(23), Pilocarpine for cystic fibrosis
diagnosis(24), Fentanyl for pain relief(25), Acyclovir for herpes labialis
treatment(21) and Extraction of glucose for glucose monitoring(26), Gemcitabine
to pancreatic cancer tumor(27).
-
*Limitation
1: Slowness of transport (minutes to hours).
2: Small optimal operation windows for
safety and delivery.
*For improvement: the combination with
electroporation, ultrasound(28,29).
---
(Disucussion)
The
additional value of this method for intravenous injection is high positional
arbitrary property (a degree of freedom for the injection site). In other
words, electroporation and iontophoresis enable topical and transdermal drug
delivery for all sites of body surface. Therefore, we can infuse the drug from
the site close to the target lesion.
//Magnetic fields//---
*Advantage
This can make drug deeply penetrate the
tissue with more minimal interaction with the ion than the driving force by the
electronic field.
-
*Typical operation condition
1: Low-frequency magnetic fields: <20kHz
2: High-frequency magnetic fields:
>100kHz
---
(1: Low-frequency magnetic fields)
*Method: Magnetic force is generated by
magnets or electromagnets.
*Mechanically deformation of soft scaffolds
by application to release the drug(30,31).
*Engineered liposome including magnetic
nanoparticles can be harnessed(32).
-
*For transdermal drug delivery: A magnet
(<450mT) is set at the skin’s surface. This makes diamagnetic hydrophilic
drug drive through skin structure. The net charge (+-) of the drug molecule
does not affect the delivery efficiency through skin.
-
*Limitation: Heavy, expensive coil, low
portability, resulting administration in only certain facility.
---
(2: High-frequency magnetic fields)
*Magnetic-field oscillation can generate
heat in metal and magnetic particles used as drug (carrier). This heating
process is due to a Joule heating effect by eddy current. Especially for
single-domain magnetic nanoparticles, Brownian / Neel fluctuation are dominant
for heat generation(33). When heated, the structure is re-arranged, resulting
the diffusion length of drug increase.
-
**Application example:
1: Drug delivery:
*Micro/nano hollow capsules including
liposomes(34-36).
*Polymer based solid particles(37-39)
*Thermal triggering of lower critical
solution temperature (LCST) hydrogels including
poly(N-isopropylacrylamide)(pNIPAM) which is networks of crosslinked long
polymer chains to release drug after heating by magnetic signal(40)(See Fig.2e)
(#)The cell-specific delivery system
LCST
hydrogel can be used as “Protector” of the nanoparticle carriers against environmental dust (corona
formation) in vivo. On-demand release is possible by magnetic signal or the
other thermogenic signals.
*The drug reservoir with the partly door
made of the material with magneto-thermal effect. This door can open
arbitrarily to release drug through magnetic field(41,42)(See Fig.2g).
2: Hyperthermia for tumor ablation(43-46).
---
(Limitation)
*No direct measure to detect temperature in
vivo.
*Precise control system is needed for
optimal operation.
*Necrosis and hypothermic shock in healthy
tissues
*Drug (Cargo) damage
//Electromagnetic radiation//---
(Radio waves)
*Wavelength: 10,000km to 1mm
*Proposed system: Microchips generating
radio waves with on-chip drug reservoir, which can be controlled by transmitter
and microcontroller. However, silicon-based pharmacy-on-a-chip is not
biodegradable, so require removal after the end cycle (full drug release). This
system is costly and uncomfortable for patients.
---
(Infrared)
*Wavelength: 700nm to 1mm.
*Light penetration in skin tissue is
maximum (~4-5 mm) around 870nm (See Fig.5)(47). Therefore, optical signal is
made function down to the deep tissue including hypodermis where blood vessels
exist.
*System: Heat generation by surface plasmon
resonance for irradiated light could release the drug from nanoparticles in
multiple ways including drug releasing surrounding nanoparticles, volume
change, membrane disruption (See Fig.6a).
*Limitation:
1: Low photon conversion efficiency(48,49)
2: Skin tissue damage(48)
3: High spatiotemporal control is needed.
4: Limited material choice
---
(Visible light)
*Wavelength: 400nm to 700nm
*System: Plasmonic resonant system / Light-responsive
organic moieties including vitamin B12 derivative, Trithiocarbonates / Transition
metal compounds (ruthenium complexes)(50,51).
*Limitation
1: Smaller penetration length
#: Limitation (may) be similar to infrared
light.
---
(Ultraviolet)
*Wavelength: 4nm to 400nm
*This energy level is harmful to human body
and could generate tumor, but low-energy side light and low-intensity condition
is useful in triggering drug release.
*System: Volume change (contraction) by
irradiation of UV-light in following materials(#).
#1: Azobenzenes undergo cis-trans
photoisomerization(52,53).
#2: Spiropyran-based nanoparticles contract
by about 52% (103nm to 49nm) when excited with 365 nm ultraviolet light which
is quite low-energy side in ultraviolet(54).
*Limitation:
1: Tissue damage in DNA level
2: Very small penetration depth (<1mm)
#: Limitation (may) be similar to infrared
light.
---
(X-ray)
*Wavelength: 0.01nm to 10 nm
*Synergetic treatment of standard
radiotherapy and drug carrier stimulation for releasing could be implemented
including tumor site(55).
*Considerable penetration length enable
widely application, but side effect by irradiation of X-ray needs to be
carefully considered.
---
(Gamma-rays)
Wavelength: 0.16pm
*Gamma-rays can be used to sterilize some
nano-carriers including chitosan microparticles, liposomes, niosomes, sphingosomes), with
almost no side-effects(56), before administration, but the side effect for
human body needs to be careful after administration.
//Discussion//---
As
reviewed by Seyed M. Mirvakili & Robert Langer(1), the spatiotemporal
controlling of drug releasing from a nano-carrier by exogenic signals including
electric field, magnetic field, light wave is promising. Furthermore, real time
monitoring and analysis including local temperature are needed. However, such
elaborate system entails cost, footprint problems and we cannot provide
administration anywhere including patient’s home. Therefore, the autonomous
drug releasing system in a specific lesion needs to be included. The
cell-specific delivery system could bind the specific site of the lesion, so
there is certain retention time at the lesion. This partly gives autonomy on
releasing in drug delivery system. Of course, we can exploit cell functions
including endocytosis, pinocytosis. Combination strategy of cell-specific
delivery system and exogenic signal for administration has room to be
considered.
//Ethics declarations(1)//---
Competing interests
S.M.M. declares no competing interests.
//Peer review information(1)//---
Nature Electronics thanks Azita Emami and the other, anonymous,
reviewer(s) for their contribution to the peer review of this work.
//Publisher’s note(1)//---
Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
(Reference)
(1)
Seyed M. Mirvakili & Robert Langer
Wireless on-demand drug delivery
Nature Electronics volume 4, pages464–477
(2021)
---
Author information
Affiliations
Koch Institute for Integrative Cancer
Research, Massachusetts Institute of Technology, Cambridge, MA, USA
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