| Remote-Controlled Nanocomposite
Invented for Drug Delivery inside Body
Editor's note: This article further illustrates evidence
of ongoing efforts in nanotechnology and pharmacology to create
methods of drug delivery via nanoparticles which can potentially
cause
DNA damage, and other
risks.
Researchers managed to develop drug delivery techniques with 'on-off
switches' that would allow controlled release of drugs into the
body by combining magnetism with nanotechnology.
Researchers created a small implantable device that encapsulates
the drug in a specially engineered membrane, embedded with magnetic
iron oxide nanoparticles.
These methods use stimuli such as an implanted heat source or
an implanted electronic chip to trigger the drug release from
the implanted reservoir. So far, none of these methods can reliably
perform all the needed actions: repeatedly turn dosing on and
off, deliver consistent doses, and adjust doses according to each
patient's need.
Quite a number of serious medical conditions, such as cancer,
diabetes and chronic pain, require medications that cannot be
taken orally, but must be dosed intermittently, on an as-needed
basis, and over a long period of time.
The application of an external, alternating magnetic field heats
the magnetic nanoparticles, causing the gels in the membrane to
warm and temporarily collapse. This collapse opens up pores that
allow the drug to pass through and into the body. When the magnetic
field is turned off, the membranes cool and the gels re-expand,
closing the pores and halting drug delivery. No implanted electronics
are required.
"We have developed an implantable system that can provide
on-demand, reproducible drug release whenever the patient - or
other operator - wants, for as long as needed, and with the intensity
that is desired, using a trigger that is external to the body
- in this case an oscillating magnetic field," Daniel Kohane
told Nanowerk Spotlight Journal.
"Most of the previously designed systems could only result
in a single release event, or involved implanted triggering systems,
or connectors to the outside world," he added.
Kohane, an associate professor of anesthesiology at Harvard Medical
School and a senior associate in critical care medicine at Children's
Hospital Boston, and his team have reported their findings in
a recent issue of Nano Letters ("A Magnetically Triggered
Composite Membrane for On-Demand Drug Delivery").
Kohane explained that composite membrane-based drug delivery
devices have the potential to greatly increase the flexibility
of pharmacotherapy and improve the quality of patients' lives
by providing repeated, long-term, on-demand drug delivery for
a variety of medical applications, including the treatment of
pain (local or systemic anesthetic delivery), local chemotherapy,
and insulin delivery.
The membrane that Kohane's team developed consists of ethyl cellulose
(the membrane support), superparamagnetic magnetite nanoparticles
(the triggering entity), and thermosensitive poly(N-isopropylacrylamide)
(PNIPAM)-based nanogels (the switching entity).
Membranes were prepared by co-evaporation so that the nanogel
and magnetite nanoparticles were entrapped in ethyl cellulose
to form a presumably disordered network. To facilitate effective
in vivo triggering, the nanogels were engineered to remain swollen
(i.e., in the 'off' state) at body temperature.
Stimulus-responsive drug delivery membrane triggering in vitro
Stimulus-responsive membrane triggering in vitro: schema of the
proposed mechanism of membrane function. (Reprinted with permission
from American Chemical Society)
"When we subjected the magnetic nanoparticles embedded in
the membrane to an external oscillating magnetic field, they heated
inductively," explained Kohane.
"The heat generated by magnetite induction heating was transferred
to the adjacent thermosensitive nanogels, causing the nanogels
to shrink and permit drug diffusion out of the device. When we
turned off the magnetic field, the nanogels cooled, causing them
to reswell, turning off the drug flow and refilling the membrane
pores," he added.
The researchers observed a 10- to 20-fold differential flux between
the 'off' and 'on' states. Furthermore, multiple on-off cycles
could be performed without significantly changing the permeability
of the membrane in the off state.
The on-off action doesn't occur immediately but was much more
rapid than that seen with bulk, interpenetrating hydrogel networks.
The devices turned 'on' with only a 1-2 minute time lag after
the solution temperature reached 40°C and turned 'off' with
a 5-10 minute lag after the stimulus was switched off.
Kohane pointed out that reproducibility will clearly be a key
consideration in devices of this type, especially with drugs with
narrow therapeutic indices.
"We have shown excellent reproducibility over four magnetically
induced cycles" he said.
"The maximum number of cycles over which that reproducibility
can be maintained remains to be determined, as does the number
of cycles over which it needs to be maintained. The latter will
depend to a large extent on the specific clinical indication and
the expected duration of therapy. Some devices might only need
to be triggered a few times, while others - e.g., for a chronic
condition requiring treatment several times a day - might require
reproducible triggering over thousands of cycles," Kohane
told the Journal.
This issue will be of great importance in the downstream development
of the device. Indeed, the ultimate design of a clinical drug
delivery device based on this membrane technology, including the
specific materials of which it will be composed, is yet to be
determined, he stressed.
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