Remote Controlled Drugs
The latest devices can deliver a drug in the right place and at the right time at the push of a button.
Brian P. Timko, Daniel S. Kohane |
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Drug delivery technology evolved in part to address the deficiencies of conventional administration routes. When drugs are delivered by injection or in pills, it is difficult to achieve drug levels within the narrow window between toxicity and under-dosing. Furthermore, drugs with short half-lives have to be administered frequently or even continuously, potentially resulting in patient discomfort or inconvenience, or requiring tethering to external devices. Today, some of these limitations have been addressed by delivery systems that release therapeutics passively at a more-or-less constant rate for an extended period (
The problem with such systems is that they are not responsive to changes in the physiological state – or wishes – of the patient. Consequently, there has been a lot of research in developing drug delivery systems that can be triggered by the patient or physician to release drugs at the time and dose of their choosing or, in other words, on demand (
Pulling the trigger
Near-infrared (NIR) light has attracted considerable attention as a trigger for drug release. It can penetrate relatively deeply into soft tissue because hemoglobin and water absorb the least light in that range of wavelengths (see Figure 1) (
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Figure 1. The NIR window, bound by hemoglobin (650 nm) and water (>900 nm) exhibits minimal absorption. Adapted from (
Going for gold
One way to trigger drug release with NIR light is by using gold nanoparticles, which come in a variety of shapes, such as rods, cubes or shells. Gold nanoparticles react to NIR light by producing heat in a process called surface plasmon resonance. The heat produced can be used to trigger another process; for example, to induce a change in a temperature-sensitive material built into the nanoparticle, resulting in drug release. In a seminal study, gold nanoshells were embedded in a macroscale hydrogel composed of the temperature-sensitive polymer poly(n-isopropylacrylamide) (pNIPAm) (
NIR-sensitive micro- or nanoparticles that contain drugs represent another route and offer the additional benefit that they are injectable. Temperature-sensitive liposomes, which typically release drugs passively, have been conjugated to gold nanorods to achieve NIR sensitivity. NIR irradiation disrupts the liposome, enabling release of the loaded drug (
The wavelengths of light that cause heating of gold nanomaterials (based on absorption spectrum) are highly dependent on particle sizes and geometry. By tuning the shape and size of the nanoparticles, the drug delivery system can be adapted to any light source within the visible or near-infrared range. Systems can also be composed of two populations of particles that are triggered by lasers firing nonoverlapping spectra, enabling independent dosing of two or more distinct drug types (
Reservoir drugs
Remotely-triggered drug delivery systems must be designed so that the range of achievable drug release rates is therapeutically acceptable. Moreover, the ratio between the fully-on and fully-off states of the device should be as high as possible so that baseline drug leakage, which reduces the lifetime of the device and could cause side effects, is minimized.
One way to achieve consistent, reproducible drug release is with reservoir-based systems, in oral, transdermal or implantable formulations, designed to achieve sustained or pulsatile release profiles. Some have already undergone clinical trials for treating conditions such as diabetes, osteoporosis or macular edema (
We recently developed an implantable reservoir that could be loaded with tens or hundreds of doses of drug and triggered with NIR light (see Figure 2A). The drug is contained in a capsule bounded by a hydrophobic membrane that is impermeable to the drug. The membrane contains an interconnecting network of nanoparticles based on pNIPAm and gold nanoshells. When irradiated with NIR light, the drug is released through pores that are created in the membrane via pNIPAm collapse (see Figure 2B) (
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Figure 2. NIR-triggered capsules. (a) Schematic of device. (b) (left) Photograph of a typical device, and (right) thermal image of the same device uniformly irradiated with 808 nm light at 186 mW/cm2. (c) Release from devices over 30-min dosing cycles. Devices were turned on with 570 mW/cm2 laser light twice per day for 5 days. Off-state release was measured 30 min before laser triggering (n = 3). (d) Photograph of a rat with an implanted capsule (black arrow). (e) One day after device implantation, blood glucose levels were measured after triggered release from devices filled with saline (n = 4) or aspart solution by using an NIR trigger (30 min duration; gray box) of 0, 142, or 570 mW/cm2 irradiance (n = 4, n = 3, and n = 6, respectively). All data are means ± SD. Adapted from (
Drug delivery rates could be modulated by adjusting the thickness or composition of the membrane. More importantly, the specific rate of drug release could be modulated by adjusting the intensity of the NIR light. As a proof of concept, we designed devices that could treat diabetic rats. Typically, a dose of 1 unit of insulin – or, in our case, a fast-acting analog such as aspart – is enough to reduce blood glucose to normal levels. We built devices loaded with over 100 doses of aspart, sealed with a membrane designed to release approximately 1 unit of aspart when triggered for 30 minutes with a laser (see Figure 2C). The devices were implanted beneath the skin of diabetic rats (see Figure 2D), and could be triggered multiple times over a 14-day period. Figure 2E shows the typical glucose response after a 30-minute NIR pulse. The blood glucose level reached a minimum about 150 minutes after triggering, but notably the magnitude of glycemic reduction could be controlled by the intensity of the laser pulse – a stronger pulse achieved a greater reduction.
If coupled to a glucose monitor, systems like these could tailor dosing to the level of hyperglycemia. They could also be used to achieve localized drug release. For example, they could be placed on a nerve, giving the patient the capability for precise titration of local analgesia to match actual needs and circumstances. These devices can moreover be used to deliver a wide range of drug types from small molecules to macromolecules, and therefore could be useful for treating a wide range of disorders (
Safety
Despite the abundance of triggered drug delivery systems, relatively few have made it into the clinic. Systems that show potential in humans will certainly need to undergo a thorough battery of tests to ensure patient safety; for example, the NIR light itself could cause burns at sufficiently high powers and/or irradiation times, which is particularly relevant in patient-controlled devices, where the a device may be activated repeatedly. Materials for drug delivery should be designed so that the irradiance required to fully activate the device is minimized, particularly in the case of systems placed deep within tissues, where a substantial portion of the light is absorbed and scattered, leading to heating.
As with all drug delivery systems, the biocompatibility of the NIR-activated carrier and the drug contained within is important (
Looking ahead
As NIR-triggered devices can, in principle, release drugs in any temporal profile – pulsatile, sustained, crescendo, and so on – they enable dosing regimens that are not achievable by conventional means. NIR can also be used to target nanoparticle carriers to specific tissues (
In short, NIR-triggered drug delivery systems could enhance efficacy, reduce side effects, increase patient compliance and, ultimately, give patients greater control over their lives. Certainly, there is much to consider in terms of both safety and efficacy in the future, but we feel the huge potential benefits are well worth the effort.
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Instructor in Anesthesia at Boston Children’s Hospital.