Technical Insights: Targeted Drug Delivery

Drug-delivery approaches that better control and target delivery are important to achieve clinical efficacy. Several recent interesting approaches involve an improved method of delivery for needle-free injection systems, gold nanoparticles for targeting tumor sites, and elastic capsules using nanosized flakes.

Needle-free injection systems

Researchers at the Massachusetts Institute of Technology (MIT) recently developed a jet-injection drug-delivery system based on a custom high-stroke Lorentz-force motor to mitigate some of the problems typically associated with controlling drug delivery through jet injection. The researchers noted that needle-free drug delivery by jet injection typically is achieved by ejecting a liquid drug through a narrow orifice at high pressure, thereby creating a fine high-speed fluid jet that can readily penetrate skin and tissue. The researchers assert that such injection systems use force- and pressure-generating principles that cause injection in an uncontrolled manner with limited ability to regulate delivery volume and injection depth. To address these shortcomings, the researchers developed a controllable jet injection device, based on a custom high-stroke linear Lorentz-force motor that is feed-back controlled during the time-course of an injection (1).

The key part of the design is the Lorentz-force actuator, a magnet surrounded by a coil of wire that is attached to a piston inside a drug ampul, according to a May 24, 2012, MIT press release. When a current is applied, it interacts with the magnetic field to produce a force that pushes the piston forward, ejecting the drug at very high pressure and velocity out through the ampul’s nozzle. The speed of the coil and the velocity can be controlled by the amount of current applied. The resulting waveforms generally consist of two distinct phases: an initial high-pressure phase in which the device ejects drug at a high-enough velocity to breach the skin and reach the desired depth, then a lower-pressure phase where drug is delivered in a slower stream that can easily be absorbed by the surrounding tissue, according to the MIT press release. Through testing, the group found that various skin types may require different waveforms to deliver adequate volumes of drugs to the desired depth.

The team is also developing a version of the device for transdermal delivery of drugs ordinarily found in powdered form by programming the device to vibrate, turning powder into a fluidized form that can be delivered through the skin much like a liquid, according to MIT release. Such a powder-delivery vehicle may help mitigate the problems associated with needing a cold-chain system for delivering vaccines and other biopharmaceuticals.

Gold nanoparticles

Researchers at the University of Sydney in Australia, led by Nial Wheate, senior lecturer in the Faculty of Pharmacy, and researchers from the University of Strathclyde and the University of Glasgow in Scotland recently reported on delivering the anticancer drug cisplatin using gold-coated iron oxide nanoparticles for enhanced tumor targeting (2). The researchers used this approach to overcome some challenges of cisplatin, namely poor bioavailability, severe dose-limiting side effects, and rapid development of drug resistance (2). The iron oxide core was coated in a protective layer of gold before the anticancer drug cisplatin was attached to the gold coating using spaghetti-like strings of polymer, according to a May 31, University of Sydney press release.

"When we take regular medication, it is difficult to manage where it goes,” said Wheate, in the release. “But this discovery means we can potentially direct exactly where in the human body a drug goes. We can move it to the desired cancer tumor site using powerful magnetic fields. Otherwise, a strong magnet could be implanted into a tumor and draw the drug into the cancer cells that way." The technology was demonstrated when the team grew cancer cells in plates. When they placed a magnet under the plates, the drug affected and killed only those cells growing near the magnet, leaving the others unharmed, The potential benefit of this targeted drug- delivery method is reduction of side-effects due to the chemotherapeutic drug traveling to other cells.

The iron oxide nanoparticles (FeNPs) were synthesised via a coprecipitation method before gold was reduced onto its surface (Au@FeNPs). Aquated cisplatin was used to attach {Pt(NH₃)₂} to the nanoparticles by a thiolated polyethylene glycol linker forming the desired product (Pt@Au@FeNP). The nanoparticles were characterized by dynamic light scattering, scanning transmission electron microscopy, UV visible spectrophotometry, inductively coupled plasma mass spectrometry, and electron probe microanalysis. Nanoparticle drug loading was found to be 7.9 × 10^-4 moles of platinum per gram of gold. External magnets were used to show that the nanoparticles could be accumulated in specific regions and that cell-growth inhibition was localized to those areas (2).

Elastic capsules

Researchers at the National Institute for Material Science in Japan recently developed a new elastic capsule using an inorganic nanometer-thickness flake-shaped material (nanosheets). Tests of the new capsule demonstrated that the release duration of anticancer drugs and other drugs can be controlled freely and can also be extended by several times by using the newly developed capsule.

The researchers were seeking to overcome some of the challenges of inorganic and organic materials conventionally used in capsules, according to a May 9, 2012, press release of the National Institute for Material Science. Inorganic capsules are hard, strong, and durable, but their structures are not easily adjusted to adapt to conditions. Organic capsules are flexible and structural adjustment is possible, but they have the drawback of low mechanical strength. Thus, the development of a drug-carrier capsule structure with the advantages of both types has been desired.

In this research, a soft capsule was developed by creating an assembly of nanosheets of silica, which is an inorganic material. While this capsule consists of a mechanically stable inorganic material, free control of its structure is also possible.

This capsule expands and contracts when heated and cooled, and the size of the pores in the outer wall, which are formed by the spaces between the nanosheets and serve as passages for drug release, can be controlled over a wide range by adjusting pH to various levels, according to the press release. As a result, the sustained-release time of the anticancer drug DOX was successfully extended by several times in comparison with conventional porous capsules having a simple structure. It was also possible to control the drug-release duration and drug-storage amount by changing the pore structure of the capsule, thereby changing the drug-release routes under appropriate pH conditions.

References

1. A. Taberner, N.C. Hogan, and I.W. Hunter, “Needle-free Jet Injection Using Real-time Controlled Linear Lorentz-Force Actuators, Medical Eng. & Physics , online, DOI/10.1016/j.medengphy.2011.12.010, Jan. 13, 2012.

2. N. Wheate et al., “Cisplatin Drug Delivery Using Gold-Coated Iron Oxide Nanoparticles for Enhanced Tumor Targeting with External Magnetic Fields,” Inorg. Chimica Acta, online, DOI10.1016/j.ica.2012.05.012, May 30, 2012.

3. Q. Ji et al.,"Flake-Shell Capsules: Adjustable Inorganic Structures," Small, online, DOI: 10.1002/chin.201223201, May 7, 2012.