Remote Actuation

Temporal and spatial control of therapeutic administration is important for eliminating off-target toxicity and achieving optimal delivery. Temporally controlled release profiles may be designed into nanoparticle carriers mentioned previously and spatial control can be improved with targeting. However, off-target effects, including eventual accumulation of nanoparticles in RES organs, limit many aspects of these methods of control. The ability to trigger the therapeutic activity of administered nanoparticles remotely could be a valuable tool for localizing treatments to a diseased site. Many inorganic nanocrystals and nanoemulsions used for imaging contrast absorb electromagnetic or ultrasonic energy that can also be used to remotely heat or trigger drug delivery.

Thermal ablation of tumors by nanoparticles that absorb external energy has been demonstrated both with iron-oxide nanoparticles and gold nanoshells. Superparamagnetic iron-oxide nanoparti-cles under the influence of an alternating electromagnetic (EM) field heat by Brownian relaxation, where heat is generated by the rotation of particles in the field, and Neel relaxation, where the magnetic domains are moved away from their easy axis with the resultant energy being deposited as heat in the solution.96,97 Nanoparticle concentrations of 0.1-1% are required to achieve critical temperatures for tumor ablation.98,99 Ongoing work to increase the absorption of magnetic nanoparticles using clinically safe RF frequencies and to increase the concentration of particles that can be targeted to the tumor may extend the utility of this technique. Alternatively, near-infrared-absorbing gold nanoshells targeted to the tumor can be used to thermally ablate the cancer cells upon illumination with a high intensity laser.100,101 This technique can be applied to solid tumors in close proximity to the skin, but cannot be applied to deeper lesions because of tissue absorbance.53,100,101 By synthesizing nanoshells with a plasmon resonance that has both absorption and scattering profiles, these nanoparticles may be capable of both heating and imaging

tumors.53

Remotely-triggered release of a therapy by heating is a promising extension of the use of nanoparticles that can absorb external energy. An example of this has been demonstrated with a model drug linked to an iron-oxide nanoparticle via a heat-labile tether that is released and diffuses into the peripheral tissue after irradiation with RF energy.98 By modifying the susceptibility of the linker, it is possible to tune the release profile over a range of temperatures and to enable repeated administrations. The iron core of these drug-releasing nanoparticles can be used simultaneously for imaging with MRI. Additionally, the magnetic properties of these nanoparticles can be manipulated by magnetic field gradients to target sites near externally- or internally-placed magnets.

Drug activation using EM energy has been explored extensively with photodynamic therapy (PDT). PDT agents, when irradiated by light, produce reactive oxygen species that are toxic to cells. Agents such as porphyrins have been conjugated to various nanoparticle cores including dendri-mers, liposomes, and polymers.103,104 When excited by light, these nanoparticles can produce enough reactive oxygen species to kill tumor cells. The inherent fluorescent properties of many PDT agents enable simultaneous imaging with therapeutic delivery. A multifunctional nano-particle platform combining MRI contrast and photodynamic therapy has been used to target, image, and treat brain cancer in a rat model.105 In the future, integrating these nanoparticles with peptides capable of targeting tumors and subcellularly localizing them to the nuclei or mitochondria of tumor cells may enhance the therapeutic efficacy of these treatments.

Other forms of externally applied energy such as ultrasound and x-ray radiation provide alternative mechanisms to achieve remote actuation. Acoustic energy has been shown to enhance the delivery of lipid drugs from a perfluorocarbon emulsion targeted to cell membranes and from doxorubicin-loaded polymeric micelles.106,107 Atomically dense nanoparticles have been shown to increase the absorption of x-ray radiation, enhancing their destructive effect in surrounding tissue.108 There is potential for simultaneous imaging and therapeutic delivery with these particles also.

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