Novel technique for Near-infrared triggered drug release in living tissues

Researchers from the University of California have developed a new way to release substances from polymeric capsules in living cells using Near-infrared (NIR) light.

The controlled and targeted secretion of drugs is an area of increasing interest for many biomedical researchers and a number of methods have been developed using varying stimuli to achieve it. In biological systems the use of NIR-light as a trigger is particularly attractive because of its depth of penetration, reduced light scatter and low attenuation in living tissue.

Several ways of using NIR light as a stimulus in living systems have already been developed but because of the heat generated, power required and use of toxic compounds, these often damage the tissue. Other strategies require the use of designer polymers that are not widely available.

Dr Kim Dore and her colleagues in San Diego have now developed an approach that elegantly overcomes these major problems.

In this new technique hydrated polymer particles are irradiated with NIR light resonant with the vibrational overtone of water at 980 nm. This heats the water in confined domains within the particles without significantly increasing the heat of the whole system and causes a thermal phase change within the polymer, releasing the payload into the surrounding environment.

The team used poly(lactic-co-glycolic acid) (PLGA) particles containing model compounds (fluorescein, Nile blue, Nile red and IR780) which fluoresce upon release to examine how this works.

Using these capsules they revealed that release of the contents was only induced when irradiated at 980 nm. As PLGA is inherently non-light-sensitive the mechanism involved is not directly related to the absorption of light. Further, the amount of cargo released – measured by the increased fluorescence – was proportional to the amount of energy provided to the system.

To ensure that the release was due to heating of the encapsulated water, the particles were hydrated with deuterated water (D 2 O) instead of H 2 O. D 2 O does not absorb light at 980 nm and when these capsules were irradiated at this wavelength no increase in fluorescence was observed, as expected.

As this method requires heating of the confined water it was necessary to make sure that there is no significant temperature increase in the surrounding environment that may be detrimental to biological tissue. To do this a technique called Fluorescence lifetime imaging microscopy (FLIM) was employed using a Scientifica SliceScope two-photon microscope with a custom made multiphoton detection module (MDU) (Read the Dr Kim Dore two photon case study )

This equipment allowed the researchers to indirectly measure the intraparticle temperatures during irradiation. This is done by comparing the lifetime of the fluorescence compared to a standard curve of fluorescein lifetime directly heated. The change in lifetime inside the particles reflected an increase in temperature to 34, 45 and 54 oC following 5, 10 and 15 minutes of irradiation respectively. However, the lifetime of the surrounding free fluorescein did not decrease upon irradiation. Therefore, polymeric particles are selectively heated while the temperature of the aqueous environment does not increase.

This method has overcome a number of the issues previously related to the use of NIR light as a trigger in biological systems. Notably, it allows the use of a lower power laser continuously instead of a high-powered pulse. It also overcomes the problem of heating the whole environment and does not use toxic substances.

This means that it can work well within cells and tissues without damaging their viability or density.

Further benefits include the application of multiple doses by simply turning the laser on and off, and control of the rate of release by adding different amounts of energy to the system.

Additionally, it does not depend on a specific polymer being used; meaning other polyesters that are not inherently light sensitive at 980 nm should also work. The researchers managed to create two such polymers for which this was true and showed that they worked in macrophages without significantly damaging the cells.