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Photosensitizer delivered to tumors without using a carrier

BioPhotonics
May 2007
David L. Shenkenberg

Most photosensitizers used for photodynamic therapy (PDT) of cancer require a carrier to get them into the cell because they are hydrophobic, but Paras N. Prasad and colleagues from State University of New York and Roswell Park Cancer Institute, both in Buffalo, have delivered a photosensitizer in vivo without using a vehicle. They prepared nanometer-size crystals of the photosensitizer and ultimately used the crystallized photosensitizer to perform PDT in tumor-bearing mice.

The researchers used the photosensitizer Photochlor, or 2-devinyl-2-(1-hexyloxyethyl)pyropheophorbide. Photochlor is more effective and less toxic to healthy tissue than Photofrin, currently the only FDA-approved photosensitizer. Photochlor also may enable greater tissue penetration because it maximally absorbs at 665 nm — longer than Photofrin’s 630-nm absorption peak.

To prepare nanocrystals of the photosensitizer, the investigators employed the reprecipitation method, a technique that permits control of nanocrystal size by varying the time of formation. In addition, the process requires little time or effort. Preparing the nanocrystals only required dissolving the photosensitizer in an organic solvent at room temperature, injecting the resulting organic solution into water and performing overnight dialysis to remove the organic solvent.

BNTween_FLUOR.jpg
Researchers caused a photosensitizer to form nanometer-size crystals. They delivered the nanocrystals to cancer cells and imaged the cells using confocal microscopy. They ultimately used the crystallized photosensitizer in tumor-bearing mice. Image reprinted with permission of Molecular Pharmaceutics.

After crystallizing the photosensitizer, they characterized the size and electrical potential of the crystals, important for both their stability and cellular uptake. The researchers made the measurements with a dynamic light-scattering instrument from Brookhaven Instruments Corp. of Holtsville, N.Y., and showed that the nanocrystals had a –40-mV electrical potential and were relatively the same size, with diameters ranging from 100 to 120 nm. These characteristics allowed the nanocrystals to disperse and to be stable in water.

In an early in vitro experiment, the scientists added the nanocrystals to radiation-induced fibrosarcoma cells, generally accepted as a model for PDT. They used a Leica confocal microscope to monitor the cellular entry of the nanocrystals. To induce PDT, they irradiated the cells with a dye laser pumped by an argon-ion laser, both from Spectra-Physics of Mountain View, Calif. They determined the efficacy of PDT using a conventional cell viability assay.

They compared the results achieved by the nanocrystals with those achieved by the conventional surfactant vehicle Tween-80. Conventional vehicles are less desirable than a pure drug because they may introduce toxicity to healthy tissue. The researchers observed that both PDT and cellular uptake occurred just as effectively with the nanocrystal formulation as with the conventional vehicle. The photosensitizer converted from nanocrystal form to its phototoxic molecular form upon interaction with either serum proteins, the cell membrane or intracellular components. The researchers said that they did not know the exact mechanism of these interactions, but that they were less concerned with the explanation than with the outcome.

For their in vivo experiment, they injected the nanocrystals into mice bearing radiation-induced fibrosarcomas. They irradiated the tumor site at 665 nm and with a 135 J/cm2 fluence for 30 minutes, using the same laser employed in their in vitro experiment. They considered the mice cured if they had minimal or no tumor regrowth after 60 days. The efficacy of the nanocrystal formulation compared well with the Tween-80 solution, as reported in the April issue of Molecular Pharmaceutics.

Prasad said that nanocrystallization can be used to deliver imaging agents and other drugs, and he has applied for a patent. He said that the group is currently trying to crystallize chemotherapy drugs and that it plans to do additional in vivo studies. It also is studying the possibilities of electrostatic binding with targeting units to direct the nanocrystals to tumors.


GLOSSARY
photodynamic therapy (pdt)
A medical technology that uses lasers or other light sources in combination with photosensitizing drugs to treat cancerous tumors.
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