Traditional photodynamic therapy (PDT) is based on photoactive drugs that produce excited singlet-state oxygen molecules from local (ground-state) oxygen molecules under illumination with visible light.¹ The singlet oxygen produces reactive oxygen species, primarily free radicals such as ·OH. These free radicals attack DNA and other vital biomolecules in the cell, leading to cell death. Due to the limited tissue penetration of visible light, PDT has mostly been utilized for skin cancers.

Often injected into the area of the tumor, the photodynamic drug is composed of non-toxic molecules that efficiently absorb red wavelengths. Excitation of these molecules, usually a triplet state excitation deriving its energy from the excited singlet state, is quenched by oxygen molecules through an energy exchange that excites the oxygen molecule from its ground triplet state to its excited singlet state. This “singlet oxygen” is often called “killer oxygen,” as it quickly reacts with neighboring molecules, including water, to produce highly-reactive free radicals that, in turn, kill the cell. The United States Food and Drug Administration (FDA)-approved PDT drug is made of red blood cell hemoglobin-based molecules (trade name Photofrin), but other PDT molecules are awaiting FDA approval, and several are approved in Canada and Europe.

PDT has three primary problems. First, PDT is limited to superficial tumors, or tumors that are reachable by optical fibers. Second, the PDT drug molecule is not very selective and thus kills neighboring healthy cells. Third, a lesser concern is the photo-toxicity of the drug; treated patients must be kept in the dark for days or longer. At the same time, PDT has several advantages: the therapeutic laser beam can be selectively aimed at the tumor only; the visible radiation (usually 488nm or 633 nm) will not penetrate far beyond the tumor, even if non-tumor cells contain the drug; and PDT will not cause damage to cells that neither the light nor the drug reach. Thus, compared to chemotherapy and radiation therapy, PDT is quite benign. The question that now arises is whether we can extend this approach to the treatment of non-superficial tumors or to tumors that are diagnosed non-visually (with later confirmation by biopsy).

Some researchers have suggested the use of infrared active dyes in PDT,² as the activating infrared photons can penetrate deeper into tissue than visible light. An analogous approach involves pulsed infrared photons used in combination with two-photon-absorbing PDT drug molecules.³ While this method also provides deeper photon penetration, it exacerbates the non-selectivity of the method as well: more non-tumorous tissue will be harmed.

The new PDT paradigm addressed here consists of nanoplatforms, which are nanoparticles (NP) that combine PDT with tumor detection and tumor imaging (see Figure 1). These NP, when injected into the bloodstream, find the cancer cells and enter them using selective molecular targeting. At the same time, they enable external MRI or optical imaging of the tumor. This allows one to aim a laser, via an optical fiber, at the tumor.

The NP PDT approach has been demonstrated⁴ on rats bearing the deadliest human brain cancer, 9L Glioma. Control mice with 5mm brain tumors survive only one week; those treated with existing therapeutic approaches live less than two weeks. But 60% of NP PDT treated rats were cured of their brain tumors. The procedure involved only 5min illumination by a 1W helium-neon laser, using a fiber inserted through the skull with a hemispherical diffuser.

With the same tumor, survival time for humans is only 4–6 months, and neither chemotherapy nor radiation therapy are effective. More details on these nano-drugs, including their synthesis, composition, and toxicology, are given in a paper by Yong-Eun Koo et al.⁵

The latest additions to these “photonic drugs” are PDT NPs that utilize two-photon excitation.⁶ Using an experimental two-photon PDT dye (embedded in the NP) and a pulsed Ti:sapphire laser, we demonstrated the effectiveness of this technique on live breast-cancer cells (see Figures 2 and 3).

Once more-efficient two-photon dye-based NP are perfected, a second generation of such nano-drugs should work not only for highly-transparent brain tumors but also for other tumors in areas of the body with lower optical transparency.