Effect of PDT on Cytokine Gene Expression and Immune Response

The subjects of intensive studies include (i) immune suppression after cutaneous PDT, (ii) immune potentiation after tumor PDT on other tumors, (iii) molecular mechanisms of regulation of some of the cytokines involved in potentiation, and (iv) different gene expression models, with different photosensitizers.

Tissue Oxygen Level Limitation. An important limitation of PDT utilizing photosensitizers that act by a type II process (Section 12.1) producing singlet oxygen is that the oxygen level is depleted both by consumption of singlet oxygen in a photoinduced chemical reaction and by vascular damage, leading to the shrinkage of its radius. This effect limits further therapy for producing direct tumor cell killing. This limitation is being addressed in a number of ways:

1. Adjusting the light fluence rate to slow oxygen consumption sufficiently so that the tumor tissue oxygen level can be maintained at the necessary level. A useful method has been the delivery of light in fractions, such as very short (20-50 sec) light and dark intervals, which allows reoxy-genation during dark periods.

2. Providing PDT treatment in oxygen-enriched conditions (such as in a hyperbaric oxygen chamber)

3. Developing oxygen-independent photosensitizers that utilize free radicals (such as hydroxyl groups) as the active agent. However, these photosensitizers are not very efficient because one can only use each photosensitizer molecule once.

New Photosensitizers. Further acceptance of photodynamic therapy, increasing its efficacy, reducing side effects, and broadening the scope of its applications are crucially dependent upon the development of new photosen-sitizers. This provides unique opportunities for chemists. Some areas of opportunities are:

• One-photon PDT sensitizers that operate in the near IR (l > 800nm)

• Efficient multiphoton-absorbing photosensitizers

• Dendrimers carrying multiple photosensitizers

• Targeting photosensitizers that carry an antibody, small proteins or pep-tides, sugars, and so on

• Oxygen-independent sensitizers

• Amphiphilic photosensitizers

The benefits of these types of photosensitizers have been discussed at various sections in this chapter. For example, it has recently been shown that por-phyrins can be designed and synthesized with dramatically enhanced two-photon cross sections (up to two orders of magnitude enhancement) (Karotki et al., 2001). These new materials have also exhibited very efficient singlet oxygen production in in vitro studies.

Enhanced Transport of PDT Drugs. The more efficient transport of a photosensitizer into a tumor tissue can increase the efficacy of PDT treatment and shorten the waiting period. A highly active area of research is the use of various methods as well as chemical conjugation with various carrying units to enhance the transport of the sensitizer (Konan et al., 2002). For example, transdermal transport of amino levulinic acid, ALA, a PDT pro-drug for protoporphyrin IX, can be enhanced severalfold by electroporation as compared to topical application. Electroporation is a technique whereby pulsed electrical stimulation of the skin results in the opening of the interdermal spaces (spaces between the cells), allowing for more efficient transport of the sensi-tizer into the tissue. Another approach is to attach an imaging reagent conjugated to a small peptide that can bind to over-expressed receptor sites on the tumor.

Enhanced Drug Delivery to Tumors by Low-Dose PDT. Subcurative PDT for tumors can make the tumor vasculature highly permeable to large molecules. The subclinical dose disrupts the tumor vasculature as a result of cell destruction and/or activation of inflammatory processes. The result is increased permeability to large molecules, toxic drugs such as doxorubicin that are encapsulated and delivered locally after application of PDT (Henderson and Dougherty, 1992).

New Light Sources. In order for PDT to gain wide acceptance by the medical community, there is a need for lasers that are compact, low cost, user-friendly, and relatively maintenance-free. Furthermore, the need to activate more than one photosensitizer requires a multiwavelength laser source. New-generation diode lasers, other solid-state lasers, and optical parametric oscillators offer great opportunities for laser physicists and engineers. Looking futuristically, one can even think of implantable high-fluence diode light sources and low-fluence attachable device "patches" for long treatment.

Real-Time Monitoring of PDT. There is a real need for further development of techniques that will allow real-time monitoring of the parameters that determine PDT action. Some of these parameters are photosensitizer tissue concentration, photobleaching rates, blood flow, and oxygen pressure in tissue (pO2). These types of studies will provide insights into ways to enhance treatment effectiveness and selectivity.

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