**2. Nanotechnology in combination with PDT**

#### **2.1 Main hindrances of PDT**

There is a plethora of photosensitizing compounds available, but the majority of them did not present the requirements for clinical trials, i.e. good solubility, target selectivity, sufficient light absorption on the desired wavelength, and low accumulation in distant sites, especially the skin [1]. One of the biggest hindrances of photosensitizers is their hydrophobicity and consequent tendency to aggregate in aqueous environments, making the intravenous administration difficult unless some kind of delivery system is used [2, 3]. Besides, it is desirable that the photosensitizers accumulate preferentially in the target tissue rather than in healthy sites in order to avoid toxicity, therefore strategies of targeted delivery are often necessary to increase the therapeutic efficiency, and nanoparticle systems offer great advantages in this regard [1].

Besides the tendency to aggregate when photosensitizers are injected intravenously, they tend to be distributed to the whole body in a non-specific way, and to be taken up by plasma proteins or phagocytes, decreasing significantly the efficiency of PDT. To increase the specific delivery and avoid side effects, several carriers have been developed to take advantage of the enhanced permeation and retention (EPR) effect or to actively target tumors and enhance specific accumulation, such as polymer and metal nanoparticles, micelles and liposomes, and magnetic nanoparticles. The EPR effect is caused by the leaky vasculature common to tumor tissues, due to the sinusoid capillaries and the fenestrated endothelial cells, plus the inefficient lymphatic drainage from tumor sites. The active targeting, on the other hand, is actually a plethora of strategies to increase specific tumor accumulation of a drug or therapeutic compound [3].

Another obstacle for photodynamic therapy is the limited penetration of light, so it is used mostly for superficial tumors, or with the help of optic fibers introduced in the patient. Recently, researchers have been developing strategies to produce light inside of the body with the help of nanoparticle scintillators. These materials are able to convert external X-ray photons, which can reach deeper sites in the organism, into visible light photons that could excite a photosensitizer in a process called X-PDT. Another approach to excite photosensitizers with endogenous light is with Cherenkov radiation in a process referred as CR-PDT. Cherenkov radiation is generated when a particle exceeds the speed of light in a defined medium, and is common with the decay of several medical radioactive isotopes [4].

Photosensitizers that absorb in the NIR region, such as indocyanine green (absorption around 800 nm) and aluminum sulfophthalocyanine (absorption around 790 nm), although being able to be used in deeper regions due to the deeper penetration of NIR light, tend to be less efficient in generating singlet oxygen than other photosensitizers that absorb in lower wavelengths. Upconversion nanoparticles (UCNs) can overcome these limitations. The process where the absorption of multiple photons – usually two or three – from a given wavelength leads to the

*Nanomaterials for Enhanced Photodynamic Therapy DOI: http://dx.doi.org/10.5772/intechopen.94255*

emission of photons from a shorter wavelength is referred as photon upconversion. This can be used as a strategy to reach deeper tissues with longer wavelengths and excite photosensitizers that absorb in shorter wavelengths and would not be reachable by light otherwise [5].

UCNs usually consist in inorganic luminescent materials, usually made with lanthanide elements that absorb NIR light and emit UV-visible light that can be used to excite more efficient photosensitizers. Other than the possibility of exciting photosensitizers in deeper regions and prevent photobleaching, enhancing PDT efficacy, they can carry a plethora of hydrophobic photosensitizers, either loaded physically or chemically [6, 7].
