*Targeted Photodynamic Therapy as Potential Treatment Modality for the Eradication of Colon… DOI: http://dx.doi.org/10.5772/intechopen.84760*

exposed to laser irradiation light at a specific wavelength [26]. Thus when a tumor (which contains the localized PS drug) is exposed to laser irradiation light, the PS absorbs the photons and becomes excited [2]. This excitation promotes the PS from a ground state to a higher level of energy known as a singlet state [27]. This singlet state is very short lived and PSs return to their ground state rapidly after losing their energy to fluorescence or internal heat conversion [27]. However, the singlet state PS may also convert to a triplet state via intersystem crossing, resulting in an electron spin change, which if reacted with molecular oxygen (as found in cells), it will give rise to free reactive oxygen species (ROS), which can result in tumor destruction [27].

Since the colon can be easily accessed via the rectum opening of the large intestine using an endoscope, this form of oncological PDT treatment for CRC tumors is possible [8]. Studies by Hodgkinson et al. [2] and Kawczyk-Krupta et al. [8] have noted that the PDT treatment of CRC which are inoperable, have only slightly advanced lesions/polyps or massive advanced tumors is a safe and feasible treatment option. Thus, colonoscopy endoscopes are used to directly deliver PS drugs to target tumor regions, as well as administer the required wavelength of laser irradiation light to activate a PS drug [2, 8].

The overall ability of PDT to successfully destroy cancer cells depends of the efficacy of ROS production in target cells. ROS can be produced via two different types of photoreactions (**Figure 2**) [26]. Within photoreaction type I, the PS drug reacts with surrounding cellular biomolecules via a hydrogen atom electron transfer to form free radicals, which react with cellular molecular oxygen, generating ROS, which in turn induces oxidative stress in target cells and so destroys them [27]. Whereby within photoreaction type II, the PS drug reacts directly with molecular oxygen in the cell to form singlet oxygen species, which are able to oxidize various substrates within target cells and so induce cell death [27]. When ROS and singlet oxygen species are generated from a PDT reaction, they are cytotoxic and so oxidize various substrates in a tumor cell inducing stress that triggers various cell death pathways such as apoptosis, autophagy or necrosis. Both types of photoreactions may occur simultaneously, however type I reactions generally favor apoptotic death in tumor cells [28]. Additionally, the effectivity of both photoreaction pathways depends on the type of

### **Figure 2.**

*Multidisciplinary Approach for Colorectal Cancer*

growth and so metastasize [6].

for CRC (**Figure 1**) [8].

expansion and invasiveness, the metastatic cellular potential of CRC to spread is high [24]. Lastly, another important factor in CRCs resistance to conventional therapies and metastasis, is the presence of cancer stem cells, since these cells have the ability to go by undetected (due to their slow growth) and so enhances CRC treatment resistance, as well as allows this type of cancer to initiate new tumor

dire need to investigate other alternative therapies for the treatment of CRC.

**3. Photodynamic therapy an unconventional treatment for CRC**

Thus, currently conventional treatments are not very successful at curing CRC and patients are at high risk of developing secondary cancers, due to the ease at which this cancer can migrate through the blood and lymphatic systems to other parts of the body, such as the liver, lungs and digestive system [8, 25]. Thus, there is

Photodynamic therapy (PDT) is a promising unconventional treatment method

PDT treatment is a coordinated process, which begins with the intravenous administration of a photosensitizer (PS) drug [8]. Once the PS drug enters the blood stream it is then either passively or actively absorbed in tumor site, depending on the PS drug delivery mechanism that is involved [26]. Within standard conventional PS drug delivery mechanisms the advantage is that the PS drug tend to preferentially localize in diseased tissue via the enhanced permeability retention (EPR) effect and so is passively absorbed, promoting PDT induced tumor destruction with only slight healthy tissue damage [26]. However, current research studies are focused on improving PS passive drug uptake via chemical or functional modifications in order to promote a more specific and actively targeted PS delivery in cancer cells only, so that photosensitivity, localized healthy tissue destruction and other additional unwanted side effects can possibly be eliminated [26]. Since, PS drugs are light absorbing molecules their activation is achieved when they are

*PDT treatment of CRC. PS drugs are administered to a patients CRC tumor site via a colonoscopy endoscope, whereby they localize in targeted tumor cells. Laser light irradiation is then also administered to the target tumor site via a colonoscopy endoscope, whereby it penetrates the large intestines tissues/tumor and activates the PS. The PS then undergoes a photoreaction to produce ROS and/or singlet oxygen, which in turn induces* 

**44**

**Figure 1.**

*cytotoxic cell death in CRC tumor tissues.*

*PDT photophysical and photochemical mechanism of action for PS drug activation in tumor cells. When a PS drug is activated at a specific wavelength of light it becomes excited and so reacts with either molecular oxygen or other substrates within the surrounding areas of a cell, generating ROS, which in turn induces oxidative stress in cells triggering various cell death pathways and overall tumor destruction.*

PS drug administered, where is localized in the tumor cell, as well as the amount of molecular oxygen present within the tumors microenvironment [29].

In the absence of laser irradiation light the PS drug remains inactive and so is not phototoxic in the body, therefore PDT can provide an alternative method to eradicate target tumor cells (since it is a localized treatment), while avoiding systematic toxicity and unwanted side effects when compared to conventional therapies (which affect healthy cells and tumor tissues) [26]. Thus, the major advantage of PDT over conventional therapies is that PS drugs tend to preferentially localize and be passively absorbed in tumor cells due to the enhanced permeability retention (EPR) effect and so their selective uptake can be achieved, allowing only minimal damage to healthy surrounding cells to occur during treatment [30]. Therefore, PDT can provide an alternative for the treatment of CRC, since it can avoid systematic toxicity, is minimally invasive, has a low morbidity rate, has the ability to preserve the anatomical function of healthy tissues, has minimal side effects, has no drug resistance and allows for repeated treatments [31].

However, in relation to PS drug delivery mechanisms CRC PDT research has now begun to focus on more selective passive (e.g. nanocarriers) and active (e.g. antigen–antibody targeting) uptake delivery mechanisms in tumor cells in order to further improve the efficacy of treatment [26]. These actively targeted PDT PS drug delivery mechanisms ensure preciously targeted PS drug delivery and localization in CRC only so that no damage occurs to normal healthy surrounding tissues [26].
