**4. PS drugs for CRC**

PS drugs generate cytotoxic ROS or singlet oxygen species when they become activated at a particular wavelength, which in turn induces physical or chemical damage in target tumor cells [28]. In relation to the activation of PS drugs for effective PDT, it is important that they have a high molecular absorption coefficient within the red spectrum of light (650–780 nm), as to ensure maximum light absorption for PS excitation (as some endogenous human body pigments can absorb light), warrant minimal patient photosensitivity before treatment, as well as guarantee deep tissue penetration in target tumor sites [32, 33].

PSs are generally categorized into four different groups dependent on their functional capabilities. First generation PSs are one of the first types of PSs to be developed in PDT applications and they are stable, however have been shown to induce photosensitivity in patients and are activated within the lower red regions of light and so have a poor laser light tissue depth excitation range (e.g. haematoporphyrin derivatives) [33]. Second generation PSs have been further researched in PDT applications and since they are activated within the higher red regions of light, they have reported far less patient photosensitivity, with far deeper tissue laser light excitation (e.g. phthalocyanines, benzoporphyrins, purpurins, hypercin and chlorines [34]. Third generation PSs are currently the most promising PS drugs which are currently being researched within PDT cancer treatments [10]. Third generation PSs comprise of second generation PS drugs which have been chemically modified, functionalized or bound to nanoparticles (in order to promote their passive uptake) or active targeting biomolecules (such as aptamers, peptides, monoclonal antibodies, in order to promote their specific uptake in cancer cells only) [33]. In relation to current research, third generation PSs are reporting enhanced uptake in cancer cells with some of the most promising PDT treatment outcomes in CRC patients [33]. Lastly, most recent research has also begun to develop fourth-generation PS, which consist of second-generation PS encapsulated in a nanoparticle delivery system so its of third generation, however it is additionally co-encapsulated with a

**47**

*Targeted Photodynamic Therapy as Potential Treatment Modality for the Eradication of Colon…*

**Photosensitizer Remarks Ref.**

noted.

5-aminolevulinic acid Enhanced PS uptake and improved PDT was

5-aminolevulinic acid (ALA) After PDT prognostic factor S100 protein

5-aminolevulinic acid (ALA) Following PDT treatment autophagy cell

Chlorin e6 (Ce6) CRC *in vitro* SW620 cells noted PDT induced

Gallium phthalocyanine CaCO-2 CRC cell line reported PDT induced

Glycoconjugated chlorin (H2TFPC-SGlc) MKN28, MKN45, HT29 and HCT116 CRC

Hypericin High doses induced massive ROS generation

Indocyanine green Effective ROS generation was observed with

Meta-tetrahydroxyphenylchlorin PS reported and effective PDT dose dependent

Palmatine hydrochloride (PaH) PDT showed significant photocytotoxicity on

Pheophorbide-a methyl ester (PPME) HT-29 CRC cell line noted significant

Photofrin II (Ph II) and hypericin (Hyp) Combination of both PS post-PDT noted

post-PDT.

induced cell death.

116 CRC cells.

CRC cell lines.

was observed.

apoptotic cell death.

cytotoxic effects.

Significant apoptotic cell death within HCT-

Significant apoptotic cell death within HCT-116 CRC cells, with high yields of ROS being

noted within SW-480, HT-29 and CaCO-2

concentration was reduced by 27% in SW480 and by 30% in SW620 CRC cell lines.

death in human SW620 colon carcinoma cells

cell lines noted suppressed cell growth and

and severe ER stress, which then led apoptotic cell death while low doses triggered protective autophagy and promoted cell proliferation.

apoptotic cell death within *in vitro* cultured colon cancer cells at high PS concentrations.

Within CRC HCT116 cells, early apoptosis via Bax- and p53-dependent proteins was noted

Liposomal PS sub cellular localized localization in Colo-201 CRC cells was noted with significant cytotoxic apoptotic PDT

effectivity in inhibiting cell proliferation, decreasing migration ability and colon formation within SW620 CRC cell lines.

HT-29 cells and apoptotic cell death increased significantly in PS concentration-dependent and light dose-dependent manner.

apoptotic cell death post-PDT treatment.

more effective cell death within doxorubicinresistant LoVo DX CRC cell lines by reducing the multidrug resistance efflux protein P-glycoprotein (P-gp) and so promoted improved cytotoxic cell death.

apoptotic cell death post-PDT.

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[3]

[49]

[50]

[51]

*DOI: http://dx.doi.org/10.5772/intechopen.84760*

*In vitro* **PDT CRC research** 3,4,5-trimethoxyphenyl,

porphyrin derivatives

3-hydroxyphenyl,4-hydroxyphenyl and sulfonamide phenyl porphyrin derivatives

5,15-diaryltetrapyrrole derivatives

Lysosome localizing Chlorin e6 (Ce6)

Meta-tetra (hydroxyphenyl) chlorine

ATX-S10Na(II)

(mTHPC)

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


*Multidisciplinary Approach for Colorectal Cancer*

PS drug administered, where is localized in the tumor cell, as well as the amount of

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].

PS drugs generate cytotoxic ROS or singlet oxygen species when they become activated at a particular wavelength, which in turn induces physical or chemical damage in target tumor cells [28]. In relation to the activation of PS drugs for effective PDT, it is important that they have a high molecular absorption coefficient within the red spectrum of light (650–780 nm), as to ensure maximum light absorption for PS excitation (as some endogenous human body pigments can absorb light), warrant minimal patient photosensitivity before treatment, as well as

PSs are generally categorized into four different groups dependent on their functional capabilities. First generation PSs are one of the first types of PSs to be developed in PDT applications and they are stable, however have been shown to induce photosensitivity in patients and are activated within the lower red regions of light and so have a poor laser light tissue depth excitation range (e.g. haematoporphyrin derivatives) [33]. Second generation PSs have been further researched in PDT applications and since they are activated within the higher red regions of light, they have reported far less patient photosensitivity, with far deeper tissue laser light excitation (e.g. phthalocyanines, benzoporphyrins, purpurins, hypercin and chlorines [34]. Third generation PSs are currently the most promising PS drugs which are currently being researched within PDT cancer treatments [10]. Third generation PSs comprise of second generation PS drugs which have been chemically modified, functionalized or bound to nanoparticles (in order to promote their passive uptake) or active targeting biomolecules (such as aptamers, peptides, monoclonal antibodies, in order to promote their specific uptake in cancer cells only) [33]. In relation to current research, third generation PSs are reporting enhanced uptake in cancer cells with some of the most promising PDT treatment outcomes in CRC patients [33]. Lastly, most recent research has also begun to develop fourth-generation PS, which consist of second-generation PS encapsulated in a nanoparticle delivery system so its of third generation, however it is additionally co-encapsulated with a

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

molecular oxygen present within the tumors microenvironment [29].

drug resistance and allows for repeated treatments [31].

guarantee deep tissue penetration in target tumor sites [32, 33].

**4. PS drugs for CRC**

**46**


## **Table 1.**

*Current PDT studies which utilize different types of PS for the in vitro, in vivo or clinical treatment of CRC.*

small-molecular inhibitor system capable of blocking any tumor survival pathways post PDT, in order to halt possible tumor reoccurrence [35]. However, in relation to fourth-generation PSS this form of PDT treatment research is limited to only being able to target and inhibit VEGFs, in order to promote PS drugs uptake and so deter the neovascularization of tumors, preventing CRC tumor metastatic spread and reoccurrence [35].

**49**

**Figure 3.**

*Targeted Photodynamic Therapy as Potential Treatment Modality for the Eradication of Colon…*

To date only one single successful clinical study from 2016, utilizing Photofrin II (Ph II) PS PDT drug on 23 young patients with advanced CRC, noted improved clinical symptoms and reduce complications post-PDT treatment [63]. These findings suggest that more research is required to develop better PS drugs to withstand

Despite the many positive features of CRC PDT, within clinical settings this form of treatment has experienced some drawbacks in relation to PS drug solubility,

In order to ensure the maximum levels of ROS are generated during a PDT treatment, as to ensure complete tumor destruction, the highest possible concentrations of PS drugs must be able to be successfully delivered and localize in target tumor tissues [27]. Within PDT clinical settings using first and second generation PS drugs, poor outcomes and effectiveness has been noted, as only minor amounts of PS drugs are able to overcome the human bodies biological barriers and so passively accumulate (due to the EPR effect) in tumor cells, generating very low levels ROS and tumor destruction [2, 31]. Additionally, due to this passivation process sometimes PS drugs can accumulate in healthy tissues inducing unwanted PDT side effects such as patients' photosensitivity and dam-

*Passive PS NP drug delivery versus active targeting moiety conjugated PS NP drug delivery, which shows targeted and enhanced CRC tumor PS drug uptake for more effective PDT treatment outcomes.*

(Levulan), Methyl aminolevulinate (Metvixia), Meta tetra(hydroxyphenyl) chlorin (Foscan), N-aspartyl chlorin e6 (NPe6, Laserphyrin), Benzoporphyrin derivative monoacid ring A (Visudyne) and N-hexyl ester of ALA (Cysview) [32–35]. Whereas, first- and second-generation PSs, which are currently under clinical trials include; Hypocrellin A, Pheophorbide-a, Chlorin e6, Methylene Blue, Hypericin, Phthalocyanine, Rose Bengal, HPPH: 2-(1-Hexyl-oxyethyl)-2-devinyl pyropheophorbide-alpha [30, 34, 36]. However, in relation to third and fourth generation PSs, none to date have received clinical approval for PDT CRC treatments and so remain a commanding area of research focus [26]. **Table 1** shows various research studies currently that have been performed with different types of PSs for

*DOI: http://dx.doi.org/10.5772/intechopen.84760*

the PDT treatment of CRC.

**5. PDT CRC clinical challenges**

age to normal tissues [26].

mode of delivery and selective tumor uptake [64, 65].

clinical trials.

At the moment clinically FDA approved first and second generation PSs for PDT oncology include: Porfimer sodium (Photofrin), 5-Aminolevulinic acid

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

(Levulan), Methyl aminolevulinate (Metvixia), Meta tetra(hydroxyphenyl) chlorin (Foscan), N-aspartyl chlorin e6 (NPe6, Laserphyrin), Benzoporphyrin derivative monoacid ring A (Visudyne) and N-hexyl ester of ALA (Cysview) [32–35]. Whereas, first- and second-generation PSs, which are currently under clinical trials include; Hypocrellin A, Pheophorbide-a, Chlorin e6, Methylene Blue, Hypericin, Phthalocyanine, Rose Bengal, HPPH: 2-(1-Hexyl-oxyethyl)-2-devinyl pyropheophorbide-alpha [30, 34, 36]. However, in relation to third and fourth generation PSs, none to date have received clinical approval for PDT CRC treatments and so remain a commanding area of research focus [26]. **Table 1** shows various research studies currently that have been performed with different types of PSs for the PDT treatment of CRC.

To date only one single successful clinical study from 2016, utilizing Photofrin II (Ph II) PS PDT drug on 23 young patients with advanced CRC, noted improved clinical symptoms and reduce complications post-PDT treatment [63]. These findings suggest that more research is required to develop better PS drugs to withstand clinical trials.
