**6. Nanoparticles for enhanced passive PS drug delivery and PDT**

Passive PS uptake makes use of the drugs physiochemical factors, as well as the morphological and physiological differences between tumor and tissues (i.e. EPR effect) to allow PSs to accumulate in tumor sites [30].

There has been great interest in combining PS drugs with NPs in order to overcome some of the challenges conventional PS drug delivery mechanisms experience in clinical settings [65]. This is because NPs can enhance PS drug passive uptake, promote solubility, stability and limit non-specific toxicity [66]. Additionally, NPs can mimic biological molecules and so when combined with PSs, they go by unnoticed by immune barriers, remaining in tacked and so improved passivation of PS drug uptake in tumors [33]. Examples of nanoparticle platforms to assist in the passivation PS drug delivery for PDT CRC treatment include: liposomes, polymers, micelles, dendrimers, silica, nanoemulsion, nanotubes and nanogels [67]. Moreover, these NP platforms (especially polymeric NPs) have the additional benefit of protecting PS drugs against chemical and enzymatic gastrointestinal tract degradation, and so increase the drugs stability and cellular uptake within the intestinal epithelium [68, 69]. Various studies listing the effective passive PS drug delivery in CRC tumors utilizing NP carrier platforms have been listed in **Table 2**.


**51**

(HPPH)

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

**Photosensitizer Nanoparticle Remarks Ref.**

Showed enhanced cellular uptake, phototoxicity, and ROS generation within *in vitro* CRC cells and reported improved tumor tissue penetration and accumulation within *in vivo* animal studies.

Noted higher uptake in murine colon carcinoma CT26 tumors models with significant tumor regression and necrotic cell death.

PS and anticancer drug are colocalized in within *in vitro* CT-26 and HCT-116 CRC cells. Dual therapy induced apoptotic cell death and inhibited tumor growth in CT-26 tumor bearing mouse model

Showed improved uptake and demonstrated the ability to act as an anticancer PDT modality to eliminate LoVo and CHO-K1 CRC cells in vitro

Human colon carcinoma cell line HCT116 noted

Exhibited high intracellular fluorescence in human colon adenocarcinoma HT29 cells with

carcinoma cells noted 90% photocytotoxic cell

*In vitro* and *in vivo* HT29 CRC tumors exhibited drastic and highly significant tumor growth

photothermal activity with no dark cytotoxicity within *in vitro* murine colon carcinoma cells

Improved uptake of PS, with enhanced phototoxicity within *in vitro* SW480CRC cells and dramatic tumor-inhibiting efficacy in four-week-

Improved PS absorption with enhanced phototoxicity and cell death in HT29 cell lines.

Noted improved uptake and sustained release within *in vitro* Colon-26 carcinoma and efficient tumor deposition was found in C26 tumorbearing mice with a significant and highly effective PDT anti-tumor effect.

Enhanced tumor accumulation and superior therapeutic efficacy in HT29 tumor mouse xenographs and Colon-26 bearing BALB/c mice showed no tumor reoccurrence up to 100 days.

Synergistic chemo drug and PS dramatically enhanced *in vivo* antitumor PDT efficacy over single treatment in nude mice bearing HT-29 colon

cancer xenograft.

like cells both *in vitro* and *in vivo*.

old female athymic mice.

PDT induced apoptotic cell death.

notable photocytotoxicity

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[16]

[85]

[86]

[87]

[88]

[89]

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

Chlorin e6 (Ce6) Methoxy poly(ethylene

glycol) (MePEG)

polyvinyl alcohol

loaded micelles with mPEG lipoic acid (LA)

flavonoid derivatives for electroporation

Core-shell poly-methyl methacrylate

Alkyne-modified mesoporous silica

Curcumin and 5-fluorouracil Chitosan CRC HT29 cell line had a 3-fold increase in

Hypericin Pluronic P123 (P123) *In vitro* Caco-2 and HT-29 intestinal colon

IR780 iodide Pluronic coated gold Show enhanced phototherapeutic and

Poly(D,L-lactide-*co*glycolide) (PLGA)

Liposomal formulation

Polyethylene glycol and polylactic acid block copolymer (PN-Por)

Polymeric tubuleforming phospholipid, DC PC with PEGylated

SN-38 (7-ethyl-10 hydroxycamptothecin) chemotherapeutic drug

lipid

Porphyrin Nano micelles and

Oxaliplatin Chitosan micelles Eliminated bulk CRC cell populations and stem-

FosPeg®

death.

(C26).

retardation.

anticancer effects.

(PVA)

*In vitro* **and** *in vivo* **PDT CRC research**

Chlorin e6 (Ce6) Polymeric carrier

Chlorin e6 (Ce6) Doxorubicin (DOX)-

Cyanine IR-780 Solid lipid and

Indocyanine green (icg) Super carbonate apatite

(sCA)

Diaryl-porphyrin (PMMA@

Meso-tetra (carboxyphenyl) porphyrin (TCPP)

Meta-tetra (hydroxyphenyl) chlorine (mTHPC)

Photoprotoporphyrin IX dimethyl ester (PppIX-DME)

Porfimer sodium (PII) and 2-[1-hexyloxyethyl]-2 devinylpyropheophorbide-a

PorVa)

Dimeric zinc(II) phthalocyanine

*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*

enhance the overall efficacy of PDT (**Figure 3**) [29, 32].

effect) to allow PSs to accumulate in tumor sites [30].

*In vitro* **and** *in vivo* **PDT CRC research**

5-aminolevulinic acid Co polymer methoxy

5-(4-aminophenyl)- 10,15,20-triphenylchlorin and 5-(4-carboxyphenyl)- 10,15,20-triphenylchlorin

5,10,15,20-Tetrakis(4 hydroxy-phenyl)-21H, 23H-porphine (pTHPP)

5-aminolevulinic acid

within these organelles [29, 32].

Another issue sometimes noted in clinical settings is that PS drugs have limited solubility and so tend to aggregate during administration, limiting their overall uptake and effectivity [2]. Moreover, a PS drugs concentrated subcellular localization in a tumors mitochondria, lysosomes, endoplasmic reticulum, plasma membrane etc., is of utmost importance since ROS have only a very short half-life and so will only induce effective cell death in tumor cells if they are proximately localized

Thus, shortcomings such as poor solubility, bioavailability, maximum ROS generation and tumor subcellular localization targeting need to be overcome in order to ensure the effectivity of PDT [26]. Nevertheless third generation PS drug nanoparticle (NP) drug carriers are currently being investigated to ensure PS drug solubility and improved passive uptake, with functionalized active targeting abilities (e.g. overexpressed peptides), as to ensure specific uptake in tumor cells only to

**6. Nanoparticles for enhanced passive PS drug delivery and PDT**

Passive PS uptake makes use of the drugs physiochemical factors, as well as the morphological and physiological differences between tumor and tissues (i.e. EPR

There has been great interest in combining PS drugs with NPs in order to overcome some of the challenges conventional PS drug delivery mechanisms experience in clinical settings [65]. This is because NPs can enhance PS drug passive uptake, promote solubility, stability and limit non-specific toxicity [66]. Additionally, NPs can mimic biological molecules and so when combined with PSs, they go by unnoticed by immune barriers, remaining in tacked and so improved passivation of PS drug uptake in tumors [33]. Examples of nanoparticle platforms to assist in the passivation PS drug delivery for PDT CRC treatment include: liposomes, polymers, micelles, dendrimers, silica, nanoemulsion, nanotubes and nanogels [67]. Moreover, these NP platforms (especially polymeric NPs) have the additional benefit of protecting PS drugs against chemical and enzymatic gastrointestinal tract degradation, and so increase the drugs stability and cellular uptake within the intestinal epithelium [68, 69]. Various studies listing the effective passive PS drug delivery in CRC tumors utilizing NP carrier platforms have been listed in **Table 2**.

**Photosensitizer Nanoparticle Remarks Ref.**

5-flurouraci (5-FU) Solid lipid Enhanced delivery and PDT phototoxicity, within

Polyhydroxyalkanoates

(PHAs)

poly(ethylene glycol)-chitosan treatment.

Chitosan Drugs localized in endocytic vesicles of HCT116/

LUC human colon carcinoma cells and within tumor-bearing mice, showed strong PDT

*In vitro* photocytotoxicity in human colon adenocarcinoma cell line HT-29 revealed time and

CRC cells and chemo resistant stem-like cells.

Enhanced delivery and PDT phototoxicity. [72]

concentration dependent cell death.

Chitosan Enhanced cellular absorption in Caco-2CRC cells. [73]

[70]

[71]

[74]

**50**

(ALA)


**Table 2.**

*Passive Targeting PDT PS drug delivery mechanisms within in vitro and in vivo CRC.*
