Comparative sensitivity of microvascular endothelial cells, fibroblasts and tumor cells after in vitro photodynamic therapy with meso-tetra-hydroxyphenyl-chlorin

The phototoxic effect of meso-tetra-hydroxyphenyl-chlorin (mTHPC)-mediated photodynamic therapy (PDT) on human microvascular endothelial cells (hMVEC) was compared with that on human fibroblasts (BCT-27) and two human tumor cell lines (HMESO-1 and HNXOE). To examine the relationship between intrinsic phototoxicity and intracellular mTHPC content, we expressed cell survival as a function of cellular fluorescence. On the basis of total cell fluorescence, HNXOE tumor cells were the most sensitive and BCT-27 fibroblasts the most resistant, but these differences disappeared after correcting for cell volume. Endothelial cells were not intrinsically more sensitive to mTHPC-PDT than tumor cells or fibroblasts. Uptake of mTHPC in hMVEC increased linearly to at least 48 h, whereas drug uptake in the other cell lines reached a maximum by 24 h. No difference in drug uptake was seen between the cell lines during the first 24 h, but by 48 h hMVEC had a 1.8- to 2.8-fold higher uptake than other cell lines. Endothelial cells showed a rapid apoptotic response after mTHPC-mediated PDT, whereas similar protocols gave a delayed apoptotic or necrotic like response in HNXOE. We conclude that endothelial cells are not intrinsically more sensitive than other cell types to mTHPC-mediated PDT but that continued drug uptake beyond 24 h may lead to higher intracellular drug levels and increased photosensitivity under certain conditions.     

Fully Protected Glycosylated Zinc (II) Phthalocyanine Shows High Uptake and Photodynamic Cytotoxicity in MCF‐7 Cancer Cells

Phthalocyanine photosensitizers are effective in anticancer photodynamic therapy (PDT) but suffer from limited solubility, limited cellular uptake and limited selectivity for cancer cells. To improve these characteristics, we synthesized isopropylidene‐protected and partially deprotected tetra β‐glycosylated zinc (II) phthalocyanines and compared their uptake and accumulation kinetics, subcellular localization, in vitro photocytotoxicity and reactive oxygen species generation with those of disulfonated aluminum phthalocyanine. In MCF‐7 cancer cells, one of the compounds, zinc phthalocyanine {4}, demonstrated 10‐fold higher uptake, 5‐fold greater PDT‐induced cellular reactive oxygen species concentration and 2‐fold greater phototoxicity than equimolar (9 μm ) disulfonated aluminum phthalocyanine. Thus, isopropylidene‐protected β‐glycosylation of phthalocyanines provides a simple method of improving the efficacy of PDT.     

mTHPC-mediated photodynamic therapy is effective in the metastatic human 143B osteosarcoma cells

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality approved for palliative and curative treatment of some forms of local cancers, precancerous lesions and nononcological disorders. As a prerequisite for future studies in animal models aiming at an intraoperative application of PDT in osteosarcoma (OS), in the present study, we investigated the uptake and the dark- and photo-toxicity of the photosensitizer mTHPC in the metastatic human OS cell line 143B, which, intratibially injected into SCID mice, reproduces spontaneous, aggressive lung metastasis, the main cause of death in OS patients. The uptake of mTHPC by 143B cells was time- and dose-dependent. mTHPC accumulated to higher levels in the 143B than in the parental low-metastatic HOS cell line. A significant decrease in viability of 143B cells, reflecting mTHPC dark-toxicity, occurred upon incubation in the dark at mTHPC concentrations ≥2.5 μg mL(-1). In phototoxicity experiments with illumination by 652 nm laser light (2.5-10 J cm(-2)), the half-maximal lethal doses of mTHPC ranged from 0.012 to 0.047 μg mL(-1). This treatment activated caspase-3, -7 and -9 and Z-VAD-FMK-inhibitable PARP cleavage, indicating caspase-dependent apoptosis. In conclusion, PDT with mTHPC is effective in the metastatic 143B human osteosarcoma cell line in vitro.     

Scavenger-receptor targeted photodynamic therapy

Covalent conjugation of a photosensitizer to a ligand that specifically recognized and internalized by a cell-surface receptor may be a way of improving the selectivity of photodynamic therapy (PDT). The class A Type-I scavenger receptor of macrophages, which among other ligands recognizes maleylated serum albumin and has a high capacity is a good candidate for testing this approach. Chlorin(e6) was covalently attached to bovine serum albumin to give conjugates with molar substitution ratios of 1:1 and 3:1 (dye to protein), and these conjugates could then be further modified by maleylation. A novel way of purifying the conjugates by acetone precipitation was developed in order to remove traces of unbound dye that could not be accomplished by size-exclusion chromatography. Conjugates were characterized by polyacrylamide gel electrophoresis and thin-layer chromatography. Photosensitizer uptake was measured by target J774 murine macrophage-like cells and nontarget OVCAR-5 human ovarian cancer cells, and phototoxicity was examined after illumination by a 660 nm diode laser by a tetrazolium assay. All of the purified conjugates were taken up by and after illumination killed J774 cells while there was only small uptake and no phototoxicity toward OVCAR-5 cells. The higher dye:protein ratio and maleylation of the conjugates both produced higher uptakes and lower survival ratios in J774 cells. The uptake and phototoxicity by J774 cells were decreased after incubation at 4 degrees C demonstrating internalization, and confocal microscopy with organelle-specific green fluorescent probes showed largely lysosomal localization. Uptake and phototoxicity by J774 cells could both be competed by addition of the scavenger receptor ligand maleylated albumin. These data show that scavenger receptor-targeted PDT gives a high degree of specificity toward macrophages and may have applications in the treatment of tumors and atherosclerosis.     

Photodynamic activity of substituted zinc trisulfophthalocyanines: role of plasma membrane damage

We recently reported that variations in cellular phototoxicity among a series of alkynyl-substituted zinc trisulfophthalocyanines (ZnPcS3Cn) correlates with their hydrophobicity, with the most amphiphilic derivatives showing the highest cell uptake and phototoxicity. In this study we address the role of the plasma membrane in the photodynamic response as it relates to the overall hydrophobicity of the photosensitizer. The membrane tracker dye 1-[4(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene (TMA-DPH), which is incorporated into plasma membranes by endocytosis, was used to establish plasma membrane uptake by EMT-6 cells of the ZnPcS3C, by colocalization, and TMA-DPH membrane uptake rates after photodynamic therapy were used to quantify membrane damage. TMA-DPH colocalization patterns show plasma membrane uptake of the photosensitizers after short 1 h incubation periods. TMA-DPH plasma membrane uptake rates after illumination of the photosensitizer-treated cells show a parabolic relationship with photosensitizer hydrophobicity that correlates well with the phototoxicity of the ZnPcS3C,. After a 1 h incubation period, overall phototoxicity correlates closely with the postillumination rate of TMA-DPH incorporation into the cell membrane, suggesting a major role of plasma membrane damage in the overall PDT effect. In contrast, after a 24 h incubation, phototoxicity shows a stronger but imperfect correlation with total cellular photosensitizer uptake rather than TMA-DPH membrane uptake, suggesting a partial shift in the cellular damage responsible for photosensitization from the plasma membrane to intracellular targets. We conclude that plasma membrane localization of the amphiphilic ZnPcS3C6-C9 is a major factor in their overall photodynamic activity.     

The role of PEG on the stability in digestive fluids and in vivo fate of PEG-PLA nanoparticles following oral administration

The aim of the present work was to evaluate if the presence of a polyethylenglycol (PEG) coating around PLA nanoparticles would affect their interaction with biological surfaces, following oral administration to rats. For this purpose, a model antigen, ¹²⁵I-radiolabeled tetanus toxoid, was encapsulated in PLA and PLA-PEG nanoparticles by a modified water-in-oil-in-water solvent evaporation technique. Firstly, the stability of the nanoparticles in simulated gastrointestinal fluids was evaluated. Results showed an interaction between the nanoparticles and the enzymes of the digestive fluids, this interaction being considerably reduced by the PEG coating around the particles. On the other hand, the PLA forming the nanoparticles was found to be only slightly degraded (9% converted to lactate for PLA nanoparticles and 3% for PLA-PEG nanoparticles) and that the encapsulated tetanus toxoid remained mostly associated to the nanoparticles upon incubation in the digestive fluids for up to 4 h. Finally, the in vivo experiments showed that, after oral administration to rats, the levels of encapsulated radioactive antigen in the blood stream and lymphatics were higher for PLA-PEG nanoparticles than for PLA nanoparticles. In conclusion, the PLA-PEG nanoparticles have a promising future as protein delivery systems for oral administration.     

Activatable Type I Photosensitizer with Quenched Photosensitization Pre and Post Photodynamic Therapy

The phototoxicity of photosensitizers (PSs) pre and post photodynamic therapy (PDT), and the hypoxic tumor microenvironment are two major problems limiting the application of PDT. While activatable PSs can successfully address the PS phototoxicity pre PDT, and type I PS can generate reactive oxygen species (ROS) effectively in hypoxic environment, very limited approaches are available for addressing the phototoxicity post PDT. There is virtually no solution available to address all these issues using a single design. Herein, we propose a proof-of-concept on-demand switchable photosensitizer with quenched photosensitization pre and post PDT, which could be activated only in tumor hypoxic environment. Particularly, a hypoxia-normoxia cycling responsive type I PS TPFN-AzoCF₃ was designed to demonstrate the concept, which was further formulated into TPFN-AzoCF₃ nanoparticles (NPs) using DSPE-PEG-2000 as the encapsulation matrix. The NPs could be activated only in hypoxic tumors to generate type I ROS during PDT treatment, but remain non-toxic in normal tissues, pre or after PDT, thus minimizing side effects and improving the therapeutic effect. With promising results in in vitro and in vivo tumor treatment, this presented strategy will pave the way for the design of more on-demand switchable photosensitizers with minimized side effects in the future.     

Photophysical parameters, photosensitizer retention and tissue optical properties completely account for the higher photodynamic efficacy of meso-tetra-hydroxyphenyl-chlorin vs Photofrin

Meso-tetra-hydroxyphenyl-chlorin (mTHPC) is one of the most potent photosensitizers currently available for clinical photodynamic therapy (PDT). However the reason or reasons for its high photodynamic efficacy remain(s) unresolved. To investigate the PDT efficacy of mTHPC vs Photofrin we use the knowledge of photophysical parameters extracted from the analysis of oxygen electrode measurements in spheroids to compute and compare their respective singlet oxygen (1O2) dose depositions. The electrode measurements indirectly report the bleaching kinetics of mTHPC and indicate that its photobleaching mechanism is consistent with 1O2-mediated reactions. mTHPC's photodegradation via 1O2 reactions is confirmed by a more direct evaluation of the spatially resolved fluorescence in confocal sections of intact spheroids during irradiation. The PDT efficacy comparisons establish that mTHPC's enhanced potency may be accounted for completely on the basis of its ability to sequester tightly in cells and its photophysical properties, in particular its higher extinction coefficient at a redshifted wavelength. We extend the efficacy comparison to include the influence of hemoglobin absorption of PDT treatment light and show that incorporating the influence of wavelength-dependent light attenuation in tissue further contributes to significantly higher efficacy for mTHPC- vs Photofrin-PDT.     

Alterations in mitochondrial and apoptosis-regulating gene expression in photodynamic therapy-resistant variants of HT29 colon carcinoma cells

Photodynamic therapy (PDT) is a novel cancer therapy inducing irreversible photodamage to tumor tissue via photosensitizer-mediated oxidative cytotoxicity. The cellular and molecular responses associated with PDT are only partially understood. We have reported previously the generation of several photosensitizer-specific PDT-resistant cell variants of HT29 human colon adenocarcinoma cells by selecting cells from sequential PDT treatment using different photosensitizers. In this report, we describe the use of messenger RNA (mRNA) differential display to identify genes that were differentially expressed in the parental HT29 cells compared with their resistant variants. In comparison with parental HT29 cells, mRNA expression was increased in the PDT-resistant cell variants for BNIP3, estrogen receptor-binding fragment-associated gene 9, Myh-1c, cytoplasmic dynein light chain 1, small membrane protein I and differential dependent protein. In contrast, expression in the PDT-resistant variants was downregulated for NNX3, human HepG2 3' region Mbol complementary DNA, glutamate dehydrogenase, hepatoma-derived growth factor and the mitochondrial genes coding for 16S ribosomal RNA (rRNA) and nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 4. The reduction for mitochondrial 16S rRNA in the PDT-resistant variants was confirmed by Northern blotting, and the elevated expression of the proapoptotic BNIP3 in the PDT-resistant variants was confirmed by Northern and Western blotting analysis. We also examined the expression of some additional apoptosis-regulating genes using Western blotting. We show an increased expression of Bcl-2 and heat shock protein 27 and a downregulation of Bax in the PDT-resistant variants. In addition, the mutant p53 levels in the parental HT29 cells were reduced substantially in the PDT-resistant variants. We suggest that the altered expression in several mitochondrial and apoptosis-regulating genes contributes to PDT resistance.     

Highly Efficient Singlet Oxygen Generators Based on Ruthenium Phthalocyanines: Synthesis,Characterization and in vitro Evaluation for Photodynamic Therapy

The synthesis of ruthenium(II) phthalocyanines (RuPcs) endowed with one carbohydrate unit—that is, glucose, galactose and mannose—and a dimethylsulfoxide (DMSO) ligand at the two axial coordination sites, respectively, is described. Two series of compounds, one unsubstituted at the periphery, and the other one bearing eight PEG chains at the isoindole meta-positions, have been prepared. The presence of the axial DMSO unit significantly increases the phthalocyanine singlet oxygen quantum yields, related to other comparable RuPcs. The compounds have been evaluated for PDT treatment in bladder cancer cells. In vitro studies have revealed high phototoxicity for RuPcs unsubstituted at their periphery. The phototoxicity of PEG-substituted RuPcs has been considerably improved by repeated light irradiation. The choice of the axial carbohydrate introduced little differences in the cellular uptake for both series of photosensitizers, but the phototoxic effects were considerably higher for compounds bearing mannose units.     

The role of the low density lipoprotein receptor pathway in the delivery of lipophilic photosensitizers in the photodynamic therapy of tumours

Lipoproteins are now recognized as major blood carriers of many hydrophobic porphyrins and related chromophores which are being investigated as possible photosensitizers in the photodynamic therapy of tumours. In vitro and in vivo studies have demonstrated the role of the low density lipoprotein (LDL) receptor pathway in the delivery of photosensitizers to tumour cells and its importance in porphyrin accumulation by tumours. Lysosomes, which are involved in the cellular processing of LDL, are important intracellular targets in the LDL-porphyrin-induced phototoxicity. The use of the LDL receptor pathway as a tool for enhancing the selectivity of photosensitizer delivery to tumour cells appears to be a promising field of research in the photodynamic therapy of tumours.     

Albumin–Folate Conjugates for Drug‐targeting in Photodynamic Therapy

Photodynamic therapy (PDT) is based on the cytotoxicity of photosensitizers in the presence of light. Increased selectivity and effectivity of the treatment is expected if a specific uptake of the photosensitizers into the target cells, often tumor cells, can be achieved. An attractive transporter for that purpose is the folic acid receptor α (FRα), which is overexpressed on the surface of many tumor cells and mediates an endocytotic uptake. Here, we describe the synthesis and photobiological characterization of polar β‐carboline derivatives as photosensitizers covalently linked to folate‐tagged albumin as the carrier system. The particles were taken up by KB (human carcinoma) cells within <90 min and then co‐localized with a lysosomal marker. FRα antibodies prevented the uptake and also the corresponding conjugate without folate was not taken up. Accordingly, a folate‐albumin‐β‐carbolinium conjugate proved to be phototoxic, while the corresponding albumin–β‐carbolinium conjugates without FA were nontoxic, both with and without irradiation. An excess of free folate as competitor for the FRα‐mediated uptake completely inhibited the photocytotoxicity. Interestingly, the albumin conjugates are devoid of photodynamic activity under cell‐free conditions, as shown for DNA as a target. Thus, phototoxicity requires cellular uptake and lysosomal degradation of the conjugates. In conclusion, albumin–folate conjugates appear to be promising vehicles for a tumor cell targeted PDT.     

The Effects of Serum on Cellular Uptake and Phototoxicity of Mono-L-Aspartyl Chlorin e6 (NPe6) In Vitro

Abstract— Previous reports showed that the photosensitizer mono- l -aspartyl chlorin e6 (NPe6) binds to serum proteins. However, the influence of this binding on the cellular uptake and photodynamic therapy (PDT) phototoxicity of NPe6 is still undefined. In this paper, we studied how serum in medium affected the P388 cellular uptake and PDT phototoxicity of NPe6 in vitro. This was assessed by (1) detection of the red shift (654 nm Q band peak of absorption) induced by protein binding NPe6; (2) detection of intracellular concentration of NPe6 by HPLC and (3) measurements of the cell survival ratio after PDT by MTT assay. The 654 nm Q band peak of NPe6 shifted to 665 nm after binding of NPe6 and serum proteins. The protein-bound NPe6 cannot be uptaken by cells, thus there was no PDT phototoxicity. Nevertheless, phototoxicity recovered when the concentration of NPe6 excessed the serum protein binding ability or there was free serum protein in the medium. These data suggested that the cellular uptake of NPe6 is inhibited by serum components in the medium, and that only free NPe6 is accumulated by P388 cells even during relatively long incubations. The cytotoxicity of PDT mainly depends on the free NPe6 level in the medium.     

Photodynamic properties of naphthosulfobenzoporphyrazines, novel asymmetric, amphiphilic phthalocyanine derivatives.

Metallo naphthosulfobenzoporphyrazines sulfonated to different degrees (M-NSBP) were prepared, and their potential as photosensitizers for the photodynamic therapy (PDT) of cancer was evaluated. M-NSBP can be viewed as hybrid molecules between sulfophthalocyanines and naphthalocyanines resulting in distinct differences in the absorption spectra between the mono-through tetrasulfonated derivatives. This feature greatly facilited their purification. Using V-79 Chinese hamster cells in vitro, the disulfonated derivatives were found slightly more photoactive than the hydrophilic trisulfonated derivatives while the monosulfonated derivative was inactive, in spite of a sixfold higher cell uptake. In the case of the di- and trisulfonated derivatives, differences in phototoxicity correlated well with their relative cell uptake. Substitution of Al for Zn had little effect on the extent of phototoxicity of the M-NSBP. In vitro PDT of the EMT-6 cells after in vivo dye administration, revealed a similar potency for direct cell killing between the di- and trisulfonated AlOH-NSBP, while the monosulfonated analog was inactive. PDT with the amphiphilic disulfonated AlOH-NSBP on the EMT-6 mammary tumor in BALB/c mice induced a significant tumor response, while the monosulfonated derivative was much less active.     

Photodynamic Mechanisms induced by a Combination of Hypericin and a Chlorin Based‐Photosensitizer in Head and Neck Squamous Cell Carcinoma Cells

The aim of this study was to elucidate photodynamic therapy (PDT) effects mediated by hypericin and a liposomal meso‐tetrahydroxyphenyl chlorin (mTHPC) derivative, with focus on their 1:1 mixture, on head and neck squamous cell carcinoma cell lines. Absorption, excitation and photobleaching were monitored using fluorescence spectrometry, showing the same spectral patterns for the mixture as measured for single photosensitizers. In the mixture mTHPC showed a prolonged photo‐stability. Singlet oxygen yield for light‐activated mTHPC was Φ_Δ = 0.66, for hypericin Φ_Δ = 0.25 and for the mixture Φ_Δ = ~0.4. A linear increase of singlet oxygen yield for mTHPC and the mixture was found, whereas hypericin achieved saturation after 35 min. Reactive oxygen species fluorescence was only visible after hypericin and mixture‐induced PDT. Cell viability was also more affected with these two treatment options under the selected conditions. Examination of death pathways showed that hypericin‐mediated cell death was apoptotic, with mTHPC necrotic and the 1:1 mixture showed features of both. Changes in gene expression after PDT indicated strong up‐regulation of selected heat‐shock proteins. The application of photosensitizer mixtures with the features of reduced dark toxicity and combined apoptotic and necrotic cell death may be beneficial in clinical PDT. This will be the focus of our future investigations.     

Theranostic gold cluster nanoassembly for simultaneous enhanced cancer imaging and photodynamic therapy

As one of near-infrared (NIR) fluorescent (FL) nanoprobes, gold nanoclusters (Au NCs) are delicated to passive-targeting tumors for NIR FL imaging, but which easily cleared by the kidneys for the small size (<1.5 nm). Herein, the well-defined gold clusters nanoassembly (Au CNA) was synthesized by the selfassembly of Au NCs based on protein cross-linking approach. The as-prepared Au CNA demonstrated highly effective cellular uptake and precise tumor targeting compared to that of Au NCs. Moreover, with the irradiation of 660 nm laser, Au CNA generated largely reactive oxygen species (ROS) for photodynamic therapy (PDT). In vitro and in vivo PDT revealed that Au CNA exhibited largely cell death and significantly tumor removal at a low power density of 0.2 W/cm². It could be speculated that the laser-excited Au CNA produced photon energy, which further obtained electron from oxygen to generate radical species. Therefore, Au CNA as a photosensitizer could realize NIR FL imaging and NIR laser induced PDT.     

Targeted and Oxygen-Enriched Nanoplatform for Enhanced Photodynamic Therapy: In Vitro 2D Cell and 3D Spheroid Model Evaluation

Hypoxic microenvironment and limited penetration of photosensitizers within solid tumors are two crucial factors that restrict photodynamic therapy (PDT) efficacy. Herein, a new fluorinated mixed micelle ( M60@PFC-Ce6 ) is developed as a tumor-penetrating and oxygen-enriching nanoplatform, which consists of chlorin e6 (Ce6) and perfluorocarbons (PFCs) co-loaded into fluorinated micelles to relieve hypoxia conditions as well as folate as targeting ligand that facilitates the selective biodistribution within tumor solids. The incorporation of fluorinated copolymers into mixed micelles exhibits not only a great increase in the oxygen-loading capacity, but also improves the stability of liquid PFCs emulsion within micelles without leakage. M60@PFC-Ce6 shows excellent oxygen delivery capability, good intracellular reactive oxygen species (ROS) generation, and superior phototoxicity in vitro for both 2D monolayer of cells and 3D multicellular spheroid model. These results indicate the enriched oxygen delivery and increased cellular uptake resulting from folate-targeted ability to enhance ROS production and PDT efficacy. The penetration study of M60@PFC-Ce6 into a 3D spheroid confirms that small micellar size and folate-conjugation are beneficial for micelles to penetrate and accumulate within spheroids. Thus, a new nanoplatform with enriched oxygen-carrying amounts, better drug penetration, and stable micellar properties that relieve tumor hypoxia and improve PDT efficacy is provided.     

Intracellular localization is a cofactor for the phototoxicity of protoporphyrin IX in the gastrointestinal tract: in vitro study

Photodynamic therapy (PDT) is a new treatment modality for solid tumors as well as for flat lesions of the gastrointestinal tract. Although the use of 5-aminolevulinic acid-induced protoporphyrin IX (PPIX) shows important advantages over other photosensitizers, the main mechanisms of phototoxicity induced are still poorly understood. Three human colon carcinoma cell lines with variable degrees of differentiation and a normal colon fibroblast cell line were used to generate a suitable in vitro model for investigation of photosensitizer concentration as well as the applied light dose. Also, the effects of intracellular photosensitizer localization on efficiency of PDT were examined, and cellular parameters after PDT (morphology, mitochondrial transmembrane potential, membrane integrity and DNA fragmentation) were analyzed to distinguish between PDT-induced apoptosis from necrosis. The fibroblast cell line was less affected by phototoxicity than the tumor cells to a variable degree. Well-differentiated tumor cells showed higher toxicity than less-differentiated cells. After irradiation, cell lines with cytosolic or mitochondrial PPIX localization indicate a loss of mitochondrial transmembrane potential resulting in growth arrest, whereas membrane-bound PPIX induces a loss of membrane integrity and consequent necrosis. Although the absolute amount of intracellular photosensitizer concentration plays the main determining role for PDT efficiency, data indicate that intracellular localization has additional effects on the mode of cell damage.     

Photosensitizer-Mesoporous Silica Nanoparticles Combination for Enhanced Photodynamic Therapy†

Mesoporous silica nanoparticles (MSNs) are widely known for their versatile applications. One of the most extended is as drug delivery systems for the treatment of cancer and other diseases. This review compiles the most representative examples in the last years of functionalized MSNs as photosensitizer carriers for photodynamic therapy (PDT) against cancer. Several commercially available photosensitizers (PSs) demonstrated poor solubility in an aqueous medium and insufficient selectivity for cancer tissues. The tumor specificity of PSs is a key factor for enhancing the PDT effect and at the same time reducing side effects. The use of nanoparticles and particularly MSNs, in which PS is covalently anchored or physically embedded, can overcome these limitations. For that, PS-MSNs can be externally decorated with compounds of interest in order to act as an active target for certain cancer cells, demonstrating enhanced phototoxicity in vitro and in vivo. The objective of this review is to collect and compare different nanosystems based on PS-MSNs pointing out their advantages in PDT against diverse types of cancers.