PDT Treatment Research Articles

Antimicrobial effects of photodynamic therapy with antiseptics on Staphylococcus aureus biofilm on titanium surface.

S. aureus biofilm plays a predominant role in the establishment and development of peri-implantitis. It is suggested to combine different modalities as peri-implantitis treatment. The aim of this study was to evaluate the disinfection efficacy of combined application of antiseptics with PDT on Staphylococcus aureus (S. aureus) biofilm formed on titanium(Ti) disks with different surface roughness. S. aureus biofilm was incubated on polished and sandblasted large-grit acid-etched (SLA) Ti surfaces for 48 h. 72 contaminated Ti disks (36 polished, 36 SLA) were randomly divided into 6 different groups as follows: (a) PBS, (b) 0.2% chlorhexidine digluconate (CHX), (c) 3% hydrogen peroxide (H2O2), (d) PDT, (e) 0.2% CHX + PDT, and (f) 3% H2O2+PDT. Colony forming unit (CFU) was measured to determine antimicrobial effects. Biofilm structure was assessed using scanning electron microscopy (SEM) and confocal laser scanning microscope (CLSM). All disinfection methods significantly reduced bacteria amounts compared to control group on both polished and SLA Ti surfaces (P < 0.001). PDT demonstrated stronger decontamination ability in eliminating S. aureus from Ti surfaces than CHX and H2O2 did (P < 0.05). The combined CHX or H2O2 with PDT treatment were more effective in bacterial disinfection than a single administration of these treatments (P < 0.001). The combination of CHX or H2O2 administration with PDT was more effective in eradicating S. aureus on both polished and SLA Ti disks in comparison with either treatment alone, suggesting that combined usage of antiseptics with PDT could be a more efficient method for the treatment of peri-implantitis.

Tumor Acidic Microenvironment Targeted Pyropheophorbide a Dimer, an Alternative Strategy for Simultaneous Tumor Fluorescence Imaging and PDT Treatment

Tumor Acidic Microenvironment Targeted Pyropheophorbide a Dimer, an Alternative Strategy for Simultaneous Tumor Fluorescence Imaging and PDT Treatment

A two-year study of diffused retinal pigment epitheliopathy treated with half-dose photodynamic therapy guided by simultaneous angiography and optical coherence tomography

ObjectivesDiffused retinal pigment epitheliopathy (DRPE) is not necessarily the same as chronic central serous chorioretinopathy (CSC), but a severe subgroup under the umbrella of chronic CSC. This study was to evaluate the efficacy and safety of half-dose PDT treating DRPE.MethodsA retrospective case series design was used. Forty-eight consecutive patients (48 eyes) with DRPE treated with half-dose PDT underwent follow-up at baseline, 3 months, 6 months, 12 months and 24 months. Simultaneous FA, ICGA and OCT were used for the treatment and follow-up. The primary outcomes were the subretinal fluid and best-corrected visual acuity in optical coherence tomography.ResultsComplete fluid absorption was achieved in 95.8% of eyes at 3 months and 100.0% of eyes at 24 months. The baseline logarithm of the minimum angle of resolution (logMAR) BCVA, which was 0.51 ± 0.36, significantly improved to 0.43 ± 0.38 (p < 0.001) at 6 months. The boost continued to 0.29 ± 0.37 (p < 0.001) at 12 months and 0.19 ± 0.39 (p < 0.001) at 24 months. The integrities of the ellipsoid zone (EZ) and interdigitation zone (IZ) improved throughout. Regression analyses showed the BCVA in logMAR was inversely correlated with the EZ (p < 0.01) and IZ (p < 0.01). The recurrence rate was 6.3%. No severe complications were witnessed.ConclusionsIn 48 eyes with DRPE, simultaneous angiography and OCT facilitated a more comprehensive guidance for half-dose PDT treatment and follow-up. The BCVA improvement occurred at 6 months, which may be attributed to the restoration of the outer retinal structure.

Perspective clinical study on effect of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in treating condylomata acuminata in pregnancy.

To observe the clinical efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in treating vulval condylomata acuminata (CA) in pregnancy. The clinical efficacies of ALA-PDT on 16 cases of CA in pregnancy as well as cryotherapy on 22 cases of CA in pregnancy were analyzed in this prospective study. The treatment group showed a wart clearance rate of 93.8% after 3 PDT treatments, while the control group showed a wart clearance rate of 72.7% after 3 cryotherapy treatments. After the 3-month follow-up period, the treatment group registered a recurrence rate of 6.3%, whereas the control group recorded a recurrence rate of 36.4%, indicating a statistically significant difference (χ2 = 4.674, p = 0.031 < 0.05). After the 1-month postpartum follow-up period, the newborns grew and developed well, without any abnormality in physical examinations. ALA-PDT is safe and effective in treating CA in pregnancy.

A glycoporphyrin story: from chemistry to PDT treatment of cancer mouse models.

Photodynamic therapy (PDT) represents a non-toxic and non-mutagenic antitumor therapy. The photosensitizer's (PS) chemo-physical properties are essential for the therapy, being responsible for the biological effects induced in the targeted tissues. In this study, we present the synthesis and development of some glycoconjugated porphyrins based on lectin-type receptor interaction. They were tested in vitro for finally choosing the most effective chemical structure for an optimum antitumor outcome. The most effective photosensitizer is substituted by three diethylene glycol α-d-mannosyl groups. In vivo studies allow firstly the determination of some characteristics of the biological processes triggered by the initial photochemical activation. Secondly, they make it possible to improve the therapeutic protocol in the function of the structural architecture of the targeted tumor tissue.

Cytotoxic and Photocytotoxic Effects of Cercosporin on Human Tumor Cell Lines

Cercosporin is a naturally occurring perylenequinone. Although other perylenequinones have been extensively studied as photosensitizers in photodynamic therapy of cancer (PDT), cercosporin has been studied in this light only within the remits of phytopathology. Herein, we investigated the photocytotoxicity of cercosporin against two glioblastoma multiforme (T98G and U87) and one breast adenocarcinoma (MCF7) human cell lines. Cercosporin was found to be a potent singlet oxygen producer upon 532nm excitation, while its cell loading was similar for MCF7 and U87, but approximately threefold higher for T98G cells. The subcellular localization of cercosporin was in all cases in both mitochondria and the endoplasmic reticulum. Light irradiation of cercosporin-incubated cells around 450nm showed that T98G cells were more susceptible to cercosporin PDT, mainly due to their higher cercosporin uptake. Metabolic studies before and 1h following cercosporin PDT showed that cercosporin PDT instigated a bioenergetic collapse in both the respiratory and glycolytic activities of all cell lines. In the dark, cercosporin exhibited a synergistic cytotoxicity with copper only in the most respiratory cell lines (MCF7 and T98G). Cercosporin is a potent photosensitizer, but with a short activation wavelength, mostly suitable for superficial PDT treatments, especially when it is necessary to avoid perforations.

Photophysical properties and photodynamic anti-tumor activity of corrole-coumarin dyads

A new non-conjugated corrole-coumarin dyad and its gallium complex has been synthesized. Photophysical properties of the dyads were tested in two solvents, exhibiting strong solvent effect on the absorption and fluorescence spectra. Absorption spectra of the dyads are a linear combination of the spectra of their corresponding monomers, demonstrating a negligible electronic communication between coumarin and corrole moiety. However, fluorescence emission of coumarin entity in all dyads were quenched significantly as compared to pristine coumarin; this was attributed to intramolecular energy transfer from coumarin to the corrole. Photodynamic anti-tumor tests revealed that gallium corrole-coumarin dyads (2-Ga) exhibited good PDT activity towards SiHa cells. After PDT treatment, 2-Ga could induce apoptosis in SiHa cells, which was associated to cell S phase arrest, collapse of the mitochondrial membrane potential and increase of the intracellular ROS level.

PO-204 Vascular effects of targeted photodynamic therapy of human glioblastoma with theranostic AGuIX nanoparticles

IntroductionPhotodynamic therapy (PDT), a local and minimally invasive procedure for cancer treatment is a very promising approach in comparison to traditional forms of anticancer therapies. The aim of the study was to check the feasibility of functionalized AGuIX nanoparticles to act as a photosensitizer in photodynamic therapy against glioblastoma multiforme and its vasculature.Material and methodsChicken chorioallantoic membrane (CAM) model Human glioblastoma U87-MG xenografts were engrafted on CAM on embryo developement day 7. PDT treatment was applied in embryo development day 10. Effects of vasculature were investigated by fluorescence angiography.Mouse ectotopic tumourmodelU87-MG tumours were grown in Balb nude mouse legs. Effects on vasculature were investigated by USG with Doppler and PW mode (VEVO 2100), EPR oximetry and IHC.Mouse orthotopic tumourmodelU87-MG tumours were implanted in Balb nude mouse brains using stereotactic device. Effects on vasculature were investigated by MRI and IHC.PDTAGuIX photosensitizer solution in various doses was injected i.v. and after drug-light interval of 15 min and 1 hour tumours were irradiated with various light doses (λ=650 nm).Results and discussionsThere were visible changes in total vessel area, vessel density and size of vessels after photodynamic treatment in PDT-treated tumours, consistent with destruction of vasculature structure. Blood flow and blood flow velocity reflected a loss of vessel function in tumours and surrounding tissues after PDT with AGuIX nanoparticles.ConclusionVascular-targeted photodynamic therapy with AGuIX nanopartilcles led to vascular disruption of human glioblastoma xenografts in investigated animal models.

PO-435 Photoactivation of nanoparticles delivered by mesenchymal stem cells induces osteosarcoma cell death in in vitro 3D co-culture models

IntroductionOsteosarcoma (OS) is a rare and aggressive tumour that mainly affects long bones of adolescents. Currently, OS patients are treated with a combination of multi-agent chemotherapy and surgery. However, 30% of patients do not respond to standard treatment. Therefore, innovative therapeutic agents are needed. Mesenchymal stem cells (MSCs) display a specific tumour-tropism and have been previously used in successful preclinical studies to deliver several therapeutic agents. Furthermore, the safety of genetically engineered MSCs was demonstrasted in ongoing clinical trial. The goal of the present study was to test in vitro whether MSCs could uptake photoactivable nanoparticles (NPs) and induce cell death of OS cells upon photoactivation.Material and methodsPtl@PMMA NPs were produced by adding tetrasulfonate aluminium phthalocyanine (Ptl) to an aqueous solution of positively charged poly-methylmethacrylate (PMMA) nanoparticles. The photosensitizer Ptl is activated in near-infrared light allowing a deep tissue penetration. Human MSC lines, isolated from the bone marrow of multiple donors, were loaded with Ptl@PMMA NPs. The MSCs’ ability to internalise and retain NPs, along with their migratory properties, were tested. Cell death upon photoactivation (PDT) was evaluated in vitro, on a monolayer co-culture of MSCs and OS cells and in 3D multicellular spheroids, generated via cell suspension in ultralow attachment platesResults and discussionsMSCs showed an internalisation rate of Plt@PMMA>95%, which did not alter cell viability and migratory capacity. When Ptl@PMMA-MSCs were co-cultured with a human OS cell line (SaOS-2) in monolayers, they efficiently triggered cell death upon PDT. In particular, AnnexinV/PI and CalceinAM/EthD staining showed 70% of cell death in the co-culture system. These results were also validated by a metabolic assay. Interestingly, in a 3D co-culture of the OS cell line MG63 and Ptl@PMMA-MSCs, we observed a marked reduction of the viability (<5%) measured by the ATP content 24 hours after PDT. A massive cell necrosis induced by the photoactivation of the Ptl in the whole spheroid mass was confirmed by CalceinAM/EthD staining and TEM imaging.ConclusionFor the first time, we demonstrated that photoactivation of MSCs loaded with Ptl@PMMA NPs can successfully induce OS cell death in a three-dimensional OS model. These results encourage further in vivo evaluation to demonstrate the specific targeting of Plt@PMMA loaded MSCs to the tumour stroma and the efficacy of PDT treatment

Biodegradable Black Phosphorus Nanosheets Mediate Specific Delivery of hTERT siRNA for Synergistic Cancer Therapy.

Human telomerase reverse transcriptase (hTERT) has been found to be closely related to tumor transformation, growth, and metastasis. Thus, the delivery of hTERT small interfering RNA (siRNA) is an important approach for cancer gene therapy. However, the single anticancer effect of gene silencing is often limited by poor specificity or low efficiency in siRNA delivery and release. In this work, we present small and thin black phosphorus (BP) nanosheets as a biodegradable delivery system for hTERT siRNA. The BP nanosheets prepared with poly(ethylene glycol) (PEG) and polyethylenimine (PEI) modification (PPBP), exhibited high siRNA loading capacity and robust cell uptake. The PPBP nanosheets also exhibited potent photodynamic therapy/photothermal therapy (PDT/PTT) activities when exposed to different wavelengths of laser irradiation. More importantly, PPBP nanosheets underwent a gradual degradation when presented in a mixture of low pH and reactive oxygen species (ROS)-rich environment. The degradation of PPBP was strengthened especially after local and minimal invasive PDT treatment, because of excessive ROS production. Further delivery and release of siRNA to the cytoplasm for gene silencing was achieved by PEI-aided escape from the acidic lysosome. Thus, PPBP-siRNA efficiently inhibited tumor growth and metastasis by specific delivery of hTERT siRNA and a synergistic combination of targeted gene therapy, PTT and PDT.

Functional role of a long non-coding RNA LIFR-AS1/miR-29a/TNFAIP3 axis in colorectal cancer resistance to pohotodynamic therapy

Colorectal Cancer (CRC) is one of the most common digestive system malignant tumors. Recently, PDT has been used as a first-line treatment for colon cancer; however, limited curative effect was obtained due to resistance of CRC to PDT. During the past decades, accumulating CRC-related long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs have been reported to exert diverse functions through various biological processes; their dysregulation might trigger and/or promote the pathological changes. Herein, we performed microarrays analysis to identify dysregulated lncRNAs, miRNAs and mRNAs in PDT-treated HCT116 cells to figure out the lncRNA-miRNA interactions related to the resistance of CRC to PDT treatment, and the downstream mRNA target, as well as the molecular mechanism. We found a total of 1096 lncRNAs dysregulated in PDT-treated CRC HCT116 cells; among them, LIFR-AS1 negatively interacted with miR-29a, one of the dysregulated miRNAs in PDT-treated CRC cells, to affect the resistance of CRC to PDT. LIFR-AS1 knockdown attenuated, whereas miR-29a inhibition enhanced the cellular effect of PDT on HCT116 cell proliferation and apoptosis. Furthermore, among the dysregulated mRNAs, TNFAIP3 was confirmed to be a direct target of miR-29a and exerted a similar effect to LIFR-AS1 on the cellular effects of PDT. In summary, LIFR-AS1 serves as a competitive endogenous RNA (ceRNA) for miR-29a to inhibit its expression and up-regulate downstream target TNFAIP3 expression, finally modulating the resistance of CRC to PDT. We provide an experimental basis for this lncRNA/miRNA/mRNA network being a promising target in CRC resistance to PDT treatment.

Photodynamic therapy of necrobiosis lipoidica using methyl aminolevulinate: A retrospective follow-up study.

Necrobiosis lipoidica (NL) is a rare, treatment-resistant, granulomatous skin disease of unknown origin, frequently seen in patients with diabetes. In this retrospective study we evaluated the long-term efficacy of methyl aminolaevulinate-based photodynamic therapy (MAL-PDT), including 80 treatments (70 conventional and 10 daylight PDT), on 65 unselected NL patients treated routinely in our clinic. Superficial curettage, avoiding skin oozing or bleeding, was performed prior to MAL application. Conventional MAL-PDT had a 100% cure rate (CR) in 64% (45/70) of the treatment series. With daylight PDT we observed a 100% CR in 80% of the treatment series (8/10), an insignificant difference compared to conventional PDT (p = 0.48). The overall cure rate was 66% (53/80). We observed no correlation between CR and gender, age at first PDT treatment, duration of NL prior to PDT treatment, number of NL elements, or diabetes. New lesions faded, whereas old lesions were clearly visible after inactivation of NL. MAL-PDT proved to have full efficacy in 66% of the treatments, with conventional PDT and daylight PDT producing an almost identical result. We observed no correlation between CR and time of follow-up. However, we recommend at least six months to pass before final evaluation of treatment effect.

Translating phototherapeutic indices from in vitro to in vivo photodynamic therapy with bacteriochlorins.

To compare hydrophilic and lipophilic bacteriochlorin photosensitizers in the photodynamic therapy of cancer, and relate their properties and in vitro phototoxicities to the efficacy of in vivo PDT treatments. Photochemical characterization of a hydrophilic bacteriochlorin (F2 BOH) photosensitizer, and its use in PDT was compared with the performance of a closely related but water-insoluble bacteriochlorin (F2 BMet or redaporfin). Biodistribution, pharmacokinetics, skin photosensitivity, PDT efficacy and immune responses of two bacteriochlorins were compared. PDT in vitro employed CT26 colon carcinoma cells. BALB/c mice bearing CT26 cells were treated according to a protocol where the illumination of the subcutaneous tumor is performed 15 minute after intravenous administration of the photosensitizer, while it is in the vascular compartment (vascular-PDT). F2 BOH has photochemical properties comparable to redaporfin and both are promising photosensitizers for PDT. Although, F2 BOH is 10 times less phototoxic in vitro than redaporfin, the phototoxicity of F2 BOH in vascular-PDT is comparable to that of redaporfin. This is consistent with the fact that the vasculature is the main target of vascular-PDT. F2 BOH-PDT led to long-term cures and stimulation of the immune system. F2 BOH is soluble in aqueous media, photostable, has a convenient elimination half-life of 44 hours and leads to very low skin photosensitivity one week after administration. F2 BOH and redaporfin are both very phototoxic in vascular-PDT, but this could not be anticipated from their widely different phototherapeutic indices in vitro. PDT with F2 BOH enabled long-term cures of BALB/c mice with subcutaneously implanted CT26 tumors, and the cured mice rejected tumor re-inoculation one year after the treatment. Lasers Surg. Med. 50:451-459, 2018. © 2018 Wiley Periodicals, Inc.

In vitro and in vivo evaluation of improved EGFR targeting peptide-conjugated phthalocyanine photosensitizers for tumor photodynamic therapy

Phthalocyanine (Pc) is one of the most promising photosensitizer candidates because of its strong absorption (extinction coefficient ε>105Lmol−1cm−1) at long wavelengths and strong singlet oxygen generation abilities (a singlet oxygen quantum yield of approximately 50%). However, low tumor targeting, low water solubility and a high tendency to aggregate appear to significantly restrict the compound’s application in tumor treatment. Conjugating Pc with peptide ligands could be a useful strategy for alleviating these problems. Here, to further optimize the structures of peptide-conjugated zinc Pcs for PDT therapy, we finely tuned the hydrophilicity of the modified Pc aromatic macrocycle with varied length of polyethylene glycol (PEG) and added an extra PEG linker and an extra glutamic acid between the Pc ring and the peptide ligand to reduce the influence of the ligand on the Pc aromatic ring. Among the synthesized conjugates, Pc-3 showed greatly improved targeting towards tumors and abolished inoculated tumors with only a single PDT treatment in a subcutaneous xenograft tumor model, making this approach a promising therapeutic agent for the treatment of cancer.

Peripherally and non-peripherally tetra-HBME (4-hydroxybenzyl methyl ether) substituted metal-free and zinc(II) phthalocyanines: Synthesis, characterization, and investigation of photophysical and photochemical properties

Abstract This paper reports on the synthesis and characterization of non-peripherally and peripherally tetrasubstituted metal-free and zinc(II) phthalocyanines functionalized with the phenolic compound “4-hydroxybenzyl methyl ether (HBME)”. Synthesized compounds have been characterized by elemental analysis, FT-IR, 1H NMR, 13C NMR, MALDI-MS and UV–Vis spectral data. Besides, spectral, photophysical (fluorescence quantum yields and lifetimes) and photochemical (singlet oxygen generation and photodegradation under light irradiation) properties of newly synthesized phthalocyanines were investigated in DMF solution. We obtained very high singlet oxygen quantum yields as 0.86, 0.91, suggesting its potential as photosensitizer in PDT treatment.

Determination of optical properties, drug concentration, and tissue oxygenation in human pleural tissue before and after Photofrin-mediated photodynamic therapy.

PDT efficacy depends on the concentration of photosensitizer, oxygen, and light delivery in patient tissues. In this study, we measure the in-vivo distribution of important dosimetric parameters, namely the tissue optical properties (absorption μa (λ) and scattering μs ' (λ) coefficients), photofrin concentration (cphotofrin), blood oxygen saturation (%StO2), and total hemoglobin concentration (THC), before and after PDT. We characterize the inter- and intra-patient heterogeneity of these quantities and explore how these properties change as a result of PDT treatment. The result suggests the need for real-time dosimetry during PDT to optimize the treatment condition depending on the optical and physiological properties.

Synthesis and biological characterization of novel rose bengal derivatives with improved amphiphilicity for sono-photodynamic therapy

Sono-Photodynamic therapy (SPDT) utilizing ultrasound and light has been demonstrated that this novel approach can lower dosage resulting in reduction of the potential side effects caused by sensitizers. Recently, a new formulation of rose bengal (RB) as an intralesional injection has completed clinical trials phase II for PDT treatment of melanoma cancer. However, the inherent unfavorable pharmacological properties of RB hindered its extensive clinical development. With the aim to identify new RB derivatives (RBDs) with enhanced photodynamic and sonodynamic anticancer efficiency, a series of amphiphilic RBDs have been designed, synthesized and biological characterized. Among them, RBD4 significantly improved cellular uptake and enhanced intracellular ROS generation efficiency upon light and ultrasound irradiation, resulting in dramatically improved anticancer potency. Notably, RBD4 has a relative potency similar to sinoporphyrin sodium (DVDMS), indicating its further potential application for SPDT.

Luminescent supramolecular polymer nanoparticles for ratiometric hypoxia sensing, imaging and therapy

The first example of a multi-functional supramolecular polymer-based nanoprobe for ratiometric hypoxia sensing, imaging and PDT treatment is reported.

Comparative Studies of Photophysicochemical Properties of Non-Peripherally Anisole/Thioanisole-Tetrasubstituted Gallium (III) Phthalocyanines Containing Oxygen/ Sulfur Bridge

This work reports on the synthesis and characterization of gallium (III) phthalocyanines (4-6) which is non-peripherally tetra-substituted with anisole or thioanisole functional groups containing oxygen or sulfur bridge. Confirmation of the phthalocyanine structures performed with a combination of elemental analysis, FTIR, 1 H-NMR, UV-vis and MALDI-MS spectral data. Also, investigated and discussed the effects of non-peripherally tetra-substitution with different functional groups on the photochemical (Singlet oxygen quantum yields and photodegradation quantum yields) and photophysical properties (Fluorescence quantum yields and flouresans behavior). In every substituent, we obtained very similar singlet oxygen quantum yields as 0.64 for (4) , 0.56 for (5) and 0.65 for (6) suggesting its potential as photosensitizer in PDT treatment.

The Effect of Photodynamic Therapy in the Treatment of Chronic Periodontitis: A Review of Literature.

Introduction: Chronic periodontitis is the most common periodontal disease which is related to the chronic accumulation of bacterial plaque. Since mechanical methods are not sufficient in the treatment of this disease, administration of local/systemic antibiotic is recommended following mechanical debridement. However, side effects of antibiotics such as microbial resistance and patient allergy led to development of alternative methods. One of these suggested methods is the antimicrobial photodynamic therapy (aPDT). PDT is a local noninvasive treatment modality without the side effects caused by antibiotics. The aim of this study was to review the articles related to the application of PDT with laser in the treatment of chronic periodontitis. Review of literature: In the present review of literature, the authors used key words such as chronic periodontitis, laser and photodynamic therapy, and conducted a literature search via Google Scholar and PubMed for the period of 1990 to 2015. A total of 47 articles in English were found. The articles that were not associated with the topic of research and review articles were deleted and only clinical trials were evaluated. After reviewing 23 articles' abstracts, the full texts of 16 articles were analyzed. Conclusion: Considering the safety, the lack of side effects and general advantages like more patient compliance, the PDT treatment with scaling and root planing (SRP) is recommended as an efficient adjunctive modality for the treatment of localized chronic periodontitis especially during the maintenance phase in non-surgical treatment.