PDT Treatment Research Articles

621 A novel painless ALA-PDT in the treatment of skin diseases

Pain during conventional photodynamic therapy (C-PDT) is the main limiting adverse effect in its use in dermatology. During the course of C-PDT, most patients experience sensations of burning and tingling pain that vary in intensity. In some cases, patients have to stop the treatment because of unbearable pain. It is generally believed that C-PDT pain is mediated by free radicals generated by PpIX; ROS can either stimulate nerve endings directly or mediate pain through inflammatory by-products. Pain remains the top obstacle that prevents C-PDT application to all patients. Here, we modified C-PDT into a painless PDT treatment (Modified photodynamic therapy , M-PDT, also named novel painless ALA-PDT) by decreasing ALA incubation time and increasing light dose. Our study showed that pain in M-PDT group was significantly reduced in the treatment of actinic keratosis, acne, and condyloma acuminate. Even, in some cases the pain almost vanished. And M-PDT has better efficacy than C-PDT. Further investigation confirmed that M-PDT also inhibit tumor growth on cutaneous squamous cell carcinoma (SCC). Interestingly, compared with C-PDT, M-PDT induced more ROS which should stimulate nerve endings but not. We elucidated a mechanism that the low average amount of ROS may be the reason why M-PDT is painless. Our findings indicate that M-PDT have wide clinical value in skin disease.

In vitro photodynamic treatment of cancer cells induced by aza-BODIPYs.

Two aza-BODIPY photosensitizes (PSs, compounds 7 and 8), featuring an iodine atom on each pyrrolic unit of their structure, were synthesized in fairly good yields starting from commercial products and tested in vitro on two human cancer cell lines (HCT116 and SKOV3) to assess their photodynamic efficacy. After treating the cell cultures with variable concentrations of 7 or 8 and incubating for the desired incubation time, the cells were irradiated for two hours with a red-light emitting diode (LED) device; afterwards the extent of cell death was determined by MTT assay. Besides the killing effect, the new PSs were also studied to determine further parameters related to photodynamic efficacy, such as the resistance towards photobleaching, the rate of singlet oxygen production, the fluorescence quantum yields, the cellular uptake and the localization inside the cells and, finally, flow cytometric analysis for apoptosis. Considering the results as a whole, these aza-BODIPYs can be considered to be promising photosensitizers because of their IC50 values being below micromolar concentrations and for more rather interesting features. Actually, these molecules have proved to be: (a) quite stable towards photobleaching; (b) good producers of singlet oxygen and (c) highly penetrating the cells with a wide distribution in the cytosol. Furthermore, in accordance with the good rate of singlet oxygen production, the apoptotic cells reach 30% and this allows us to assume a low inflammatory effect of the in vivo PDT treatment; thus a possible in vivo application of these aza-BODIPYs might be plausible.

Oral Spironolactone versus Conservative Treatment for Non-Resolving Central Serous Chorioretinopathy in Real-Life Practice.

ObjectiveTo compare the efficacy of oral spironolactone treatment versus conservative treatment for patients with persistent central serous chorioretinopathy (CSC) in real-life practice.DesignRetrospective comparative study.Patients and MethodsMedical records and retinal images of 62 patients with non-resolving CSC were reviewed. Twenty-one patients received oral spironolactone (50 mg/day) while 41 patients received conservative treatment. Primary outcome was proportion of eyes with complete resolution of subretinal fluid (SRF) within 6 months. Secondary outcome measures included changes in SRF height, central macular thickness (CMT), lesion size and best-corrected visual acuity (BCVA). The occurrence of drug side effect was also assessed.ResultsThere was no significant difference in demographic data, clinical characteristics, optical coherence tomography parameters and leaking patterns in fluorescein fundus angiography between two groups. Complete resolution of SRF was significantly higher and faster in the spironolactone group than the conservative treatment group (p=0.03). Although significant anatomical improvement in SRF height, CMT and lesion size were observed in both groups (p < 0.001), final BCVA was improved significantly in only the spironolactone group (p < 0.05). The recurrence of SRF after complete resolution was observed in 4/12 eyes (33.33%) in the treatment group. None of the patients experienced any side effects of spironolactone.ConclusionOral spironolactone (50 mg/day) could achieve both significant anatomical and visual improvement, while the significant visual gain could not be provided with the conservative treatment. Spironolactone should be considered as an alternative treatment option in non-resolving CSC patients who cannot afford the PDT treatment.

Assessment of 5-Aminolaevulinic Acid Photodynamic Therapy (ALA-PDT) in Chinese patients with actinic keratosis: Correlation of dermoscopic features with histopathology.

The study examines the changes in dermoscopic features of actinic keratosis (AK) after photodynamic therapy, and delineates the association between AK dermoscopic and histopathological findings. A total of 21 patients (23 lesions) with pathologically confirmed actinic keratosis who received 5-aminolaevulinic acid (ALA) photodynamic therapy (ALA-PDT) were enrolled. The numbers of PDT treatments were: 1, n=1; 2, n=2; 3, n=10; 4, n=6; 5, n=2; 6, n=2). The dermoscopic features before and after the PDT were compared. There were statistically significant decreases in the positive rates of dermoscopic features including scales (P<0.001), follicular plugs with whitish halo (P=0.013), and red pseudonetwork (P=0.022) among patients treated with ALA-PDT. Dermoscopic feature was significantly associated with pathological grade (P<0.001). Histopathological hyperkeratosis was significantly associated with dermoscopic red pseudonetwork (P=0.034) and wavy vessel (P=0.005). Parakeratosis was associated with wavy vessels (P=0.001). For vascular hyperplasia in dermal papillae, the significant correlates included scales (P=0.011), follicular plugs with whitish halo (P=0.011), red pseudonetwork (P<0.001); coiled vessels (P=0.003) and rosette sign (P=0.004). Wavy vessels was the only feature correlating keratosis pilaris (P=0.003). The findings of the present study support dermoscopy as having potential to be useful for diagnosing and monitoring of actinic keratosis.

Photodynamic therapy for port-wine stains in extremities: Report of 4 cases

To observe the clinical efficacy of photodynamic therapy mediated by hemoporfin (HMME-PDT) for port-wine stains (PWS) on extremities and explore its possible influencing factors. Four patients with PWS in extremities were treated by HMME-PDT, and patients with negative results in the skin test were given an intravenous injection of 5 mg/kg of HMME. The patients were irradiated with 532 nm LED green light, and immediately applied cold compress after treatment. These patients were informed to stay away from light for two weeks. A follow-up every 2 weeks was conducted with treatment for 2 or 3 times in total. After the end of treatment, a follow-up was carried out for 6-12 months and the efficacy and safety were evaluated. Three of the four patients were considered cured, and the treatment was ineffective for one patient. During the follow-up observation, all patients had different degrees of edema, and there were no signs of chromatosis or scarring. PDT treatment for patients with extremity PWS demonstrate high efficiency and safety, without obvious adverse reactions and recurrence.

Polydopamine Coated PB-MnO2 Nanoparticles as an Oxygen Generator Nanosystem for Imaging-Guided Single-NIR-Laser Triggered Synergistic Photodynamic/Photothermal Therapy.

Exploring a combined phototherapeutic strategy to overcome the limitations of a single mode therapy and inducing high anticancer efficiency is highly promising for precision cancer nanomedicine. However, a single-wavelength laser activates dual photothermal/photodynamic therapy (PTT/PDT) treatment is still a formidable challenge. Herein, we strategically design and fabricate a multifunctional theranostic nanosystem based on chlorin e6-functionalized polydopamine (PDA) coated prussian blue/manganese dioxide nanoparticles (PB-MnO2@PDA-Ce6 NPs). Interestingly, the obtained PB-MnO2@PDA NPs not only offer an effective delivery system for Ce6 but also provide strong optical absorption in the near-infrared range, endowing high antitumor efficacy of PTT. More importantly, the as-prepared PB-MnO2@PDA-Ce6 nanoagents exhibit an effective oxygen generation, superior reactive oxygen species (ROS), and outstanding photothermal conversion ability to greatly improve PTT and PDT treatments. As a result, both in vitro and in vivo treatments guided by MR imaging on liver cancer cells reveal the complete cell/tumor eradication under a single wavelength of 660 nm laser irradiation, implying the simultaneous synergistic PDT/PTT effects triggered by PB-MnO2@PDA-Ce6 nanoplatform, which are much higher than individual treatment. Taken together, our phototherapeutic nanoagents exhibit an excellent therapeutic performance, which may act as a nanoplatform to find safe and clinically translatable routes to accelerate cancer therapeutics.

Preservation of sturgeon using a photodynamic non-thermal disinfection technology mediated by curcumin

The effect of a photodynamic non-thermal disinfection technology mediated by curcumin (PDT) on the shelf life and quality of sturgeon during storage at 4 ± 1 °C were measured. The disinfection conditions for PDT were as follows: 30 μM curcumin, 15 W LED light (470 nm) power and 90 s exposure. Using these conditions, sensory, biochemical (TVB-N, pH) and microbiological analyses were used to measure the shelf life of sturgeon. The shelf life of sturgeon after the PDT treatment was extended by 3 days. Texture, free amino acids (FAA), fatty acids (FA), electronic nose and volatile component analyses were used to measure the quality of the sturgeon. There was no significant change in texture after the PDT treatment. At the end of the storage period, the total free amino acids (control: 210 ± 10 mg/100 g; PDT: 410 ± 20 mg/100 g) and the total polyunsaturated fatty acids (control: 5.0 ± 0.6 mg/g; PDT: 6.5 ± 0.4 mg/g) in the PDT group were higher than that in control group, while the volatile substance from decay in the PDT group was lower than the control. These results suggested that the sturgeon after the PDT treatment had a reduced degree of oxidation, a slower flesh decay, a lower level of metabolism by spoilage microorganisms and less decomposition of nutrients. In conclusion, the PDT treatment has a positive effect on extending the shelf life and improving quality of sturgeon.

A Randomized Trial of Broad Area ALA–PDT for Field Cancerization Mitigation in High-Risk Patients

The relationship between actinic keratoses (AKs) and nonmelanoma skin cancers (NMSCs) is well established. Patients with field cancerization are at high risk of developing new lesions. A treatment to interrupt new lesion formation or progression is required. To evaluate occurrence of AKs in high-risk patients after field aminolevulinic acid&ndash;photodynamic therapy (ALA&ndash;PDT). In this randomized, parallel-group, evaluator-blinded, 52-week study, patients with 4&ndash;15 facial AKs (N = 166) were random-ized (ALA 2x vs ALA 3x vs vehicle [VEH]-pooled [VEH 2x+VEH 3x], 1:1:1) to receive 2 or 3 PDT treatments (1-hour incubation) following cryotherapy at screening. More ALA-treated patients than VEH-treated patients had no AKs at week 52 (ALA 2x, 36.0%, P=0.0102; ALA 3x, 37.5%, P=0.0089; VEH, 18.9%). Week 52 lesion recurrence rates were 7.7% (P=0.0004) and 6.1% (P&lt;0.0001) for ALA 2x and ALA 3x, respec-tively, versus 15.5% for VEH. Therapy was well tolerated; no patient requested early termination of light treatment. ALA 3x reduced NMSC development versus VEH (5 vs 12 lesions, P=0.0014). 2 or 3 ALA&ndash;PDT treatments with 1-hour incubation can significantly reduce occurrence of AKs after 1 year in patients at high risk of NMSC versus VEH&ndash;PDT (NCT02239679). J Drugs Dermatol. 2020;19(5):452-458. doi:10.36849/JDD.2020.4930.

Treatment of herpes labialis by photodynamic therapy: Study protocol clinical trial (SPIRIT compliant).

Background:Lesions of herpes labialis are caused by the herpes simplex virus type 1 and cause pain and aesthetic compromise. It is characterized by the formation of small vesicles that coalesce and rupture forming extremely painful ulcers, that evolve to crusts, dry desquamations until their complete remission. Currently the treatment of these lesions is done with acyclovir. Although it diminishes the symptomatology, it causes viral resistance and does not prevent the recurrence of the lesions. It is known that antimicrobial photodynamic therapy (aPDT) has numerous advantages, among them: the reduction of the time of remission, and does not cause resistance. This protocol will determine the effectiveness of PDT in lesions of herpes labialis.Materials and methods:A total of 30 patients with herpes labialis in the prodromal stage of vesicles, ulcers, and crusts will be selected to participate in the study and randomized into 2 groups: G1 control and G2 experimental. After signing Research Ethics Committee and TA, patients in group G1 will undergo the standard gold treatment for herpes labialis with acyclovir and simulated PDT treatment. Patients in the experimental G2 group will be treated simulating the gold standard treatment of herpes labialis (placebo) and PDT. In all patients, saliva samples will be collected for analysis of cytokines, and will be performed exfoliative cytology in the lesions. The pain will be assessed through a pain scale and a questionnaire of quality of life related to oral health (OHIP-14) will be given to them. Patients will continue to be followed up after 7 days, 1 month, 3 months, and 6 months; if there is a recurrence of the lesion, they will contact the researchers.Clinical registration: clinicaltrials.gov - NCT 04037475. Registered on July 2019.

Association between CFH single nucleotide polymorphisms and response to photodynamic therapy in patients with central serous chorioretinopathy.

To evaluate the association between single nucleotide polymorphisms (SNPs) in the complement factor H (CFH) gene and response to PDT in patients with CSC. 103 eyes from 93 patients with CSC were enrolled from Department of Ophthalmology of the People's Hospital Peking University. Genotyping for selected SNPs in the CFH gene was performed, and multivariate linear analysis was used to identify factors influencing PDT treatment outcomes. Genetics associations between SNPs in the CFH gene and response to PDT in patients with CSC were analyzed. None of the seven SNPs examined in this study (rs800292, rs1061170, rs3753394, rs3753396, rs2284664, rs1329428, and rs1065489) showed significant associations with 1-month outcomes after PDT in patients with CSC (P > 0.05). Baseline BCVA changed at 1month after PDT (P < 0.001), and baseline retinal thickness was associated with changes in retinal thickness at 1month after PDT (P < 0.001). Age was significantly associated with resolution of SRF at 1month after PDT (P = 0.004). There were no significant associations between SNPs in the CFH gene and 1-month outcomes after PDT in patients with CSC. However, baseline BCVA, baseline retinal thickness, and age were significantly associated with response to PDT in patients with CSC. Larger studies with more power are necessary to further determine whether an association exists between SNPs in the CFH gene and PDT in patients with CSC.

Analgesic and anti-inflammatory effects and mechanism of action of borneol on photodynamic therapy of acne

This study aims to explore the analgesic and anti-inflammatory effects of borneol, a traditional Chinese medicine, on photodynamic treatment of acne. Here, we found that borneol significantly decreased the auricular swelling rate and pain threshold of rats. We also showed that borneol noticeably reduced macrophage and lymphocyte infiltration. The number of Th cells was significantly higher in the control PDT group than in the PDT plus borneol treatment group (P < 0.05). The expression of IL-6, TNF-α, and IL-8 mRNA and proteins were noticeably lower in the treatment group in comparison to those of the PDT control group, while PDT plus borneol activated the p38-COX-2-PGE2 signaling pathway, increasing expression in the treatment group. Borneol has significant analgesic and anti-inflammatory effects on PDT of acne, and enhances the healing of acne by activating p38-COX-2-PGE2 signaling pathway.

Comparative study in photodynamic therapy using the same photosensitizer in tissue repair after second-degree burns in an experimental model

Photodynamic therapy is a therapeutic resource used to treat different pathologies such as neoplasias and wound healing. It consists of a light coupled to a photosensitizer that is used to react with oxygen and forming reactive oxygen species that reach target cells. This study aimed to evaluate the effect of PDT on the healing of second-degree burns. The study used 45 Wistar Rattus Norvegicus divided into three groups, two with lesions and treatment and one with lesions and without treatment (control group). Group PDT6 was lesioned and treated with 630- nm LED PDT and group PDT9 was lesioned and treated with 945- nm LED PDT. The results suggest collagen deposition and development of cellular structures of normal tissue in the treated groups compared to the control groups. It was concluded that the PDT treatment induced enhanced tissue repair in the treated groups; the best results were observed using the 630- nm LED.

Reactive Oxygen Species Explicit Dosimetry for Photofrin-mediated Pleural Photodynamic Therapy.

Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical PDT. Tissue oxygen, however, is not routinely monitored intraoperatively even though it is one of the three major components of treatment. Quantitative information about in vivo tissue oxygenation during PDT is desirable, because it enables reactive oxygen species explicit dosimetry (ROSED) for prediction of treatment outcome based on PDT-induced changes in tumor oxygen level. Here, we demonstrate ROSED in a clinical setting, Photofrin-mediated pleural photodynamic therapy, by utilizing tumor blood flow information measured by diffuse correlation spectroscopy (DCS). A DCS contact probe was sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (blood flow index) during intraoperative PDT treatment. Isotropic detectors were used to measure treatment light fluence and photosensitizer concentration. Blood-flow-derived tumor oxygen concentration, estimated by applying a preclinically determined conversion factor of 1.5×109 μMscm-2 to the blood flow index, was used in the ROSED model to calculate the total reacted reactive oxygen species [ROS]rx. Seven patients and 12 different pleural sites were assessed and large inter- and intrapatient heterogeneities in [ROS]rx were observed although an identical light dose of 60Jcm-2 was prescribed to all patients.

The new ball-type zinc phthalocyanine with S[sbnd]S bridge; Synthesis, computational and photophysicochemical properties

In this study, the starting compound 4,4′-disulfanediyldiphthalonitrile (1) and its ball-type zinc phthalocyanine (2) were synthesized and characterized by standard spectroscopic methods. The molecular structure and supramolecular dynamics of the compound (1) have been investigated by the analysis of the single crystal X-ray diffraction data. To further understand the intermolecular interactions of compound (1), the Hirshfeld surface analysis has been carried out. The compound (1) and (2) were investigated by quantum chemical calculations. Their quantum chemical parameters such as highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), chemical hardness were performed by B3lyp, HF, M062x method. The ΔG values of the compound (1) and (2) were calculated by using the obtained results. The calculated Infrared spectroscopy, Nuclear Magnetic Resonance, and UV–vis spectra of the compounds were investigated. In addition, photophysical (fluorescence quantum yields) and photochemical (singlet oxygen generation and photodegradation under light irradiation) properties of newly synthesized ball-type zinc phthalocyanine (2) were investigated in dimethyl sulfoxide (DMSO) solutions. We obtained very high singlet oxygen quantum yields as 0.89, suggesting its potential as photosensitizer in PDT treatment.

Low-level PDT treatment modulated photoaging mediated by UVA irradiation through regulating Bach2.

To investigate low-level ALA-PDT (Aminolevulinic acid photodynamic therapy) effects on photorejuvenation in vitro and in vivo, exploring the basic mechanism of Bach2 involved in PDT treatment in photoaging. Photoaging model was established by UVA chronic irradiation in human fibroblasts and mice skins. Cell viability was determined by MTS assay and cell senescence was detected by SA-β-gal activity. PDT treatment and Bach2 knockdown with adenovirus in fibroblasts were confirmed by Western blot. UVA chronic irradiation induced photoaging in vitro and in vivo. Treatment of low-level PDT reduced photoaging by decreasing SA-β-gal activity and cell senescence-related proteins levels of p16 and p21 in fibroblasts. Moreover, low-level PDT treatment accompany with Bach2 accumulation increased in fibroblasts and in mice skin tissues. Bach2 knockdown with adenovirus induced cell senescence and Bach2 depletion with PDT treatment some extent decreased SA-β-gal activity, but was with no significant change of Bach2 itself and p16 protein levels in fibroblasts. Low-level PDT treatment decreased skin photoaging which might be through up-regulating Bach2.

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 feasibility of using Saffron to reduce the photosensitivity reaction of selected photosensitizers using red blood cells and staphylococcusAureus bacteria as targets.

The photosensitivity reaction which appears after a Photodynamic therapy treatment session is a challenge that needs further investigation. The goal of this research is to evaluate the possibility of using saffron to reduce or control this photosensitivity reaction and to present mathematical modeling of the cell survival curves and their dependency on saffron concentration. Red blood cells (RBC) and Staphylococcus aureus Bacteria (STB) were used as targets in this study. The Photosensitivity of Rose Bengali, Methylene Blue, and Photofrin independently and incorporated with saffron was investigated for continued irradiation at different Saffron concentrations. Gompertz's function was used to fit the survival curve parameters. The 50% cell survival rate was fit to an empirical formula based on Saffron concentrations. Saffron inhibits the photosensitivity reaction of the three photosensitizers and causes a significant increase in the 50% survival rate time (t50) for RBC`s and STB. Saffron didn't show phototoxicity when incubated alone with RBC`s and STB. The survival curve parameters of the RBCs and STB showed a good fit to the Gompertz function. Saffron concentration is related to the RBC`s t50 based on power dependency of 0.56, 0.38 and 0.31 for Photofrin, Methylene Blue and Rose Bengali respectively and 0.1 on STB for Rose Bengali. Saffron can efficiently be used to reduce the photosensitivity reaction of Photosensitizers after a PDT treatment session. Gompertz function was found to be an appropriate mathematical model for survival rate curves. The t50 and the saffron concentration are well related through a power dependence empirical formula.

310P - Laser and PDT for the oral leukoplakia

BackgroundLeukoplakia is a oral pathology characterized by an increased risk for malignant transformation. Histopathology of leukoplakia can disclose hyperkeratosis with dysplasia or carcinoma or hyperkeratosis or parakeratosis without dysplasia. Existence of the different treatment options not decrease the the rates of recurrence up to 35%. MethodsTotally 40 patients with OL (homogenous type - 35 cases; verrucous type - 4 case; erythroleukoplakia - one case) were recruited for the study. In a period September 2017 – may 2019 all the patients were screened, and only those patients with clinically, and histologically proven OL was included under the study. All the patients had the history of using tobacco in smoking or smokeless form (Nasvay). 1470nm diode laser ablation was done under 5- ALA induced spectroscopy. In case of detection a pathological fluorescence after the session treatment was accompanied with PDT treatment. 10% ALA emulsion (0.1g of 99.9% ALA powder in 1 ml liquid paraffin) was used freshly just before the start of the therapy to avoid deterioration of the emulsion on contact with light. Diode lamp (Vostok -1, Uzbekistan) with power - 5 W, wavelength -630 ± 5nm was used as the light source. Total dose delivered per session was 100 J/cm 2. The therapy was performed in a one session. All patients were recalled at 4 weeks after completion of the last session of modified therapy. Lesion response was characterized as follows: Complete response (CR), ; partial response (PR), reduction at least 20% in diameter; no response (NR). The patients were followed-up for a period of 1 year. ResultsOne month (4 weeks) after 1470nm diode laser ablation + ALA-PDT, the response was evaluated based on clinical examination. CR was obtained in 35 out of 40 patients; PR in 5 out of 40 patients; and NR no patient. During the follow-up, no changes in the clinical appearance of the treated lesions were recorded. There was no recurrence of the lesion noted in CR cases. During the incubation period of 3 h after ALA application, the patients did not have any adverse effect in the form of pain, redness or discomfort. Patients did not have any other side effects. ConclusionsOur observations suggest that topical ALA mediated PDT with laser ablation is a promising means of treating OL. Legal entity responsible for the studyTashkent medical academy. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.

Synthesis and Anticancer Activity of Gold Porphyrin Linked to Malonate Diamine Platinum Complexes.

Recently, gold(III) porphyrins have gained great interest as anticancer drugs not only for the stability of gold(III) but also for the functionalization of the porphyrin to allow bridging with another metal such as platinum(II). We report here, for the first time, the synthesis of three new bimetal compounds containing a gold(III) porphyrin conjugated to a platinum diamine moiety through malonate bridging to obtain enhanced cytotoxicity from both metals combined with the phototoxicity of the porphyrin. The three complexes differ in the type of diamine ligand around platinum(II): ammonia (NH3), cyclohexanediamine (CyDA), and pyridylmethylamine (Py). The synthesis was carried out using the complexation of activated malonic acid derivatives with aquadiaminoplatinum(II) complexes, and the products were characterized by IR, NMR, mass spectra, and elementary analysis. The cytotoxic activity of the conjugates was screened in both healthy cell lines and cancer cell lines, human fibroblast cells (FS-68) and human breast cancer cells (MCF-7), and was compared to that of the corresponding platinum(II) complexes. The cyclohexyldiamine (CyDA) derivative exhibited the greatest cytotoxic effect among the series. The results showed that Au(III)/Pt(II) conjugates are more potent by 2-5.6-fold than the corresponding platinum complexes. Moreover, the dyad AuP-PtCyDA is 18% more potent and also more selective toward cancer cells than the parent gold porphyrin substituted with malonic acid. On the other hand, the IC50 of the dyad AuP-PtCyDA is 43% lower than that of AuTPP but is more selective toward healthy cells. Singlet oxygen measurements indicated that gold(III) porphyrin derivatives are poor oxygen sensitizers and cell death occurred potentially due to generation of other reactive oxygen species (ROS) upon reductive quenching of the gold porphyrin excited state. In addition, the increase in cancer cell death obtained after light irradiation is totally absent in healthy cells, demonstrating the specificity of this PDT treatment on cancer cells. Our findings imply that the incorporation of two different cytotoxic metals in the same molecule represents a remarkable cytotoxic effect in comparison to traditional homometallic Pt(II) drugs.

Fluorinated Polyethylenimine to Enable Transmucosal Delivery of Photosensitizer‐Conjugated Catalase for Photodynamic Therapy of Orthotopic Bladder Tumors Postintravesical Instillation

AbstractPhotodynamic therapy (PDT) by insertion of an optical fiber into the bladder cavity has been applied in the clinic for noninvasive treatment of bladder tumors. To avoid systemic phototoxicity, bladder intravesical instillation of a photosensitizer may be an ideal approach for PDT treatment of bladder cancer, in comparison to conventional intravenous injection. However, the instillation‐based PDT for bladder cancer treatment remains to be less effective due to the poor urothelial uptake of photosensitizer, as well as the tumor hypoxia‐associated PDT resistance. Herein, it is uncovered that fluorinated polyethylenimine (F‐PEI) achieved by mixing with Chorin‐e6‐conjugated catalase (CAT‐Ce6) is able to form self‐assembled CAT‐Ce6/F‐PEI nanoparticles, which show greatly improved cross‐membrane, transmucosal, and intratumoral penetration capacities compared with CAT‐Ce6 alone or nonfluorinated CAT‐Ce6/PEI nanoparticles. Owing to the decomposition of tumor endogenous H2O2 by CAT‐Ce6/F‐PEI nanoparticles penetrating into bladder tumors, the tumor hypoxia would be effectively relieved to further favor PDT. Therefore, bladder intravesical instillation with CAT‐Ce6/F‐PEI nanoparticles could offer remarkably improved photodynamic therapeutic effect to destruct orthotopic bladder tumors with reduced systemic toxicity compared to hematoporphyrin, the first‐line photosensitizer used for bladder cancer PDT in clinic. This work presents a unique photosensitizer nanomedicine formulation, promising for clinical translation in instillation‐based PDT to treat bladder tumors.