Antitumor Efficacy Of Photodynamic Therapy Research Articles

Schottky Barrier-Based Built-In Electric Field for Enhanced Tumor Photodynamic Therapy.

Photodynamic therapy's antitumor efficacy is hindered by the inefficient generation of reactive oxygen species (ROS) due to the photogenerated electron-hole pairs recombination of photosensitizers (PS). Therefore, there is an urgent need to develop efficient PSs with enhanced carrier dynamics. Herein, we designed Schottky junctions composed of cobalt tetroxide and palladium nanocubes (Co3O4@Pd) with a built-in electric field as effective PS. The built-in electric field enhanced photogenerated charge separation and migration, resulting in the generation of abundant electron-hole pairs and allowing effective production of ROS. Thanks to the built-in electric field, the photocurrent intensity and carrier lifetime of Co3O4@Pd were approximately 2 and 3 times those of Co3O4, respectively. Besides, the signal intensity of hydroxyl radical and singlet oxygen increased to 253.4% and 135.9%, respectively. Moreover, the localized surface plasmon resonance effect of Pd also enhanced the photothermal conversion efficiency of Co3O4@Pd to 40.50%. In vitro cellular level and in vivo xenograft model evaluations demonstrated that Co3O4@Pd could generate large amounts of ROS, trigger apoptosis, and inhibit tumor growth under near-infrared laser irradiation. Generally, this study reveals the contribution of the built-in electric field to improving photodynamic performance and provides new ideas for designing efficient inorganic PSs.

Nanoplatform-based strategies for enhancing the lethality of current antitumor PDT.

Photodynamic therapy (PDT) exhibits great application prospects in future clinical oncology due to its spatiotemporal controllability and good biosafety. However, the antitumor efficacy of PDT is seriously hindered by many factors, including tumor hypoxia, limited light penetration ability, and strong defense mechanisms of tumors. Considering that it is difficult to completely solve the first two problems, enhancing the lethality of antitumor PDT has become a good idea to extend its clinical application. Herein, we summarize the nanoplatform-involved strategies to effectively amplify the tumoricidal capability of current PDT and then discuss the present bottlenecks and prospects of the nanoplatform-based PDT sensitization strategies in tumor therapy. We hope this review will provide some references for others to design high-performance PDT nanoplatforms for tumor therapy.

Experimental in vivo studies of the antitumor efficacy of photodynamic and radiodynamic therapy and their combinations

The authors studied the antitumor efficacy of photodynamic therapy (PDT) in combination with radiodynamic therapy (RDT) in an in vivo experiment. The study was approved by the Ethics Committee of the N.N. Alexandrov National Cancer Center of Belarus (protocol dated February 25, 2022, № 180). The work was performed on 26 white non-linear rats weighing 200 ± 50 g. Pliss lymphosarcoma (PLS) was used as a tumor model, which was transplanted subcutaneously. Photosensitizer (PS) «Photolon» (RUE «Belmedpreparaty», Belarus) was administered intravenously at a dose of 2.5 mg/kg of body weight. The RDT session was performed by the contact method (CRT) once 2.5–3 times after the end of the infusion of the PS on the «microSelectron-HDR V3 Digital apparatus» (Elekta, Sweden) using γ-radiation (192Ir) in a single focal dose 6 Gy. A PDT session was performed once immediately after exposure to ionizing radiation using a «PDT diode laser» (LTD Imaf Axicon, Belarus, λ=660±5 nm) at an exposure dose of 100 J/cm2 with a power density of 0.2 W/cm2 and a power of 0.353 watts. All rats were divided into 4 groups of 6–7 animals each: intact control (IC), PS + PDT, PS + CRT, PS + CRT + PDT. The criteria for evaluating antitumor efficacy were: the average volume of tumors (Vav, cm3 ), the coefficient of absolute growth of tumors (K, in RU), the coefficient of tumor growth inhibition (TGI, %), the frequency of complete tumor regressions (CR, %), the proportion of cured rats (%), an increase in the average duration of dead rats (%). Differences were considered statistically significant at p<0.05. On the 18th day of the experiment, Vav. in groups was 63.25±2.76 cm³; 29.03±6.06 cm³ (p=0.0002); 22.18±5.94 cm³ (р<0.0001); 11.76±3.29 cm³ (p=0.0000), respectively. Coefficients K – 4516.86 RU; 2638.09 RU; 2024.45 RU; 979.00 RU. TGI coefficients – 54.10% (PS + PDT); 64.93% (PS + CRT); 81.41% (PS + CRT + PDT). An increase in the average duration of dead rats indicator – 48.57% (PS + PDT); 60.00% (PS + CRT); 97.71% (PS + CRT + PDT). On the 60th and 90th days of the experiment, the frequency of PR and the proportion of cured rats were the same and amounted to 0%; 16.7%; 14.3%, and 28.6%, respectively. The results obtained indicate the prospects and relevance of further research in this scientific direction.

Photobiomodulation Improves Anti-Tumor Efficacy of Photodynamic Therapy against Resistant MCF-7 Cancer Cells.

Cancer resistance is a primary concern in cancer treatment, and developing an effective modality or strategy to improve therapeutic outcomes is imperative. Photodynamic therapy (PDT) is a treatment modality that targets the tumor with a photoactive molecule and light for the specific destruction of cancer cells. Photobiomodulation (PBM) is a light exposure of cells to energize their biomolecules to respond to therapy. In the present study, we used PBM to mediate and improve the anti-tumor efficacy of zinc phthalocyanine tetrasulfonic acid (ZnPcS4)-PDT on resistant MCF-7 breast cancer cells and explore molecular changes associated with cell death. Different laser irradiation models were used for PBM and PDT combination. The combined treatment demonstrated an additive effect on the viability and Annexin-V/PI-staining cell death assessed through MTT assay and mitochondrial release of cytochrome c. Rhodamine (Rh123) showed increased affinity to mitochondrial disruption of the strategic treatment with PBM and PDT. Results from the autophagy assay indicate an interplay between the mitochondrial and autophagic proteins. These findings were indicative that PBM might improve the anti-tumor of PDT by inducing autophagy in resistant MCF-7 breast cancer cells that evade apoptosis.

Efficacy of Photodynamic Therapy with Chlorine-Based Photosensitizer in the Treatment of Basal Cell Carcinomas

The aim of this study is to evaluate a safety and antitumor efficacy of photodynamic therapy (PDT) with chlorine-based photosensitizer (PS) for treatment patients with basal cell skin carcinomas (BCC).
 Material and Methods: The work was performed on the basis of the Department of hyperthermia and photodynamic therapy. The object of the study were 172 patients with a verified diagnosis of BCC (T1N0M0, I stage), who received treatment from 2007 to 2022. PS «Photolon» (RUE «Belmedpreparaty», Republic of Belarus) was administrated intravenously at a dose of 2.0-2.5 mg/kg. The session of PDT was performed 2.5-3 h after intravenous injection of PS using semiconductor lasers (λ=660±5 nm) with exposure doses 50-250 J/cm² and power density – 0.15-0.5 W/cm². Frequency and severity of side effects after treatment session was assessed based on the criteria CTCAE (Version 4.03; 2010). The antitumor efficacy was evaluated 3 months after treatment. Clinical outcome was evaluated visually and morphologically by cytological or histopathological examination. Performance criteria were as follows (according to WHO, 1979).
 Results: The phenomenon of skin phototoxicity due to violation of the light regime (hyperemia, burning, slight swelling of the soft tissues of the face; CTCAE, I-II grades) was registered in 5.8% of cases (n=10). Serious adverse reactions (anaphylactic shock, Quincke's edema, severe pain syndrome) after the administration of PS and photoirradiation were not identified. Complete and partial regressions of tumors was observed in 93.0% and 4.7% of patients, respectively. The objective answer was 97.7%. The frequency of local relapses of the disease 1, 2, 3, 4 and 5 years after PDT was 3.1%, 3.1%, 4.6%, 4.6% and 6.9%, respectively.
 Сonclusion: PDT is a well-tolerated and highly effective therapeutic option in patients with BCC.

Anti-Tumor Efficacy of Photodynamic Therapy of Solid Tumors in Laboratory Animals with Guanidine and Biguanidine Derivatives of Chlorine e6.

We evaluated antitumor efficacy of photodynamic therapy of murine Ehrlich carcinoma and rat sarcoma M-1 with new photosensitizers 131-N-(4-aminobutyl)amydo chlorine e6 (1), 132-(5-guanidylbutanamido)-chlorine e6 (2), and 132-(5-biguanidylbutanamido)-chlorine e6 (3). The inhibiting effect of the photodynamic therapy was evaluated by the following parameters: tumor growth inhibition, complete regression of the tumors, and absolute growth rate of the tumor nodes in animals with the continued neoplasia growth. The criterion of cure was the absence of tumors up to 90 days after the therapy. It is shown that the studied photosensitizers have high antitumor activity in the photodynamic therapy of the Ehrlich carcinoma and sarcoma M-1.

On the Pathomorphological Pattern of the Efficiency of Photodynamic Therapy of Murine Melanoma B16 Using a New Photosensitizer Based on Chlorin e6 Conjugate with a Prostate-Specific Membrane Antigen.

Photodynamic therapy (PDT) is an effective treatment for a number of solid malignancies. In this work, the antitumor efficacy of photodynamic therapy for murine B16 melanoma with intravenous administration of a new photosensitizer (PS) based on the chlorin e6 conjugate with a prostate-specific membrane antigen (PSMA) was studied in vivo. We have previously published the data obtained in the first part of the study: the dynamics of PS accumulation in the tumor and surrounding tissues and the antitumor efficacy of the photodynamic therapy, which was evaluated by the regression parameters and morphological characteristics of the tumors—including by the complete regression of the tumors, the absolute growth rate of the tumors among the mice with continued tumor growth, and an increase in life expectancy compared to the control. The criterion for a complete cure was the absence of signs of tumor recurrence within 90 days after therapy. The conducted studies demonstrated the high efficiency of the new photosensitizer for the photodynamic therapy of B16 melanoma. This article presents a continuation of this work, including histological studies of the zones exposed to laser irradiation on the 21st day after treatment and an assessment of the therapeutic potential of photodynamic therapy for the destruction of tumor cells. Pathological studies in the zones of photodynamic exposure revealed that the effectiveness of the PDT depended on the PS dose and the laser irradiation parameters.

A dual-responsive nanoplatform with feedback amplification improves antitumor efficacy of photodynamic therapy.

A good photosensitizer (PS) delivery system could enhance the efficiency and reduce the side effects of anti-tumor photodynamic therapy (PDT) by improving accumulation in the tumor, uptake by tumor cells, and intracellular release of the PS. Thus, we rationally developed a multi-stimulus-responsive PS nanocarrier with a double-layered core-shell structure: mPEG-azo-hyaluronic acid-sulfide-Ce6 (PaHAsC). In PaHAsC, the mPEG coat provides protection before entering the hypoxic tumor microenvironment, where mPEG leaves to expose the HA layer. HA then targets overexpressed CD44 on tumor cells for enhanced internalization. Finally, GSH-mediated intracellular release of Ce6 augments ROS generation and O2 consumption under light stimulation. This also aggravates hypoxia in tumor sites to accelerate mPEG removal, forming a positive feedback loop. Data show that PaHAsC dramatically improved the PDT efficacy of Ce6, eliminating most tumors and 80% of tumor-bearing mice survived. With a safe profile, PaHAsC has potential for further development and is a useful example of a PS delivery system.

Photodynamic Therapy of Melanoma B16 with Chlorin E6 Conjugated with a PSMA-Ligand.

The efficacy of a new photosensitizer of chlorin E6 conjugated with a prostate-specific membrane antigen (PSMA) in photodynamic therapy of murine melanoma B16 was studied in in vivo experiments. The dynamics of photosensitizer accumulation in the tumor and surrounding tissues was evaluated and antitumor efficacy of photodynamic therapy was assessed by parameters of regression and morphological characteristics of experimental transplanted melanoma B16. The inhibitory effect of photodynamic therapy on melanoma was evaluated by complete regression of the tumor, absolute tumor growth coefficient in animals with continuation of tumor growth, and the increase in life span in comparison with the control; the criterion of cure was the absence of signs of tumor recurrence in mice within 90 days after therapy. The therapeutic potential of photodynamic therapy was determined by devitalization of tumor cells (histological examination of the zones of laser exposure on day 21 after treatment). The photosensitizer with PSMA-ligand exhibited high antitumor activity in photodynamic therapy for melanoma B16. Photodynamic therapy carried out at the optimum time after photosensitizer injection with experimentally determined parameters of laser exposure allows achieving the maximum inhibitory effect on melanoma. Pathomorphological study in the zones of exposure detected no survived tumor cells.

Photodynamic therapy for preinvasive vaginal cancer.

5592 Background: Photodynamic therapy (PDT) is an effective method for the treatment of various cancers resulting in apoptosis, autophagy and ischemic necrosis of irradiated tissues. The purpose of the study was to analyze the efficacy of PDT for pre-invasive vaginal cancer treatment. Methods: PDT results were studied in 20 patients aged 32-65 years with verified pre-invasive vaginal cancer. All patients received PDT with the Latus diode laser and Photolon or Photolan photosensitizers. The effect was evaluated with extended colposcopy. The criteria for efficiency included normalization of the colposcopic picture and the absence of atypical cells. The sizes of the irradiation fields varied from 1.5 to 2 cm, the number of fields - from 1 to 4, the power density - from 0.1 to 0.17 W/cm2, the light dose - from 40 to 100 J/cm2. The duration of a PDT session varied from 10 to 30 min, depending on the number of irradiation fields. The irradiation field necessarily included an area of normal tissue 3-5 mm surrounding the lesion. 4 to 6 sessions were required to restore the normal layer of stratified squamous epithelium. The antitumor efficacy of PDT was evaluated based on the results of visual observation of changes in the area of the treated pathological foci and information on the presence or absence of clinical symptoms of the disease 1 and 3 months after the treatment (WHO criteria). Results: Complete regression was registered in 100% of patients after 3 months. Repeated courses of PDT were required in cases with a wide spread of pathological foci and the impossibility of their simultaneous irradiation. At follow-up after 1 month, 3 of 20 patients (15%) showed local foci of atypical changes in the epithelium managed with repeated PDT courses. In 6 months, stable remission of the disease clinical symptoms in the treated pathological foci was registered. The results of the cytological study performed 3 months after PDT were normal in 100% patients; no negative changes were registered 6 and 12 months after PDT. Conclusions: The results of PDT in the treatment of patients with pre-invasive vaginal cancer demonstrated its high therapeutic efficacy and a minimal number of adverse reactions, which allows recommending PDT in the treatment of pre-invasive vaginal cancer.

Zeolitic Imidazolate Framework Platform for Combinational Starvation Therapy and Oxygen Self-Sufficient Photodynamic Therapy against a Hypoxia Tumor.

The antitumor efficacy of photodynamic therapy (PDT) is greatly impeded by the nonspecific targeting of photosensitizers and limited oxygen supply in hypoxic tumors. Aiming to overcome the problem, a dual-locked porphyrin/enzyme-loading zeolitic imidazolate framework (ZIF) nanoplatform was constructed for starvation therapy and O2 self-sufficient PDT. The fluorescence recovery and PDT of photosensitizers could be cooperatively triggered by dual pathological parameters, the low pH and overexpressed GSH in tumor tissues, which makes the PDT process conduct precisely in a tumor microenvironment. The cascade catalysis of glucose oxidase and catalase promotes the nanoplatform dissociation, inhibits the energy supply of tumors (starvation therapy), and provides enough O2 to ameliorate the hypoxia and enhance PDT efficacy. In vitro and in vivo studies were performed to confirm the high antitumor efficacy of the porphyrin/enzyme-loading ZIF nanoplatform. Thus, this work offers a path for precise and efficient PDT-based combination therapy against a hypoxia tumor.

Transforming growth factor-β blockade modulates tumor mechanical microenvironments for enhanced antitumor efficacy of photodynamic therapy.

Photodynamic therapy (PDT) is frequently used in cancer treatment in clinical settings. However, its applications in stroma-rich solid tumors, e.g., triple negative breast cancer, are limited by abnormal mechanical microenvironments. Solid stress accumulated in stroma-rich solid tumors compresses tumor blood vessels, hampers the delivery of photosensitizers (PSs) in tumor tissues, and poses a major challenge for potent PDT. Here, we report a novel combination strategy to augment PDT based cancer therapy by combining hydroxyethyl starch-chlorin e6 conjugate self-assembled nanoparticles (HES-Ce6 NPs) with the transforming growth factor-β (TGFβ) inhibitor LY2157299 (LY). HES-Ce6 conjugates, as synthesized by one step esterification reaction, could self-assemble into uniform HES-Ce6 NPs, which exhibited enhanced photostability and generated more reactive oxygen species (ROS) under 660 nm laser irradiation than free Ce6. Prior to PDT, intragastric administration of LY decreased collagen deposition, alleviated solid stress, and decompressed tumor blood vessels. As a result, the reconstructed tumor mechanical microenvironment promoted accumulation and penetration of HES-Ce6 NPs into tumor tissues, contributing to augmented antitumor efficacy of HES-Ce6 NP mediated PDT. Modulating tumor mechanical microenvironments using TGFβ blockade to enhance the delivery of PSs in tumors with excessive extracellular matrix represents an efficient strategy for treating stroma-rich solid tumors.

Photodynamic therapy in patients with skin metastases of disseminated melanoma

The aim of the study was to evaluate the immediate results of photodynamic therapy (PDT) in patients with intradermal metastases of skin melanoma. The study included 50 patients who received treatment at the department of hyperthermia and photodynamic therapy. The study included 23 (46%) men and 27 (54%) women with an average age of 60.7±10.4 years. PDT of tumors was carried out 3–4 hours after intravenous administration of a chlorine-based photosensitizer (Photolon) in doses of 1.5–3 mg/kg using a semiconductor laser «UPL-PDT» (Lemt, Belarus, λ=660±5 nm). The exposure doses varied from 100 to 400 J/cm2; power density – from 0.2 to 0.9 W/cm2; power – from 0.25 to 1 W and time of PDT of one focus was dependent on the size and location of the tumor and was 5 to 20 minutes. Evaluation of antitumor efficacy of PDT was carried out according to WHO criteria. The terms of follow-up of patients were between 3 and 23 months. At follow-up observation, 1–3 months after the treatment, complete regression of intradermal metastases of skin melanoma was achieved in 9 (18%) patients, partial – in 28 (56%), process stabilization in 8 (16%) and progression in 5 (10%)) patients. The objective effect was achieved in 74% of patients, the therapeutic – in 90%. PDT can be used in the treatment of intradermal metastases of disseminated skin melanoma with palliative purposes and allows reducing the tumor volume, which significantly improves the quality of life of patients.

Multifunctional Micelles Dually Responsive to Hypoxia and Singlet Oxygen: Enhanced Photodynamic Therapy via Interactively Triggered Photosensitizer Delivery.

Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from the limited dose accumulation in tumor. Herein, we report dually hypoxia- and singlet oxygen-responsive polymeric micelles to efficiently utilize the photosensitizer deposited in the disease site and hence facilely improve PDT's antitumor efficacy. Tailored methoxy poly(ethylene glycol)-azobenzene-poly(aspartic acid) copolymer conjugate with imidazole as the side chains was synthesized. The conjugate micelles (189 ± 19 nm) obtained by self-assembly could efficiently load a model photosensitizer, chlorin e6 (Ce6) with a loading of 4.1 ± 0.5% (w/w). The facilitated cellular uptake of micelles was achieved by the triggered azobenzene collapse that provoked poly(ethylene glycol) shedding; rapid Ce6 release was enabled by imidazole oxidation that induced micelle disassembly. In addition, the singlet oxygen-mediated cargo release not only addressed the limited diffusion range and short half-life of singlet oxygen but also decreased the oxygen level, which could in turn enhance internalization and increase the intracellular Ce6 concentration. The hypoxia-induced dePEGylation and singlet oxygen-triggered Ce6 release was demonstrated both in aqueous buffer and in Lewis lung carcinoma (LLC) cells. The cellular uptake study demonstrated that the dually responsive micelles could deliver significantly more Ce6 to the cells, which resulted in a substantially improved cytotoxicity. This concurred well with the superior in vivo antitumor ability of micelles in a LLC tumor-bearing mouse model. This study presented an intriguing nanoplatform to realize interactively triggered photosensitizer delivery and improved antitumor PDT efficacy.

Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway

We and others have shown that stresses, including photodynamic therapy (PDT), can disrupt the de novo sphingolipid biosynthesis pathway, leading to changes in the levels of sphingolipids, and subsequently, modulation of cell death. The de novo sphingolipid biosynthesis pathway includes a ceramide synthase-dependent reaction, giving rise to dihydroceramide, which is then converted in a desaturase-dependent reaction to ceramide. In this study we tested the hypothesis that combining Foscan-mediated PDT with desaturase inhibitor fenretinide (HPR) enhances cancer cell killing. We discovered that by subjecting SCC19 cells, a human head and neck squamous cell carcinoma cell line, to PDT+HPR resulted in enhanced accumulation of C16-dihydroceramide, not ceramide. Concomitantly, mitochondrial depolarization was enhanced by the combined treatment. Enhanced activation of caspase-3 after PDT+HPR was inhibited by FB. Enhanced clonogenic cell death after the combination was sensitive to FB, as well as Bcl2- and caspase inhibitors. Treatment of mouse SCCVII squamous cell carcinoma tumors with PDT+HPR resulted in improved long-term tumor cures. Overall, our data showed that combining PDT with HPR enhanced apoptotic cancer cell killing and antitumor efficacy of PDT. The data suggest the involvement of the de novo sphingolipid biosynthesis pathway in enhanced apoptotic cell killing after PDT+HPR, and identify the combination as a novel more effective anticancer treatment than either treatment alone.

Antitumor Efficacy of Photodynamic Therapy Using Novel Nanoformulations of Hypocrellin Photosensitizer SL052

Recent preclinical and clinical testing of hypocrellin-based photosensitizer SL052 for use in photodynamic therapy (PDT) of cancer has shown encouraging results. Further optimization of its formulation for delivery could considerably extend the therapeutic efficiency of this drug. A nanoformulation encapsulating SL052 into biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) was developed using a single-emulsion solvent evaporation technique and characterized in terms of particle size and loading of the photosensitizing agent. This nanoformulation, SL052-PLGA-nanoparticles (NPs), was compared with recently created nanoformulation based on polyvinylpyrrolidone (SL052-PVP-NPs) and standard liposomal SL052 preparation in terms of efficacy when used for PDT treatment of squamous cell carcinomas SCCVII growing subcutaneously in syngeneic mice. The therapeutic effect of PDT using these three different SL052 formulations was tested for both 1 and 4 h intervals between drug injection and tumor light exposure. The longer time interval produced higher tumor cure rates with all SL052 preparations. With both drug-light intervals, PDT based on SL052-PLGA-NPs produced superior therapeutic benefit compared with the other two SL052 formulations.

IL-6 potentiates tumor resistance to photodynamic therapy (PDT)

Photodynamic therapy (PDT) is an anticancer modality approved for the treatment of early disease and palliation of late stage disease. PDT of tumors results in the generation of an acute inflammatory response. The extent and duration of the inflammatory response is dependent upon the PDT regimen employed and is characterized by rapid induction of proinflammatory cytokines, such as IL-6, and activation and mobilization of innate immune cells. The importance of innate immune cells in long-term PDT control of tumor growth has been well defined. In contrast the role of IL-6 in long-term tumor control by PDT is unclear. Previous studies have shown that IL-6 can diminish or have no effect on PDT antitumor efficacy. In the current study we used mice deficient for IL-6, Il6(-/-) , to examine the role of IL-6 in activation of antitumor immunity and PDT efficacy by PDT regimens known to enhance antitumor immunity. Our studies have shown that elimination of IL-6 had no effect on innate cell mobilization into the treated tumor bed or tumor draining lymph node (TDLN) and did not affect primary antitumor T-cell activation by PDT. However, IL-6 does appear to negatively regulate the generation of antitumor immune memory and PDT efficacy against murine colon and mammary carcinoma models. The inhibition of PDT efficacy by IL-6 appears also to be related to regulation of Bax protein expression. Increased apoptosis was observed following treatment of tumors in Il6(-/-) mice 24 hours following PDT. The development of PDT regimens that enhance antitumor immunity has led to proposals for the use of PDT as an adjuvant treatment. However, our results show that the potential for PDT induced expression of IL-6 to enhance tumor survival following PDT must be considered.