Combination Of Photodynamic Therapy Research Articles

In vivo Realization of Dual Photodynamic and Photothermal Therapy for Melanoma by Mitochondria Targeting Dinuclear Ruthenium Complexes under Civil Infrared Low-power Laser.

A series of dinuclear RuII complexes with extremely high TPA cross sections in the range of 800-900 nm have been designed. The amphiphilic complex Ru3 containing tert-butyl groups has balanced performance in singlet oxygen generation and photothermal conversion and becomes the ideal drug candidate of the series. Ru3 targets mitochondria without penetrating the nucleus, which substantially increases its photodynamic therapy activity and reduces its dark cytotoxicity. Ru3 successfully suppresses melanoma tumor growth in vitro and in vivo with combined photodynamic and photothermal therapy under low light dose irradiation of an 808 nm low-power laser, avoiding the known PDT resistance in melanoma. The excellent therapeutic effect of Ru3 facilitates its applications in further human trials for larger or deeper buried tumors, thereby becoming a prospective candidate for a new generation of low-power IR-driven dual PDT/PTT drugs.

In vivo Realization of Dual Photodynamic and Photothermal Therapy for Melanoma by Mitochondria Targeting Dinuclear Ruthenium Complexes under Civil Infrared Low‐power Laser

AbstractA series of dinuclear RuII complexes with extremely high TPA cross sections in the range of 800–900 nm have been designed. The amphiphilic complex Ru3 containing tert‐butyl groups has balanced performance in singlet oxygen generation and photothermal conversion and becomes the ideal drug candidate of the series. Ru3 targets mitochondria without penetrating the nucleus, which substantially increases its photodynamic therapy activity and reduces its dark cytotoxicity. Ru3 successfully suppresses melanoma tumor growth in vitro and in vivo with combined photodynamic and photothermal therapy under low light dose irradiation of an 808 nm low‐power laser, avoiding the known PDT resistance in melanoma. The excellent therapeutic effect of Ru3 facilitates its applications in further human trials for larger or deeper buried tumors, thereby becoming a prospective candidate for a new generation of low‐power IR‐driven dual PDT/PTT drugs.

Type I photodynamic therapy with a self-degradable conjugated polyelectrolyte in combination with CpG adjuvant for cancer immunotherapy

In Photodynamic therapy (PDT), reactive oxygen species (ROS) generated by photosensitizers (PSs) can cause endoplasmic reticulum oxidative stress response to induce immunogenic cell death (ICD). However, most PDT-induced ICD cannot generate enough antitumor immune responses to inhibit metastatic cancer. Here, we developed a self-degradable conjugated polyelectrolyte (CP+) to load the immune adjuvant (CpG) for the combination of PDT and immunotherapy. Interestingly, the final nanoparticles (CP+-CpG NPs) can effectively generate superoxide radical (O2−•) through type-I process under light irradiation, which is ideal for hypoxic tumor treatment. Meanwhile, CP+-CpG NPs can be degraded by the self-generated O2−• in return to release the CpG. The release of CpG can further promote PDT-induced ICD, activating immune responses and inducing systemic antitumor immunity. Taken together, a novel strategy has been developed to enhance PDT therapeutic effects and induce immunotherapy, which is greatly promising for cancer treatment in the future.

Iridium Complex-Loaded Sorafenib Nanocomposites for Synergistic Chemo-photodynamic Therapy of Hepatocellular Carcinoma.

Although sorafenib, a multi-kinase inhibitor, has provided noteworthy benefits in patients with hepatocellular carcinoma (HCC), the inevitable side effects, narrow therapeutic window, and low bioavailability seriously affect its clinical application. To be clinically distinctive, innovative drugs must meet the needs of reaching tumor tissues and cause limited side effects to normal organs and tissues. Recently, photodynamic therapy, utilizing a combination of a photosensitizer and light irradiation, was selectively accumulated at the tumor site and taken up effectively via inducing apoptosis or necrosis of cancer cells. In this study, a nano-chemo-phototherapy drug was fabricated to compose an iridium-based photosensitizer combined with sorafenib (IPS) via a self-assembly process. Compared to the free iridium photosensitizer or sorafenib, the IPS exhibited significantly improved therapeutic efficacy against tumor cells because of the increased cellular uptake and the subsequent simultaneous release of sorafenib and generation of reactive oxygen species production upon 532 nm laser irradiation. To evaluate the effect of synergistic treatment, cytotoxicity detection, live/dead staining, cell proliferative and apoptotic assay, and Western blot were performed. The IPS exhibited sufficient biocompatibility by hemolysis and serum biochemical tests. Also, the results suggested that IPS significantly inhibited HCC cell proliferation and promoted cell apoptosis. More importantly, marked anti-tumor growth effects via inhibiting cell proliferation and promoting tumor cell death were observed in an orthotopic xenograft HCC model. Therefore, our newly proposed nanotheranostic agent for combined chemotherapeutic and photodynamic therapy notably improves the therapeutic effect of sorafenib and has the potential to be a new alternative option for HCC treatment.

Red fluorescent AIEgens based multifunctional nonviral gene vectors for the efficient combination of gene therapy and photodynamic therapy in anti-cancer

Precise molecular engineering of AIEgens-based cationic delivery systems for high transfection efficiency (TE) and effective photodynamic therapy (PDT) holds a huge potential for cancer treatment. Herein, three amphiphiles (DT-C6/8/12-M) consisting of di(triazole-[12]aneN3) (M) and 1,1-dicyano-2-phenyl-2-(4-diphenylamino)phenyl-ethylene (DT) units have been developed to achieve luminescent tracking, efficient TE, and effective PDT in vitro and in vivo. These compounds exhibited strong aggregated induced emission (AIE) at 630 nm and mega Stokes shifts of up to 160 nm. They were able to bind DNA into nanoparticles with suitable sizes, positive surface potential, and good biocompatibility in the presence of DOPE. Among them, vector DT-C12-M/DOPE with n-dodecyl linker achieved a transfection efficiency as high as 42.3 folds that of Lipo2000 in PC-3 cell lines. DT-C12-M/DOPE exhibited the capability of successful endo/lysosomal escape and rapid nuclear delivery of pDNA, and the gene delivery process was clearly monitored via confocal laser scanning microscopy. Moreover, efficient reactive oxygen species (ROS) generation by DT-C12-M upon light irradiation led to effective PDT in vitro . We further show that combination of p53 gene therapy and PDT dramatically enhanced cancer therapeutic outcome in vivo. This “three birds, one stone” strategy offers a novel and promising approach for real-time tracking of gene delivery and better cancer treatment

Enhancement of the cytotoxic effect of dihydroartemisinin in high-risk human papillomavirus-infected cells by aminolevulinic acid via the Bax/Bcl-2-caspase pathway

BackgroundTraditional treatments for human papillomavirus-related cutaneous diseases include 5-aminolevulinic acid photodynamic therapy, cryotherapy, microwave ablation, and surgical resection. These treatment methods involvevarious adverse reactions; therefore, it remains necessary to explore new treatment methods. Dihydroartemisinin shows cytotoxic effects against several malignancies by producing reactive oxygen species, and heme environments reportedly enhance its activity. However, the underlying mechanismsare still unclear. Therefore, we investigated the mechanism of dihydroartemisininin inhuman papillomavirus-infected cells. MethodsHeLa cells were treated with dihydroartemisinin, 5-aminolevulinic acid, and succinylacetone. The cell viability, apoptosis, mitochondrial membrane potential, and reactive oxygen species levels were investigated, and via western blotting analysis and polymerase chain reaction, dihydroartemisinin activity-related pathways were also determined. ResultsDihydroartemisinin inhibited HeLa cell proliferation and promoted cell apoptosis via the Bax/Bcl-2-Caspase pathway in a concentration-dependent manner. The specific cytotoxicity toward HeLa cells was enhanced by the addition of 5-aminolevulinic acid, a clinically used heme-synthesis precursor, owing to an increase in heme levels. Conversely, following the addition of succinylacetone, a heme synthesis blocker, heme levels decreased. Furthermore, dihydroartemisinin significantly increased reactive oxygen species levels as intracellular heme synthesis increased. Moreover, photodynamic therapy following dihydroartemisinin and 5-aminolevulinic acid treatment further enhanced the cytotoxic effect of dihydroartemisinin on high-risk human papillomavirus-infected cells. ConclusionsDihydroartemisinin exerts acytotoxic effect on high-risk human papillomavirus-infected cells by modulating heme levels via the Bax/Bcl–2-Caspase pathway, and the dihydroartemisinin, 5-aminolevulinic acid, photodynamic therapy combination treatment significantly enhanced its cytotoxic effect on human papillomavirus-infected cells.

Sinoporphyrin sodium (DVDMS)- loaded nanoliposomes- mediated B-mode ultrasound- guided sono- photodynamic combination therapy of early stage atherosclerosis

Background and Aims : Excessive lipid accumulation by macrophages plays a crucial role in atherosclerosis. Sinoporphyrin sodium (DVDMS) is a novel sensitizer and widely used in photodynamic and sonodynamic therapy. We developed an experimental sono- photodynamic combination therapy system and investigated its effectiveness on macrophages- derived foam cells density (inflammation) reduction.

Photodynamic therapy in combination with photothrombosis therapy of atherosclerotic plaques with neovessels, using rose bengal and polarized green laser

Background and Aims : Atherosclerotic lesions are considered to be advanced when the accumulation of lipid, immune cells, and matrix is associated with the disorganization, thickening and deformity of the arterial wall. One of the most vulnerable type of advanced atherosclerotic plaques, is neovessels- rich plaque. In this study, we investigated the effectiveness of combined photodynamic therapy and photothrombosis therapy on the intraplaque neovessels reduction, wherein a high resolution diagnostic ultrasound is adjuncted with the therapy system, with a goal of increased safety.

In vitro 5-Fluorouracil resistance produces enhanced photodynamic therapy damage in SCC and tumor resistance in BCC.

Non-melanoma skin cancer (NMSC) is the most common malignancy worldwide, with rising incidence in the recent years. It includes basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Several non-invasive therapies have been developed for its treatment such as topical 5-Fluorouracil (5FU) and photodynamic therapy (PDT), among others. Despite both are appropriated for NMSC treatment, recurrence cases have been reported. To prevent this, in this work we explore the potential of the combination of PDT and 5FU to treat SCC and BCC. First we evaluate the efficacy of PDT in cells resistant to 5FU. For this purpose, we use SCC-13 and CSZ-1 cells, obtained from a human SCC and a murine BCC, respectively. We first induced 5FU resistance in these cell lines by repeated treatments with the drug and then, the efficacy to PDT was evaluated. The results obtained indicated that SCC-5FU resistant cells were sensible to PDT administration, whereas BCC-5FU resistant cells were also resistant to PDT. The observed responses in both cell lines are in concordance to Protoporphyrin IX (PpIX) and reactive oxygen species (ROS) levels produced after the incubation with MAL and subsequent light exposure. The obtained data support the fact that PDT seems to be an appropriate therapeutic option to be administered after 5FU resistance in SCC. However, PDT would not be a choice therapy for resistant BCC cells to 5FU.

Argon laser- mediated thermal angioplasty of occluded artery accompanied by combined rose bengal and riboflavin- loaded nanoliposomes- mediated catheter- based polarized green laser photodynamic therapy

Background and Aims : The atherectomy methods that are currently in use, cause to inflammation and the subsequent restenosis. The aim of this study was to evaluate the effect of combined photodynamic therapy on inflammation and intimal hyperplasia reduction after laser angioplasty.

Photodynamic therapy of cervical intraepithelial neoplasia and cervical cancer

Purpose: to study the effectiveness of photodynamic therapy in combination with diathermoelectroconization in the treatment of cervical intraepithelial neoplasia and cervical cancer.Materials and methods. The study included 108 patients aged 33.13 ± 1.18 years. Human papillomavirus was detected in all patients. The study group consisted of 62 patients with cervical diseases. The fi rst subgroup included 28 patients with moderate to severe cervical intraepithelial neoplasia and pT1AN0M0 cervical cancer who underwent diathermoelectroconization and photodynamic therapy. The second subgroup included 34 patients with severe cervical intraepithelial neoplasia who underwent only cervical diathermoelectroconization. The control group included 46 patients with unchanged cervix. To carry out fl uorescent diagnostics and photodynamic therapy, the patients of the fi rst subgroup were intravenously injected with a solution of photosensitizer “Fotoditazin” (“Vetagrand”, Russia) at a dose of 0.8–1.2 mg/kg. Three hours later, using the AFS device (“Polironik”, Russia), fl uorescent diagnostics was performed followed by photodynamic therapy with an ALHT-ELOMED laser (“Elomed”, Russia) in continuous mode. The wavelength was 662 nm, the output power – 3 W, the radiation dose – 200–300 J/cm2 for the cervix and 100–125 J/cm2 – for the cervical canal. All patients underwent complex antiviral therapy.Results. All patients after photodynamic therapy showed complete eradication of human papillomavirus and regression of cervical intraepithelial neoplasia. Morphological studies have shown that the effectiveness of combined treatment of moderate and severe cervical intraepithelial neoplasia, reaching 100 %, was higher than with the use of diathermoelectroconization alone (95 %). There were no recurrences of cervical intraepithelial neoplasia and cervical cancer after combined treatment.Conclusion. Photodynamic therapy of cervical intraepithelial neoplasia and cervical cancer is a highly effective method.

Light triggered release of a triple action porphyrin-cisplatin conjugate evokes stronger immunogenic cell death for chemotherapy, photodynamic therapy and cancer immunotherapy

Photodynamic therapy (PDT) has emerged as an attractive therapeutic approach which can elicit immunogenic cell death (ICD). However, current ICD inducers are still very limited as the representative ICD induces of photosensitizers can only evoke insufficient ICD to achieve unsatisfactory cancer immunotherapy. Herein, we demonstrated the use of a triple action cationic porphyrin-cisplatin conjugate (Pt-1) for drug delivery by a reactive oxygen species (ROS) sensitive polymer as nanoparticles (NP@Pt-1) for combined chemotherapy, PDT and immunotherapy. This unique triple action Pt-1 contains both chemotherapeutic Pt drugs and Porphyrin as a photosensitizer to generate ROS for PDT. Moreover, the ROS generated by Pt-1 can on the one hand degrade polymer carriers to release Pt-1 for chemotherapy and PDT. On the other hand, the ROS generated by Pt-1 subsequently triggered the ICD cascade for immunotherapy. Taken together, we demonstrated that NP@Pt-1 were the most effective and worked in a triple way. This study could provide us with new insight into the development of nanomedicine for chemotherapy, PDT as well as cancer immunotherapy.

Iridium photosensitizer constructed liposomes with hypoxia-activated prodrug to destrust hepatocellular carcinoma

Hypoxic tumor microenvironment is a major challenge for photodynamic therapy (PDT). To overcome this problem, PDT combined hypoxia-activated chemotherapy is a promising strategy for hypoxic cancer therapy. Herein, a multifunctional liposome (AQ4N-Ir1-sorafenib-liposome) is prepared by encapsulating a hypoxia-activated prodrug AQ4N, a photosensitizer iridium(III) complex and hepatocellular carcinoma (HCC) targeting drug sorafenib, for synergistic therapy of HCC. Ir1-mediated PDT upon irradiation induces ROS generation and hypoxic environment, which leads to the disassembly of the liposome and activates the antitumor activity of AQ4N. Meantime, the co-delivered sorafenib could effectively target therapy of HCC. It is noted that ferroptosis mechanism is proved during the treatment. This work contributes to the design of hypoxia-responsive multifunctional liposome for combination of chemotherapy, targeting therapy and PDT. It is a promising strategy for hypoxic HCC therapy.

A pH-response multifunctional nanoplatform based on NaGdF4:Yb,Er,Fe@Ce6@mSiO2-DOX for synergistic photodynamic/chemotherapy of cancer cells

Cancer is one of the major diseases that seriously threaten human health. Drug delivery nanoplatforms for tumor treatment have attracted increasing attention owing to their unique advantages such as good specificity and few side effects. This study aimed to fabricate a pH-responsive drug release multifunctional nanoplatform NaGdF 4 :Yb,Er,Fe@Ce6@mSiO 2 -DOX. In the platform, Fe 3+ doping enhanced the fluorescence intensity of NaGdF 4 :Yb, Er by 5.8 folds, and the mSiO 2 shell substantially increased the specific surface area of nanomaterials (559.257 m 2 /g). The loading rates of chlorin e6 and doxorubicin hydrochloride (DOX) on NaGdF 4 :Yb,Er,Fe@Ce6@mSiO 2 -DOX reached 28.58 ± 0.85% and 87.53 ± 5.53%, respectively. Additionally, the DOX release rate from the nanoplatform was only 24.4% after 72 h at pH 7.4. However, under tumor microenvironment conditions (pH 5.0), the release rate of DOX increased to 85.3% after 72 h. The nanoplatform could generate reactive oxygen species (ROS) under 980 nm near-infrared excitation. Moreover, the nanoplatform exhibited a strong comprehensive killing efficiency against cancer cells. The viabilities of HeLa, MCF-7, and HepG2 cancer cells were only 18.5, 11.4, and 9.3%, respectively, after being treated with a combination of photodynamic therapy and chemotherapy. The constructed nanoplatform exhibits great application potential in cancer treatment.

Time Rules the Efficacy of Immune Checkpoint Inhibitors in Photodynamic Therapy (Adv. Sci. 21/2022)

Time Determines the Combined Effect In article number 2200999, Lei Luo and co-workers reveal the importance of “time” in the combination of photodynamic therapy and immune checkpoint blocking therapy. Immune checkpoint inhibitors (red cartoon people) need to intervene at the best timing of T cell infiltration to exert the best anti-tumor and anti-metastatic efficacy.

A mutually beneficial macrophages-mediated delivery system realizing photo/immune therapy.

The accumulation of nanomedicines in tumor tissues determines their therapeutic efficacy. We herein exploit the tropism of macrophages to improve the accumulation and retention time of nanomedicine at tumors. Interestingly, macrophages are not merely as transporters, but killers activated by nanomedicine. The system(M@C-HA/ICG) was established by decorating macrophages with hyaluronic acid-modified hollow mesoporous carbon (C) nanoparticles loading indocyanine green (ICG). Notably, C nanoparticles with superior photothermal conversion capability not merely guarantee the efficient delivery of ICG through high drug loading efficiency and inhibiting the premature leaky, but effectually activate the polarization of macrophages. The results exhibited that those activated macrophages could release pro-inflammatory cytokines (NO, TNF-α, IL-12), while M@C-HA/ICG afforded about 2-fold higher tumor accumulation compared with pure nanoparticle C-HA/ICG and produced heat and singlet oxygen (1O2) under irradiation of an 808nm laser, realizing the combination of photodynamic therapy (PDT), photothermal therapy (PTT) and cytokines-mediated immunotherapy. Specially, we also investigated the relationship of singlet oxygen (1O2) or temperature and tumor-killing activity for understanding the specific effectual procedure of PDT/PTT synergistic therapy. Overall, we firstly established an "all active" delivery system integrating the features of nanomedicine with biological functions of macrophages, providing a novel insight for cell-mediated delivery platform and tumor targeted multimodality anti-cancer therapy.

Combined Photothermal and Photodynamic Therapy for Cancer Treatment Using a Multifunctional Graphene Oxide.

Graphene oxide (GO) is one of the most studied nanomaterials in many fields, including the biomedical field. Most of the nanomaterials developed for drug delivery and phototherapies are based on noncovalent approaches that lead to an unspecific release of physisorbed molecules in complex biological environments. Therefore, preparing covalently functionalized GO using straightforward and versatile methods is highly valuable. Phototherapies, including photothermal therapy (PTT) and photodynamic therapy (PDT), have shown great potential as effective therapeutic approaches against cancer. To overcome the limits of a single method, the combination of PTT and PDT can lead to a combined effect with a higher therapeutic efficiency. In this work, we prepare a folic acid (FA) and chlorin e6 (Ce6) double-functionalized GO for combined targeted PTT/PDT. This conjugate can penetrate rapidly into cancer cells and macrophages. A combined effect of PTT and PDT is observed, leading to a higher killing efficiency toward different types of cells involved in cancer and other diseases. Our work provides a simple protocol to prepare multifunctional platforms for the treatment of various diseases.

Advantages of combined photodynamic therapy in the treatment of oncological diseases.

When conducting combined therapy of malignant neoplasms, treatment methods with various mechanisms of antitumor effects are used, while an additive or even synergistic effect can be realized. Combination treatment regimens are aimed at increasing the efficiency and, above all, at the complete eradication of the tumor, which can be achieved either by suppressing the survival mechanisms in PDT-resistant tumor cells or by pre-attenuation of tumor cells so that they become more susceptible to subsequent PDT. Photodynamic therapy is an approved medical technology for the treatment of various malignant neoplasms, and several precancerous and non-cancer diseases. To date, numerous data have been published on the combined use of PDT with traditional and innovative methods of treatment. This review considers research in this area in recent years.

Multifunctional Hybrid Hydrogel System Enhanced the Therapeutic Efficacy of Treatments for Postoperative Glioma.

Glioma is the most lethal brain tumor with a poor prognosis, and a combination of multiple therapeutic strategies is critical for postoperative glioma treatment. Herein, a multifunctional hybrid hydrogel system (designated as CP&CL@RNPPTX-Gel) was developed for local treatment of postoperative glioma. The system was composed of self-illuminating chlorin e6 (Ce6) conjugated with luminol molecule (CL)-loaded glioma-targeting paclitaxel prodrug nanoparticles and copper peroxide nanodots (CP NDs) coembedded into a three-dimensional thermosensitive hydroxypropyl chitin hydrogel frame. After injection of CP&CL@RNPPTX-Gel into the cavity of postoperative glioma, the solution could be cross-linked into the gel as a drug reservoir under body temperature stimulation. Then, the sustained-released CP NDs decomposed into Cu2+ and H2O2 in the acidic microenvironment of the glioma cells to exert chemodynamic therapy (CDT). Meanwhile, Cu2+ could catalyze the self-luminescence of CL to induce photodynamic therapy (PDT) without external excitation light. Moreover, paclitaxel prodrug nanoparticles degraded into paclitaxel to restrain residual glioma cells in response to intracellular reduced glutathione (GSH). The in vitro and in vivo results showed that CP&CL@RNPPTX-Gel had great potential as a multifunctional hybrid hydrogel system with remarkable therapeutic effects for postoperative glioma treatment via a combination of chemotherapy, CDT, and PDT.

Combination of Photodynamic Therapy and Oral Antifungals for the Treatment of Onychomycosis

Onychomycosis accounts for 50% of nail disorders, making it one of the most prevalent fungal diseases and a therapeutic challenge. Photodynamic therapy (PDT) could constitute a therapeutic alternative, owing to its good adherence, the low probability of resistance, the lack of interaction with antimicrobials, and its favorable adverse effect profile. This retrospective observational study included all patients with a microbiological diagnosis of onychomycosis treated with PDT at Miguel Servet University Hospital, Zaragoza (Spain), between January 2013 and June 2021. The protocol consisted of pre-treatment with 40% urea for 7 days, followed by 16% methyl-aminolevulinate (MAL) for 3 h and subsequent irradiation with a red-light LED lamp (37 J/cm2), every 1 or 2 weeks. Combined treatment with oral and/or topical antifungals was recorded. Of the 20 patients included (mean age, 59 ± 17 years), 55% were men. The most frequently detected microorganism was Trichophyton rubrum (55%). The most commonly affected location was the feet (90%): 50% of these cases were associated with tinea pedis. The median (standard deviation) number of PDT sessions was 6 (2.8). PDT was combined with systemic terbinafine (250 mg/day) in 10 cases (in 8 cases, this was administered for only 1 month), and with topical terbinafine in 3 cases. A complete clinical response was achieved in 80% (16) of cases and microbiological cure in 60% (12). PDT is a therapeutic alternative for onychomycosis, and can be administered either in monotherapy or combined with antifungals, allowing for a reduction in the duration and possible adverse effects of antifungal treatment and achieving higher cure rates than those obtained with either treatment alone.