Single Photodynamic Therapy Research Articles

Imaging treatment efficacy of repeated photodynamic therapy in glioblastoma using chemical exchange transfer saturation MRI.

To observe the tumor responses during photodynamic therapy in a murine glioblastoma model using chemical exchange saturation transfer (CEST) MRI and to compare the treatment effectiveness between single photodynamic therapy (sPDT) and repeated PDT (rePDT). After tumor cell implantation in NSG mouse brain(n = 27), mice were subjected to four PDT sessions (rePDT), sPDT after the administration of 5-aminolevulinic acid 6 h before each session, and a non-PDT session (control). A 630-nm LED light was used to effectuate PDT. After 24 h for each PDT session, T2-weighted and CEST MRI were performed over 7 days. We observed that rePDT resulted in a continuous suppression of tumors according to T2-weighted images; thus, the tumor volume was the smallest among three groups on Day 7. Both CEST contrasts at 3.5 ppm (amide proton transfer, APT) and 3.5 ppm (relayed nuclear Overhauser enhancement, rNOE) in the rePDT group were significantly lower (p < 0.05) than those in the control group starting from Day 5, which corresponds to lower protein and cellularity in tumors in the rePDT group, respectively. CEST contrast decreased by 17.9% at 3.5 ppm and 11.3% at 3.5 ppm for rePDT group. This was validated by histology, where we observed moderatecorrelations between APTwith cell proliferation (R = 0.730, p < 0.01) and cell apoptosis (R = 0.715, p < 0.05) and moderate correlation between rNOE with cellularity (R = 0.796, p < 0.01). rePDT has a better effect in tumor growth suppression when compared with sPDT, and CEST could be a robust and noninvasive mean to assess the molecular changes related to treatment efficacy.

Upconverting Ultra-Thin Bi2O2CO3 Nanosheets for Synergistic Photodynamic Therapy and Radiotherapy.

Synergistic therapy has become the major therapeutic method for malignant tumors in clinical. Photodynamic therapy (PDT) and radiotherapy (RT) always combine together because of their identical anti-tumor mechanisms, that is reactive oxygen species are generated by the use of radiosensitizers after irradiation by X-ray to efficiently kill cancer cells, PDT also follows similar mechanism. Full exposure of energy-absorbing species in nanomaterials to X-ray or near-infrared light irradiation makes the energy interchange between nanomaterials and surrounding H2O or dissolved oxygen easier, however, it remains challenging. Herein, an ultrathin two-dimensional (2D) nanosheet (NS) is developed, Bi2O2CO3, doped with lanthanide ions to give out upconversion luminescence, where the high Z elements Bi, Yb, and Er promote the radio-sensitizing effect. To the surprise, lanthanide activator ions gave out completely different luminescence properties compared with traditional upconversion nanoparticles. Less dopant of Er ions in nanosheets lattice resulted in brighter red emission, which provides more efficient PDT. Under RT/PDT combined treatment, NS shows a good tumor growth-inhibiting effect. In addition, synergistic therapy requires lower radiation dose than conventional radiotherapy and lower light power than single photodynamic therapy, thus greatly reducing radiation damage caused by RT and thermal damage caused by PDT.

Efficacy of photodynamic therapy as an adjunct to scaling and root planing on clinical parameters and microbial composition in subgingival plaque of periodontitis patients: A split-mouth randomized clinical trial.

The aim of this study was to assess the efficacy of photodynamic therapy (PDT) as an adjunct to scaling and root planing (SRP) on clinical parameters and microbial composition in subgingival plaque of periodontitis patients. Seventeen patients were included in this split-mouth randomized clinical trial. Sites with probing pocket depth (PPD) ≥5mm in combination with bleeding on probing in different quadrants were randomized into the control group, the group with a single PDT application right after SRP, and the group with three repeated PDT applications 1week after SRP. The subgingival plaque was collected for 16S rRNA gene sequencing at baseline, Week 2, and Week 8. Seventeen patients with 60 sites completed this 8-week follow-up, and 157 subgingival plaques were successfully analyzed by sequencing. Significant improvements were observed in two primary outcomes: PPD at Week 8 and subgingival microbial composition. Compared to the control group, the repeated-PDT group showed a notable improvement in PPD, substantial alterations in the microbial profile, including a reduction in α-diversity and anaerobic bacteria, and an increase in aerobic bacteria at Week 2. Secondary outcomes, such as clinical attachment level and sulcus bleeding index, also showed improvement at Week 8. Furthermore, both the single- and repeated-PDT groups exhibited a decrease in periodontopathogens and an increase in beneficial bacteria compared with baseline. PDT promotes changes in the microbial composition of periodontitis patients' subgingival plaque in a direction favorable to periodontal health, and repeated PDT is a promising adjunctive therapy for periodontal treatment.

Enzyme-Activatable Near-Infrared Photosensitizer with High Enrichment in Tumor Cells Based on a Multi-Effect Design.

Enzyme-activatable near-infrared (NIR) fluorescent probes and photosensitizers (PSs) have emerged as promising tools for molecular imaging and photodynamic therapy (PDT). However, in living organisms selective retention or even enrichment of these reagents after enzymatic activation at or near sites of interest remains a challenging task. Herein, we integrate non-covalent and covalent retention approaches to introduce a novel "1-to-3" multi-effect strategy-one enzymatic stimulus leads to three types of effects-for the design of an enzyme-activatable NIR probe or PS. Using this strategy, we have constructed an alkaline phosphatase (ALP)-activatable NIR fluorogenic probe and a NIR PS, which proved to be selectively activated by ALP to switch on NIR fluorescence or photosensitizing ability, respectively. Additionally, these reagents showed significant enrichment (over 2000-fold) in ALP-overexpressed tumor cells compared to the culture medium, accompanied by massive depletion of intracellular thiols, the major antioxidants in cells. The investigation of this ALP-activatable NIR PS in an in vivo PDT model resulted in complete suppression of HeLa tumors and full recovery of all tested mice. Encouragingly, even a single administration of this NIR PS was sufficient to completely suppress tumors in mice, demonstrating the high potential of this strategy in biomedical applications.

Lysosome-targeted Aza-BODIPY photosensitizers for anti-cancer photodynamic therapy

Developing effective near-infrared (NIR) photosensitizers (PSs) has been an attractive goal of photodynamic therapy (PDT) for cancer treatment. In this study, we synthesized N, N-diethylaminomethylphenyl-containing Aza-BODIPY photosensitizers and comprehensively investigated their photophysical/photochemical properties, as well as cell-based and animal-based anti-tumor studies. Among them, BDP 1 has strong NIR absorption at 680 nm and higher singlet oxygen yield in PBS which showed favorable pH-activatable and lysosome-targeting ability. BDP 1 could be easily taken up by tumor cells and showed negligible dark activity (IC50 > 50 μM), however strong phototoxicity upon exposure to light irradiation. The acceptable fluorescence emission from BDP 1 allowed convenient in vivo fluorescence imaging for organ distribution studies in mice. After PDT treatment with upon single time PDT treatment at the beginning using relatively low light dose (54 J/ cm2), BDP 1 (2 mg/kg, 0.1 mL) was found to have strong efficacy to inhibit tumor growth and even to ablate off tumor without causing body weight loss. Therefore, pH-activatable and lysosome-targeted PS may become an effective way to develop potent PDT agent.

Evaluation of photodynamic therapy efficacy vs. conventional antifungal therapy in patients with poor-fitting dentures suffering from denture stomatitis. A prospective clinical study

BackgroundThe long-term use of antifungal therapy in denture stomatitis (DS) treatment could be accompanied by antifungal-resistant strain onset, leading to compromised therapeutic procedure and disease reappearance. Photodynamic therapy (PDT) has shown the ability to eradicate oral infections and resistance strains. This prospective clinical study aimed to assess the PDT's effectiveness compared to the conventional treatment on clinical and microbiological parameters in patients with DS without denture wear during the treatment and follow-ups. MethodsForty-two patients diagnosed with DS were randomly assigned to one-session single PDT application (test group) or conventional antifungal therapy (control group). Clinical and microbiological parameters were assessed and analyzed before and at 3rd, 15th, and 30th day following the treatments. Microbiological samples were analyzed by a Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The data was statistically analyzed. ResultsPrior to the treatment, Candida species, including C. albicans (100%), C. glabrata (33%), C. tropicalis (31%), C. krusei (31%) were isolated in all patients. Both treatment procedures demonstrated a statistically significant reduction in C. albicans at all follow-up time intervals (p < 0.05). However, PDT displayed a statistically significant reduction in C. krusei compared to the conventional treatment at all follow-up periods (p < 0.05). Clinical parameters improved considerably in the test group compared to the control group at the 3rd and 15th day of follow-up. ConclusionOne-session single PDT application demonstrated significant improvement in both clinical and microbiological outcomes in a short-term period, resulting in complete Candida spp. eradication compared to conventional antifungal therapy.

Modern outlook for the use of photosensitizers with aggregation-induced emission in treatment of malignant tumors

Photodynamic therapy (PDT) is actively developing, becoming one of the important methods of non-invasive treatment of various oncological and infectious diseases. It is usually carried out using three main components: a photosensitizer, light, and oxygen. The key factors for the effective use of PDT are reactogenic oxygen species, which are produced during the oxidation of photosensitizers under the influence of light irradiation.&#x0D; To increase the production of reactogenic oxygen species, a technique was proposed for creating photosensitizers with aggregation-induced emission. At the present stage in oncology, the following PDT methods using photosensitizers with aggregation-induced emission are distinguished: PDT, absorbing near infrared radiation; enzyme- or glutathione-activated PDT; hypoxic PDT, and synergistic therapy.&#x0D; Compared to visible light, near infrared radiation (7001700 nm) has been shown to be more effective and safer due to reduced photodamage, less scattering, and deeper light penetration. The development of activated photosensitizers is an effective way to overcome the uncontrolled phototoxicity of photosensitizers during long-term PDT in vivo, providing controlled death of tumor cells. The oxygen concentration in tumor tissue varies depending on tumor progression, angiogenesis, metabolism, and metastasis. Therefore, the development of photosensitizers capable of effectively fluorescing under hypoxic conditions, including catalyzing intracellular substrates with the formation of oxygen and stimulating the production of reactogenic oxygen species through the type I mechanism, has become a potential solution to the problem of PDT of solid tumors.&#x0D; The therapeutic efficacy of a single PDT method, as well as most treatment methods in modern oncology, is limited. Therefore, a significant direction is the development of multifunctional treatment systems for synergistic therapy of tumors. Synergistic chemotherapy and PDT is an important area of treatment in oncology. The combination of PDT and immunotherapy is also a promising direction in the treatment of malignant neoplasms.&#x0D; There are obvious prospects for PDT in oncology not as a separate method of treatment, but as part of a complex multimodal treatment, including chemotherapy, radiation therapy, surgical treatment, and immunotherapy.

Hydrogen Sulfide Responsive Phototherapy Agents: Design Strategies and Biological Applications.

Hydrogen sulfide (H2S) is one of the critical gasotransmitters, which play important roles in regular physiological processes, especially in vital signaling pathways. However, fluctuations in endogenous H2S concentration can be linked to serious health problems, such as neurodegenerative diseases, cancer, diabetes, inflammation, cardiovascular diseases, and hypertension. Thus, it has attracted a great deal of attention in therapeutic applications, specifically in the field of phototherapy. Photodynamic therapy (PDT) and photothermal therapy (PTT) are two subclasses of phototherapy, which utilize either reactive oxygen species (ROS) or local temperature increase upon irradiation of a photosensitizer (PS) to realize the therapeutic action. Phototherapies offer unique advantages compared to conventional methods; thus, they are highly promising and popular. One of the design principles followed in new generation PSs is to build activity-based PSs, which stay inactive before getting activated by disease-associated stimuli. These activatable PSs dramatically improve the selectivity and efficacy of the therapy. In this review, we summarize small molecule and nanomaterial-based PDT and PTT agents that are activated selectively by H2S to initiate their cytotoxic effect. We incorporate single mode PDT and PTT agents along with synergistic and/or multimodal photosensitizers that can combine more than one therapeutic approach. Additionally, H2S-responsive theranostic agents, which offer therapy and imaging at the same time, are highlighted. Design approaches, working principles, and biological applications for each example are discussed in detail.

Dual-Photosensitizer Nanoplatform Based on Near-Infrared Excitation Orthogonal Emission Nanomaterials for Enhanced Photodynamic Therapy of Tumors.

Photodynamic therapy (PDT) is considered as a promising therapeutic approach for clinical cancer treatment. However, the hypoxia of the tumor microenvironment leads to the low effect of single PDT. Here, a dual-photosensitizer nanoplatform based on near-infrared excitation orthogonal emission nanomaterials is constructed by introducing two kinds of photosensitizers into the nanosystem. Orthogonal emission upconversion nanoparticles (OE-UCNPs) were used as light conversion reagents to generate red emission under 980 nm irradiation and green emission under 808 nm irradiation. On the one hand, merocyanine 540 (MC540) is introduced as a photosensitizer (PS), which can absorb green light to generate reactive oxygen species (ROS) and trigger PDT for tumor treatment. On the other hand, another photosensitizer, chlorophyll a (Chla), which can be excited by red light, has also been introduced into the system to build a dual PDT nanotherapeutic platform. The introduction of photosensitizer Chla can synergistically increase ROS concentration to accelerate cancer cell apoptosis. Our research shows that this dual PDT nanotherapeutic platform combined with Chla has better therapeutic effects and effectively destroys cancer.

Synergistic effects of concurrent photodynamic therapy with indocyanine green and chemotherapy in hepatocellular carcinoma cell lines and mouse models.

Photodynamic therapy (PDT) using an 808nm laser irradiation with indocyanine green (ICG) has shown tumoricidal effects in a hepatocellular (HCC) orthotopic xenograft model. Recently, combining PDT with concurrent chemotherapy has shown synergistic outcomes and a better therapeutic effect for cancer treatment. In the present study, we utilized a combination of chemotherapy drugs and PDT using ICG in vitro and in vivo in a patient-derived orthotopic xenograft (PDoX) model. We independently performed PDT and chemotherapy with sorafenib or doxorubicin in the Huh-7 and Hep3b cell lines by increasing the sorafenib or doxorubicin concentration and increasing the total energy of 808nm light. Subsequently, we combined the two treatments to confirm the effects on cell viability. The combination index (CI) was evaluated in vitro, and thereafter, in the HCC PDoX mouse model, 808nm laser irradiation with intravenously injected ICG and chemotherapy using doxorubicin were performed for twelve days. The viability of the Huh-7 and Hep3B cell lines decreased rapidly as the concentration of sorafenib or doxorubicin increased and as the total energy of 808nm light increased. The cell viability of the Huh-7 and Hep3b cell lines with combined PDT and chemotherapy was less than that with PDT or chemotherapy alone. The CI was <1 in the sorafenib- or doxorubicin-treated Huh-7 and Hep3b cell lines. In the HCC PDoX mouse model, tumor size was markedly decreased, and complete remission achieved compared to that of the single chemotherapy or PDT and control groups. The synergistic effect of concurrent PDT and chemotherapy in the HCC cell line and PDoX model was confirmed with no definite adverse effect. Concurrent PDT and chemotherapy could be applied in further preclinical studies.

Carbon dots nanophotosensitizers with tunable reactive oxygen species generation for mitochondrion-targeted type I/II photodynamic therapy

Carbon dots (CDs) have emerged as promising nanomaterials for bioimaging-guided photodynamic therapy (PDT). However, designing red-emissive CDs (RCDs) with tunable type I and type II reactive oxygen species (ROS) generation to simultaneously meet PDT applications in aerobic and hypoxic scenarios still remain major challenges. Herein, three types of RCDs with maximum emission at approximately 680 nm are successfully prepared. It is noteworthy that they exhibit the adjustable ROS production with equal superoxide anion (via type I PDT) and incremental singlet oxygen (via type II PDT). Detailed structural and optical characterizations along with theoretical calculation reveal that the unique type I/II ROS formation mainly depends on the core sizes and surface states of RCDs, which determine their identical redox potentials and tapering energy gaps between singlet- and triplet states, respectively. Additionally, due to the inherent mitochondria targeting capability, RCDs enable themselves to induce cell programmed death via activating mitochondrion-mediated apoptotic pathways. This work exploits the unprecedented RCDs with tunable type I and type II ROS generation that could ensure highly efficient tumor eradication both in vitro and in vivo, even under the harsh tumor microenvironment, providing a new prospect for CDs as nanophotosensitizers to conquer the limitations of single type PDT.

O2 self-sufficient and glutathione-depleted nanoplatform for amplifying phototherapy synergistic thermodynamic therapy

Tumor hypoxia and high levels of intracellular glutathione (GSH) significantly limit the efficacy of photodynamic therapy (PDT). In addition, a single PDT treatment strategy is relatively insufficient to eliminate tumor, further limiting its application in biomedicine. Therefore, we demonstrated an omnipotent nanoplatform based on 2,2′-azobis [2-(2 imidazolin-2-yl)propane] dihydrochloride (AIPH) loaded manganese dioxide (MnO2) nanoflower (abbreviated as MnO2-AIPH) with simultaneously self-supplying oxygen (O2), depleting GSH, performing PDT, photothermal (PTT) and thermodynamic therapy (TDT) for boosting antitumor effects. By 808 nm near infrared (NIR) light irradiation, MnO2-AIPH not only reveals highly toxic reactive oxygen species (ROS) generation and excellent photothermal conversion ability for PDT and PTT, but also generates alkyl radicals by decomposing AIPH for TDT simultaneously to eliminate tumor effectively. Once internalized into the tumor, MnO2 will be degraded to Mn2+ which catalyzes endogenous hydrogen peroxide (H2O2) into O2 for enhanced PDT. Moreover, MnO2 can facilitate GSH oxidation to amplify oxidative stress, further enhancing ROS and alkyl radicals mediated cancer cell killing. In brief, this study provides a paradigm of antitumor efficiency amplification by the combination of sustained oxygen supply, potent GSH depletion, and phototherapy synergistic TDT.

A Non-Invasive Deep Photoablation Technique to Inhibit DCIS Progression and Induce Antitumor Immunity

Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity in premalignant and malignant breast disease to non-invasively detect and selectively ablate tumors using photodynamic therapy (PDT). PDT with the HSP90-targeting photosensitizer, HS201, can not only ablate invasive breast cancers (BCs) while sparing non-tumor tissue, but also induce antitumor immunity. We hypothesized that HS201-PDT would both non-invasively ablate DCIS and prevent progression to invasive BC. We tested in vitro selective uptake and photosensitivity of HS201 in DCIS cell lines compared to the non-selective parental verteporfin, and assessed in vivo antitumor efficacy in mammary fat pad and intraductal implantation models. Selective uptake of HS201 enabled treatment of intraductal lesions while minimizing toxicity to non-tumor tissue. The in vivo activity of HS201-PDT was also tested in female MMTV-neu mice prior to the development of spontaneous invasive BC. Mice aged 5 months were administered HS201, and their mammary glands were exposed to laser light. HS201-PDT delayed the emergence of invasive BC, significantly prolonged disease-free survival (DFS) (p = 0.0328) and tended to improve overall survival compared to the no-treatment control (p = 0.0872). Systemic administration of anti-PD-L1 was combined with HS201-PDT and was tested in a more aggressive spontaneous tumor model, HER2delta16 transgenic mice. A single PDT dose combined with anti-PD-L1 improved DFS compared to the no-treatment control, which was significantly improved with repetitive HS201-PDT given with anti-PD-L1 (p = 0.0319). In conclusion, a non-invasive, skin- and tissue-sparing PDT strategy in combination with anti-PD-L1 antibodies effectively prevented malignant progression of DCIS to invasive BC. This non-invasive treatment strategy of DCIS may be safe and effective, while providing an option to reduce the morbidity of current conventional treatment for patients with DCIS. Clinical testing of HS201 is currently underway.

Implantable self-powered therapeutic pellet for wireless photodynamic/sonodynamic hybrid therapy of cancer recurrence inhibition and tumor regression

Photodynamic therapy (PDT) and sonodynamic therapy (SDT) are prospective cancer therapies that have attracted considerable attention owing to their relative safety. Here, we develop a new implantable self-powered therapeutic pellet that provides wireless PDT/SDT hybrid therapy for low-dose/long-term cancer recurrence inhibition and tumor regression. The miniature pellet contains an integrated self-powered unit, light-emitting diode illuminant, and control circuit. The system is powered by ultrasound energy via the piezoelectric effect. The pellet can deliver therapeutic doses of light into tissues for PDT alongside direct SDT. The wireless PDT/SDT hybrid therapy is shown to be highly efficient in the treatment of breast cancer in mice in vivo (much higher than single PDT or SDT). The system can operate successfully inside the body, and optimized sensitizer activation and wireless control of therapeutic dosimetry mean that it has great potential for cancer treatment. Moreover, it elucidates the critical interplay between existing clinical cancer therapies and future precision therapies.

Superficial shaving combined with photodynamic therapy is effective as a treatment for condyloma acuminatum

AbstractCondyloma acuminatum is a common sexually transmitted disease caused by human papillomavirus. Its prevalence and recurrence rates are high. While there are multiple treatment options for condyloma acuminatum, no single therapy form is effective in achieving complete remission. Photodynamic therapy (PDT) was shown to be very promising as a treatment option for condyloma acuminatum. However, for some patients the therapeutic result after a single PDT session is not satisfactory. Thus, it is necessary to develop an effective treatment method for recalcitrant condyloma acuminatum.We hypothesize that suboptimal therapeutic results after a single PDT may be caused by an insufficient penetration of the photosensitizer into the tissue. Here, we applied a combination of superficial shaving and PDT to address this issue. All patients were satisfied with the effect of the treatment, and their quality of life improved significantly. Pain was the major adverse event during treatment but was acceptable to all patients. Therefore, superficial shaving in combination with PDT is safe and effective.

Biomimetic smart mesoporous carbon nanozyme as a dual-GSH depletion agent and O2 generator for enhanced photodynamic therapy

Photodynamic therapy (PDT) has been thriving in the theranostics of cancer in recent years. However, due to a series of problems such as high concentration of GSH and insufficient O2 partial pressure in the tumor micro-environment, it is difficult to achieve the desired therapeutic effects with single PDT. Mesoporous carbon (MC-COOH) has been widely used in photothermal therapy (PTT) due to its high photothermal conversion efficiency and drug loading. In addition, we have discovered that MC-COOH owned high-efficiency glutathione oxidase-like activity for intracellular lasting GSH consumption. Hence, a smart mesoporous carbon nanozyme (CCM) was designed as a dual-GSH depletion agent and O2 generator combined with PTT to overcome the dilemma of PDT. MnO2-doped carbon nanozyme (MC-Mn) was developed as the photothermal vehicles for the efficient loading of photosensitizer (Ce6). Subsequently, 4T1 membrane-coated nanozyme (Ce6/CCM) was constructed to achieve homologous targeting capability. The carbon nanozyme owned the sustained dual-GSH depletion function through MC-COOH and MnO2, which greatly destroyed the antioxidant system of the tumor. Meanwhile, MnO2 could produce affluent O2 in the presence of H2O2, thereby alleviating the hypoxic state of tumor tissues and further promoting the generation of ROS. In addition, the novel carbon nanozyme was designed as photoacoustic imaging (PAI) agent and magnetic resonance imaging (MRI) contrast for real-time imaging during tumor therapy. In summary, this work showed that the biomimetic carbon nanozyme could be used as dual-GSH depletion agent and O2 generator for dual-mode imaging-guided PTT-PDT. Statement of significance- MC-COOH with highly efficient GSH-OXD activity was first discovered and applied in PDT.- MnO2 acted as an O2 generator and GSH depletion agent to enhance PDT.- The tumor-targeting ability of the nanozyme was improved by cell membrane camouflage.- CCM nanozyme possesses both PAI and MRI dual-mode imaging modalities to guide PDT/PTT.

An Engineered Nanocomplex with Photodynamic and Photothermal Synergistic Properties for Cancer Treatment.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are promising therapeutic methods for cancer treatment; however, as single modality therapies, either PDT or PTT is still limited in its success rate. A dual application of both PDT and PTT, in a combined protocol, has gained immense interest. In this study, gold nanoparticles (AuNPs) were conjugated with a PDT agent, meso-tetrahydroxyphenylchlorin (mTHPC) photosensitizer, designed as nanotherapeutic agents that can activate a dual photodynamic/photothermal therapy in SH-SY5Y human neuroblastoma cells. The AuNP-mTHPC complex is biocompatible, soluble, and photostable. PDT efficiency is high because of immediate reactive oxygen species (ROS) production upon mTHPC activation by the 650-nm laser, which decreased mitochondrial membrane potential (∆ψm). Likewise, the AuNP-mTHPC complex is used as a photoabsorbing (PTA) agent for PTT, due to efficient plasmon absorption and excellent photothermal conversion characteristics of AuNPs under laser irradiation at 532 nm. Under the laser irradiation of a PDT/PTT combination, a twofold phototoxicity outcome follows, compared to PDT-only or PTT-only treatment. This indicates that PDT and PTT have synergistic effects together as a combined therapeutic method. Our study aimed at applying the AuNP-mTHPC approach as a potential treatment of cancer in the biomedical field.

Light-Decomposable Polymeric Micelles with Hypoxia-Enhanced Phototherapeutic Efficacy for Combating Metastatic Breast Cancer.

Oxygen dependence and anabatic hypoxia are the major factors responsible for the poor outcome of photodynamic therapy (PDT) against cancer. Combining of PDT and hypoxia-activatable bioreductive therapy has achieved remarkably improved antitumor efficacy compared to single PDT modality. However, controllable release and activation of prodrug and safety profiles of nanocarrier are still challenging in the combined PDT/hypoxia-triggered bioreductive therapy. Herein, we developed a near infrared (NIR) light-decomposable nanomicelle, consisting of PEGylated cypate (pCy) and mPEG-polylactic acid (mPEG2k-PLA2k) for controllable delivery of hypoxia-activated bioreductive prodrug (tirapazamine, TPZ) (designated TPZ@pCy), for combating metastatic breast cancer via hypoxia-enhanced phototherapies. TPZ@pCy was prepared by facile nanoprecipitation method, with good colloidal stability, excellent photodynamic and photothermal potency, favorable light-decomposability and subsequent release and activation of TPZ under irradiation. In vitro experiments demonstrated that TPZ@pCy could be quickly internalized by breast cancer cells, leading to remarkable synergistic tumor cell-killing potential. Additionally, metastatic breast tumor-xenografted mice with systematic administration of TPZ@pCy showed notable tumor accumulation, promoting tumor ablation and lung metastasis inhibition with negligible toxicity upon NIR light illumination. Collectively, our study demonstrates that this versatile light-decomposable polymeric micelle with simultaneous delivery of photosensitizer and bioreductive agent could inhibit tumor growth as well as lung metastasis, representing a promising strategy for potent hypoxia-enhanced phototherapies for combating metastatic breast cancer.

Virus-Inspired Hollow Mesoporous Gadolinium-Bismuth Nanotheranostics for Magnetic Resonance Imaging-Guided Synergistic Photodynamic-Radiotherapy.

The anti-tumor efficacy of single photodynamic therapy (PDT) and radiotherapy (RT) has been greatly affected by inadequate tumor uptake of photo/radiation sensitizers, limited laser penetration depth, and radiation sickness caused by high doses of X-rays. Here, the authors report a biomimetic coronavirus-inspired hollow mesoporous gadolinium/bismuth nanocarrier loaded with a new NIR photosensitizer HB (termed as HB@VHMBi-Gd) for magnetic resonance imaging (MRI)-guided synergistic photodynamic-RT. HB@VHMBi-Gd displayed a faster cellular uptake rate than the conventional spherical HMBi-Gd loaded with HB (HB@SHMBi-Gd) because of rough surface-enhanced adhesion. After intravenous injection, HB@VHMBi-Gd is efficiently delivered to the tumor and rapidly invades the tumor cells by surface spikes. Interestingly, lysosomal acidity can trigger the degradation of VHMBi-Gd to produce ultrasmall nanoparticles to amplify the X-ray attenuation ability and enhance MRI contrast and radiosensitization. Under laser and X-ray irradiation, HB@VHMBi-Gd significantly enhances 1 O2 generation from HB to induce activation of caspase 9/3 and inhibition of C-myc, while enhancing hydroxyl radical generation from Bi2 O3 to induce intense DNA breakage. By synergistically inducing cell apoptosis by distinct reactive oxygen species (ROS), HB@VHMBi-Gd exhibits superior anticancer efficacy with ≈90% tumor inhibition. They envision that biomimetic virus-inspired hollow hybrid metal nanoparticles can provide a promising strategy for imaging-guided synergistic photodynamic-RT.

Clinical Pharmacokinetics and Safety of a 10% Aminolevulinic Acid Hydrochloride Nanoemulsion Gel (BF-200 ALA) in Photodynamic Therapy of Patients Extensively Affected With Actinic Keratosis: Results of 2 Maximal Usage Pharmacokinetic Trials.

The nanoemulsion‐based 10% aminolevulinic acid (ALA) hydrochloride gel BF‐200 ALA optimizes epidermal penetration of its active ingredient and is approved for topical photodynamic therapy (PDT) for the treatment of actinic keratosis in the United States and Europe. To characterize systemic absorption from dermal application during PDT, ALA and its key active metabolite protoporphyrin IX (PpIX) were analyzed in 2 maximal usage pharmacokinetic trials (MUsT) in patients severely affected with actinic keratosis. The primary objective of both MUsTs was to assess baseline‐adjusted plasma concentration–time curves for ALA and PpIX after a single PDT treatment applying either 2 g (1 tube) of BF‐200 ALA on the face (MUsT‐1) or applying 6 g (3 tubes) of BF‐200 ALA on the face/scalp or body periphery (MUsT‐2), to 20 or 60 cm2, respectively. All PDTs were performed using red light at around 635 nm wavelength. Safety and tolerability were documented along with pharmacokinetics. In both MUsTs, ALA plasma concentrations were transiently increased to a maximum concentration at about 2.5 to 3.3 times above endogenous baseline with time to maximum concentration at ≈3 hours after dosing. Plasma levels subsequently returned to baseline within 10 hours after dosing. Overall baseline‐adjusted mean area under the baseline‐adjusted plasma concentration‐time curve from time zero to the last sampling time point at which the concentration was at or above the lower limit of quantification ranged from 142.8 to 146.2, indicating that a similar, minor fraction of topical ALA is systemically absorbed under both dosing regimens. Systemic PpIX exposure after administration of either dose of BF‐200 ALA was equally minimal. Application site skin reactions were treatment area size‐related, albeit transient and consistent with the known safety profile of BF‐200 ALA.