Ação antifúngica e potencial antibiofilme de diferentes terapias alternativas frente a leveduras do gênero candida / Antifungal action and antibiofilm potential of different alternative therapies against yeasts of the genus candida

As candidoses usualmente são tratadas com antifúngicos. No entanto, o efeito desses fármacos é usualmente comprometido pela resistência microbiana e pelos efeitos adversos ocasionados. Nesse sentido, o aumento da prevalência e a complexidade de microrganismos multirresistentes a antimicrobianos têm incitado a busca por terapias complementares e alternativas capazes de atuar efetivamente frente à resistência emergente aos medicamentos. Diante disso, o objetivo desse trabalho foi avaliar comparativamente a ação antimicrobiana e o potencial antibiofilme, in vitro, entre a terapia fotodinâmica antimirobiana (TFDA) com azul de metileno, a fitoterapia, utilizando o extrato hidroetanólico de Spondias mombin L (EHSM), e o probiótico Lactobacillus rhamnosus (PLR) no controle de leveduras do gênero Candida, sendo elas: Candida albicans, Candida tropicalis e Candida parapsilosis. Trata-se de um estudo experimental, in vitro, analítico e quantitativo, em que foram investigadas, em triplicata, a atividade inibidora do crescimento microbiano e a atividade antibiofilme das seguintes terapias alternativas: TFDA, EHSM e PLR, utilizando como controle positivo a Nistatina 100.000UI/mL. Quanto à análise estatística, além da interpretação descritiva, foi aplicado o teste Two-Way ANOVA e o Teste de Tukey. Dessa forma, observou-se que todas as terapias testadas exibiram atividades antifúngica e antibiofilme. Todavia, quando comparadas tais atividades entre elas e ainda com a Nistatina, verificou-se que: a TFDA apresentou a maior atividade inibitória de crescimento microbiano (p<0,05), semelhante a Nistatina, seguida pelo EHSM, exibindo o PLR a menor atividade antifúngica e a TFDA juntamente com o EHSM representaram as terapias com maior atividade antibiofilme (p<0,0001), atuando ambas de forma semelhante a Nistatina. Nesse sentido, foi possível concluir que todas as terapias estudadas possuem atividades antifúngica e antibiofilme frente às cepas do gênero Candida testadas, com destaque para a atividade inibidora de crescimento microbiano da TFDA e a atividade antibiofilme da TFDA e do EHSM, sendo tais atividades semelhantes às atividades da Nistatina (AU).

Candidoses are usually treated with antifungals. However, the effect of these drugs is usually compromised by microbial resistance and adverse effects. In this sense, the increase in the prevalence and complexity of multidrug-resistant microorganisms to antimicrobials have incited the search for complementary and alternative therapies capable of acting effectively against the emerging resistance to medicines. Therefore, the objective of this study was to comparatively evaluate the antimicrobial action and antibiofilm potential, in vitro, between antimyrobial photodynamic therapy (PDT) with methylene blue, phytotherapy, using hydroethanolic extract of Spondias mombin L (EHSM)and the probiotic Lactobacillus rhamnosus (PLR) in the control of yeasts of the genus Candida: Candida albicans, Candida tropicalis and Candida parapsilosis. This is an experimental, in vitro, analytical and quantitative study in which the inhibitory activity of microbial growth and antibiofilm activity of the following alternative therapies were investigated in triplicate: TFDA, EHSM and PLR, using 100.000UI/mL as positive control. Regarding the statistical analysis, in addition to the descriptive interpretation, the Two-Way ANOVA test and the Tukey test were applied. Thus, it was observed that all therapies tested exhibited antifungal and antibiofilm activities. However, when comparing these activities between them and still with Nystatin, it was found that: TFDA showed the highest inhibitory activity of microbial growth (p <0.05), similar to Nystatin, followed by the EHSM, exhibiting the PLR the lowest antifungal activity and the TFDA together with the EHSM represented the therapies with higher antibiofilm activity (p <0.0001), acting both similarly to Nystatin. In this sense, it was possible to conclude that all the therapies studied have antifungal and antibiofilm activities against the strains of the genus Candida tested, especially the inhibitory activity of microbial growth of TFDA and the antibiofilm activity of TFDA and EHSM, similar to the activities of Nistatina (AU).

Multifunctional Protein Hybrid Nanoplatform for Synergetic Photodynamic-Chemotherapy of Malignant Carcinoma by Homologous Targeting Combined with Oxygen Transport.

Photodynamic therapy (PDT) under hypoxic conditions and drug resistance in chemotherapy are perplexing problems in anti-tumor treatment. In addition, central nervous system neoplasm-targeted nanoplatforms are urgently required. To address these issues, a new multi-functional protein hybrid nanoplatform is designed, consisting of transferrin (TFR) as the multicategory solid tumor recognizer and hemoglobin for oxygen supply (ODP-TH). This protein hybrid framework encapsulates the photosensitizer protoporphyrin IX (PpIX) and chemotherapeutic agent doxorubicin (Dox), which are attached by a glutathione-responsive disulfide bond. Mechanistically, ODP-TH crosses the blood-brain barrier (BBB) and specifically aggregated in hypoxic tumors via protein homology recognition. Oxygen and encapsulated drugs ultimately promote a therapeutic effect by down-regulating the abundance of multidrug resistance gene 1 (MDR1) and hypoxia-inducible factor-1-α (HIF-1α). The results reveal that ODP-TH achieves oxygen transport and protein homology recognition in the hypoxic tumor occupation. Indeed, compared with traditional photodynamic chemotherapy, ODP-TH achieves a more efficient tumor-inhibiting effect. This study not only overcomes the hypoxia-related inhibition in combination therapy by targeted oxygen transport but also achieves an effective treatment of multiple tumors, such as breast cancer and glioma, providing a new concept for the construction of a promising multi-functional targeted and intensive anti-tumor nanoplatform.

Protocolo Clínico e Diretrizes Terapêuticas da Degeneração Macular Relacionada à Idade (forma neovascular) / Clinical Protocol and Therapeutic Guidelines of macular degeneration related to age (neovascular form)

CONTEXTO: Os PCDT são documentos que visam garantir o melhor cuidado de saúde diante do contexto brasileiro e dos recursos disponíveis no SUS. Podem ser utilizados como materiais educativos aos profissionais de saúde, auxílio administrativo aos gestores, regulamentação da conduta assistencial perante o Poder Judiciário e explicitação de direitos aos usuários do SUS. Os PCDT são os documentos oficiais do SUS que estabelecem critérios para o diagnóstico de uma doença ou agravo à saúde; tratamento preconizado, com os medicamentos e demais produtos apropriados, quando couber; posologias recomendadas; mecanismos de controle clínico; e acompanhamento e verificação dos resultados terapêuticos a serem seguidos pelos gestores do SUS. Os PCDT devem incluir recomendações de condutas, medicamentos ou produtos para as diferentes fases evolutivas da doença ou do agravo à saúde de que se tratam, bem como aqueles indicados em casos de perda de eficácia e de surgimento de intolerância ou reação adversa relevante,

Evaluation of Antimicrobial Photodynamic Therapy as an Adjuvant in Periodontal Treatment in Individual with Down Syndrome

Abstract Objective: To evaluate the effectiveness of Antimicrobial Photodynamic Therapy (aPDT), associated with scaling and root planing in the non-surgical periodontal treatment of individuals with Down Syndrome. Material and Methods: A controlled, randomized, split-mouth study was conducted. A total of 8 participants diagnosed with Down Syndrome aged 17-38 years of both sexes with clinical periodontitis were included in the study. Participants were treated at least three times: at the baseline, Plaque Index (PI), Bleeding on Probing (BOP), and Probing Pocket Depth (PPD) were obtained. After one week, conventional scaling and root planing were performed, and two quadrants were randomly selected for aPDT application. The reassessment was obtained one month after the aPDT application. The significance level was set at 5%. Analyses were performed considering a 95% confidence interval. Results: In the intergroup evaluation, no statistically significant differences were observed (p>0.05). In the intragroup evaluation, no statistically significant variations were observed in relation to the PI (p>0.05) and PPD (p>0.05); however, a statistically significant reduction in the BOP was observed between the test group (p=0.013) and control group (p=0.015). Conclusion: The use of aPDT as adjuvant therapy did not promote additional benefits in decreasing PI and PPD after 1 month of treatment. However, a significant reduction in the BOP was observed in the intragroup evaluation.

The Use of Lasers and Light Devices in Acne Management: An Update.

Acne vulgaris is a disease of the pilosebaceous unit and the most common inflammatory dermatosis worldwide. It is also associated with significant economic burden. Limitations of conventional topical and systemic treatments include long treatment course, intolerable adverse effects, antibiotic resistance, and patient compliance. Therefore, laser and light-based interventions present as alternative options over the past decade and have been used in combination with conventional pharmacological therapies and other physical modalities. An updated overview on the use of lasers and light-based devices in acne management is presented to help clinicians understand the safety and efficacy of these treatment options. The effectiveness of neodymium:yttrium aluminum garnet (Nd:YAG) for treating acne is supported by more high-level studies compared with other laser devices. There is limited evidence to support the use of CO2 lasers, potassium titanyl phosphate lasers, and 1565-nm non-ablative fractional lasers for treating acne. Among light devices, photodynamic therapy is the most studied, showing higher efficacies than some of the conventional topical and oral acne therapies. Intense-pulsed light and blue light therapies also show favorable outcomes. A limitation is that most studies are non-randomized and lack a control group, and report on a variety of device settings, treatment regimens, and outcome measures, making it challenging to summarize and generalize findings. Although the use of laser and light devices to treat acne is promising, further work with randomized controlled study designs and larger sample sizes will provide improved guidance on the application of these modalities.

Bright Bacterium for Hypoxia-Tolerant Photodynamic Therapy Against Orthotopic Colon Tumors by an Interventional Method.

While promising, the efficacy of aggregation-induced emission (AIE)-based photodynamic therapy (PDT) is limited by several factors including limited depth of laser penetration and intratumoral hypoxia. In the present study, a novel bacteria-based AIEgen (TBP-2) hybrid system (AE) is developed, that is able to facilitate the hypoxia-tolerant PDT treatment of orthotopic colon tumors via an interventional method. For this approach, an interventional device is initially designed, composed of an optical fiber and an endoscope, allowing for clear visualization of the position of the orthotopic tumor within the abdominal cavity. It is then possible to conduct successful PDT treatment of this hypoxic tumor via laser irradiation, as the TBP-2 is able to generate hydroxyl radicals (•OH) via a type I mechanism within this hypoxic microenvironment. Moreover, this interventional approach is proved to significantly impair orthotopic colon cancer growth and overcame PDT defects. This study is the first report involving such an interventional PDT strategy to knowledge, and it has the potential to complement other treatment modalities while also highlighting novel approaches to the design of hybrid AIEgen systems.

Management of Difficult-to-Treat Warts: Traditional and New Approaches.

Warts are regularly treated by dermatologists, and while many respond readily to first-line treatments, others may represent a therapeutic challenge. Large, deep, numerous, and extensive warts; treatment-resistant lesions with higher risk for side effects, such as hypopigmentation; or patients unable to tolerate or comply with our treatment regimen, may need alternative treatment options. In this work we review the characteristics of select modalities that should be considered for difficult-to-treat warts. We discuss efficacy and tolerability data as well as practical features that can guide us to select the best treatment for every scenario. Novel approaches, still in an investigational phase, are also discussed to illustrate potential future directions of wart treatment.

Antimicrobial and antibiofilm photodynamic therapy against vancomycin resistant Staphylococcus aureus (VRSA) induced infection in vitro and in vivo.

Biofilm mediated infection caused by multi-drug resistant bacteria are difficult to treat since it protects the microorganisms by host defense system, making them resistant to antibiotics and other antimicrobial agents. Combating such type of nosocomial infection, especially in immunocompromised patients, is an urgent need and foremost challenge faced by clinicians. Therefore, antimicrobial photodynamic therapy (aPDT) has been intensely pursued as an alternative therapy for bacterial infections. aPDT leads to the generation of reactive oxygen species (ROS) that destroy bacterial cells in the presence of a photosensitizer, visible light and oxygen. Here, we elucidated a possibility of its clinical application by reducing the treatment time and exposing curcumin to 20 J/cm2 of blue laser light, which corresponds to only 52 s to counteract vancomycin resistant Staphylococcus aureus (VRSA) both in vitro and in vivo. To understand the mechanism of action, the generation of total reactive oxygen species (ROS) was quantified by 2'-7'-dichlorofluorescein diacetate (DCFH-DA) and the type of phototoxicity was confirmed by fluorescence spectroscopic analysis. The data showed more production of singlet oxygen, indicating type-II phototoxicity. Different anti-biofilm assays (crystal violet and congo red assays) and microscopic studies were performed at sub-MIC concentration of curcumin followed by treatment with laser light against preformed biofilm of VRSA. The result showed significant reduction in the preformed biofilm formation. Finally, its therapeutic potential was validated in skin abrasion wistar rat model. The result showed significant inhibition of bacterial growth. Furthermore, immunomodulatory analysis with rat serum was performed. A significant reduction in expression of proinflammatory cytokines TNF-α and IL-6 were observed. Hence, we conclude that curcumin mediated aPDT with 20 J/cm2 of blue laser treatment (for 52 s) could be used against multi-drug resistant bacterial infections and preformed biofilm formation as a potential therapeutic approach.

Activatable Polymer Nanoenzymes for Photodynamic Immunometabolic Cancer Therapy.

Tumor immunometabolism contributes substantially to tumor proliferation and immune cell activity, and thus plays a crucial role in the efficacy of cancer immunotherapy. Modulation of immunometabolism to boost cancer immunotherapy is mostly based on small-molecule inhibitors, which often encounter the issues of off-target adverse effects, drug resistance, and unsustainable response. In contrast, enzymatic therapeutics can potentially bypass these limitations but has been less exploited. Herein, an organic polymer nanoenzyme (SPNK) with near-infrared (NIR) photoactivatable immunotherapeutic effects is reported for photodynamic immunometabolic therapy. SPNK is composed of a semiconducting polymer core conjugated with kynureninase (KYNase) via PEGylated singlet oxygen (1 O2 ) cleavable linker. Upon NIR photoirradiation, SPNK generates 1 O2 not only to exert photodynamic effect to induce the immunogenic cell death of cancer, but also to unleash KYNase and trigger its activity to degrade the immunosuppressive kynurenine (Kyn). Such a combinational effect mediated by SPNK promotes the proliferation and infiltration of effector T cells, enhances systemic antitumor T cell immunity, and ultimately permits inhibition of both primary and distant tumors in living mice. Therefore, this study provides a promising photodynamic approach toward remotely controlled enzymatic immunomodulation for improved anticancer therapy.

Antimicrobial photodynamic inactivation mediated by methylene blue: Analysis of inactivation kinetics and biochemical mechanisms / Inativação fotodinâmica antimicrobiana mediada por azul de metileno: Análises de cinética de inativação e mecanismos bioquímicos

The widespread use of antimicrobial chemotherapy in medicine and livestock production imposed an evolutive selection of drug-resistant strains worldwide. As a result, the effectiveness of our current antimicrobial armamentarium is constantly being reduced to alarming levels. Therefore, novel antimicrobial therapeutic strategies are urgently needed. Antimicrobial photodynamic therapy (APDT) comes to this scenario as a powerful tool to counteract the emergence of microbial drug-resistance. Its mechanisms of action are based on simultaneous oxidative damage of multiple targets and, therefore, it is much less likely to allow any type of microbial resistance. Therefore, the objectives of this study were focused into establishing 1) a mathematical tool to allow precise analysis of microbial photoinactivation; 2) a broad analysis of APDT effectiveness against global priority drug-resistant pathogens; 3) inhibition of ßlactamase enzymes; and 4) how the biochemical mechanisms of APDT avoid emergence of resistance. The main results obtained through the investigation led by this thesis were divided into 4 scientific articles regarding each of the above-mentioned objectives. In summary, we discovered that 1) a power-law function can precisely fit all microbial inactivation kinetics data and provide insightful information of tolerance factors and lethal doses; 2) there is no correlation between drug-resistance and APDT sensitivity, i.e., extensively drug resistant microorganisms are killed in the same kinetics as drug-sensitive controls; 3) ß-lactamases are very sensitive to photodynamic inhibition; 4) biochemical mechanisms of APDT promote oxidative damages to external cell membranes, DNA and proteins whereas the main cause of microbial death seems to be directly associated with protein degradation. Thus, we conclude that APDT is effective against a broad-spectrum of pathogens and has minimum chances of promoting resistance mechanisms

O amplo uso da quimioterapia antimicrobiana impôs uma seleção evolutiva de cepas resistentes a medicamentos. Como resultado, a eficácia dos fármacos antimicrobianos tem sido reduzida a níveis alarmantes. Portanto, novas estratégias terapêuticas antimicrobianas são urgentemente necessárias. A terapia fotodinâmica antimicrobiana (TFDA) entra neste cenário como uma ferramenta poderosa para combater a resistência microbiana. Seus mecanismos de ação são baseados no dano oxidativo sobre múltiplos alvos e, portanto, é muito menos provável que permita o surgimento de qualquer tipo de resistência. Os objetivos deste estudo foram focados ao estabelecimento de 1) modelo matemático para análise precisa da fotoinativação microbiana; 2) ampla análise da eficácia da TFDA contra patógenos resistentes a fármacos antimicrobianos de prioridade global; 3) inibição de ß-lactamases por TFDA; e 4) como os mecanismos bioquímicos da TFDA evitam o surgimento de resistência. Os principais resultados obtidos através da investigação conduzida por esta tese foram divididos em 4 artigos científicos. Em resumo, descobrimos que 1) uma função de lei de potência pode ajustar com precisão todos os dados de cinética de inativação microbiana e fornecer informações detalhadas sobre fatores de tolerância e doses letais; 2) não há correlação entre resistência à quimioterapia antimicrobiana e sensibilidade à TFDA, isto é, cepas extensivamente resistentes aos antimicrobianos são inativadas sob a mesma cinética que controles sensíveis aos antimicrobianos; 3) ß-lactamases são altamente sensíveis à inibição fotodinâmica; 4) os mecanismos bioquímicos da TFDA promovem danos oxidativos às membranas celulares e DNA, porém, a principal causa de morte microbiana é diretamente associada à degradação das proteínas. Assim, concluímos que a TFDA é eficaz contra um amplo espectro de patógenos e tem chances mínimas de promover mecanismos de resistência

ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death.

Rationale: The development of a highly effective and tumor-specific therapeutic strategy, which can act against the primary tumor and also condition the host immune system to eliminate distant tumors, remains a clinical challenge. Methods: Herein, we demonstrate a facile yet versatile ZnO-capping and Doxorubicin (DOX)-loaded multifunctional nanocomposite (AuNP@mSiO2@DOX-ZnO) that integrates photothermal properties of gold nanoparticles (NPs), pH-responsive properties and preferential selectivity to tumor cells of ZnO QDs and chemotherapeutic agent into a single NP. The photothermal performance, pH-triggered release and preferential phagocytic ability were assessed. The induced anti-tumor immunity was determined by analyzing immune cell profile in tumor in vivo and molecular mechanism were identified by detecting expression of immunogenic cell death (ICD) markers in vitro. Moreover, mice models of unilateral and bilateral subcutaneous melanoma and lung metastasis were established to evaluate the antitumor effects. Results: As an efficient drug carrier, ZnO-capped NPs guarantee a high DOX payload and an in vitro, efficient release of at pH 5.0. In murine melanoma models, the nanocomposite can significantly inhibit tumor growth for a short period upon low-power laser irradiation. Importantly, ZnO NPs not only demonstrate preferential selectivity for melanoma cells but can also induce ICD. Meanwhile, AuNP@mSiO2-based photothermal therapy (PTT) and DOX are directly cytotoxic towards cancer cells and demonstrate an elevated ICD effect. The induced ICD promotes maturation of dendritic cells, further stimulating the infiltration of effector T cells into tumor sites, preventing tumor growth and distant lung metastases. Conclusions: This study highlights the novel mechanism of ZnO-triggered anti-tumor immunity via inducing ICD. Additionally, we shed light on the multifunctionality of nanocomposites in delivering localized skin tumor therapy as well as inhibiting metastatic growth, which holds great promise in clinical applications.

Pathological Mechanism of Photodynamic Therapy and Photothermal Therapy Based on Nanoparticles.

The ultimate goal of phototherapy based on nanoparticles, such as photothermal therapy (PTT) which generates heat and photodynamic therapy (PDT) which not only generates reactive oxygen species (ROS) but also induces a variety of anti-tumor immunity, is to kill tumors. In addition, due to strong efficacy in clinical treatment with minimal invasion and negligible side effects, it has received extensive attention and research in recent years. In this paper, the generations of nanomaterials in PTT and PDT are described separately. In clinical application, according to the different combination pathway of nanoparticles, it can be used to treat different diseases such as tumors, melanoma, rheumatoid and so on. In this paper, the mechanism of pathological treatment is described in detail in terms of inducing apoptosis of cancer cells by ROS produced by PDT, immunogenic cell death to provoke the maturation of dendritic cells, which in turn activate production of CD4+ T cells, CD8+T cells and memory T cells, as well as inhibiting heat shock protein (HSPs), STAT3 signal pathway and so on.

Clinical development and potential of photothermal and photodynamic therapies for cancer.

Light-activated, photosensitizer-based therapies have been established as safe modalities of tumour ablation for numerous cancer indications. Two main approaches are available: photodynamic therapy, which results in localized chemical damage in the target lesions, and photothermal therapy, which results in localized thermal damage. Whereas the administration of photosensitizers is a key component of photodynamic therapy, exogenous photothermal contrast agents are not required for photothermal therapy but can enhance the efficiency and efficacy of treatment. Over the past decades, great strides have been made in the development of phototherapeutic drugs and devices as cancer treatments, but key challenges have restricted their widespread clinical use outside of certain dermatological indications. Improvements in the tumour specificity of photosensitizers, achieved through targeting or localized activation, could provide better outcomes with fewer adverse effects, as could combinations with chemotherapies or immunotherapies. In this Review, we provide an overview of the current clinical progress of phototherapies for cancer and discuss the emerging preclinical bioengineering approaches that have the potential to overcome challenges in this area and thus improve the efficiency and utility of such treatments.

Annealing-modulated nanoscintillators for nonconventional X-ray activation of comprehensive photodynamic effects in deep cancer theranostics.

Photodynamic therapy (PDT), which involves the generation of reactive oxygen species (ROS) through interactions of a photosensitizer (PS) with light and oxygen, has been applied in oncology. Over the years, PDT techniques have been developed for the treatment of deep-seated cancers. However, (1) the tissue penetration limitation of excitation photon, (2) suppressed efficiency of PS due to multiple energy transfers, and (3) insufficient oxygen source in hypoxic tumor microenvironment still constitute major challenges facing the clinical application of PDT for achieving effective treatment. We present herein a PS-independent, ionizing radiation-induced PDT agent composed of yttrium oxide nanoscintillators core and silica shell (Y2O3:Eu@SiO2) with an annealing process. Our results revealed that annealed Y2O3:Eu@SiO2 could directly induce comprehensive photodynamic effects under X-ray irradiation without the presence of PS molecules. The crystallinity of Y2O3:Eu@SiO2 was demonstrated to enable the generation of electron-hole (e--h+) pairs in Y2O3 under ionizing irradiation, giving rise to the formation of ROS including superoxide, hydroxyl radical and singlet oxygen. In particular, combining Y2O3:Eu@SiO2 with fractionated radiation therapy increased radio-resistant tumor cell damage. Furthermore, photoacoustic imaging of tumors showed re-distribution of oxygen saturation (SO2) and reoxygenation of the hypoxia region. The results of this study support applicability of the integration of fractionated radiation therapy with Y2O3:Eu@SiO2, achieving synchronously in-depth and oxygen-insensitive X-ray PDT. Furthermore, we demonstrate Y2O3:Eu@SiO2 exhibited radioluminescence (RL) under X-ray irradiation and observed the virtually linear correlation between X-ray-induced radioluminescence (X-RL) and the Y2O3:Eu@SiO2 concentration in vivo. With the pronounced X-RL for in-vivo imaging and dosimetry, it possesses significant potential for utilization as a precision theranostics producing highly efficient X-ray PDT for deep-seated tumors.

Nanocomposites for X-Ray Photodynamic Therapy.

Photodynamic therapy (PDT) has long been known as an effective method for treating surface cancer tissues. Although this technique is widely used in modern medicine, some novel approaches for deep lying tumors have to be developed. Recently, deeper penetration of X-rays into tissues has been implemented, which is now known as X-ray photodynamic therapy (XPDT). The two methods differ in the photon energy used, thus requiring the use of different types of scintillating nanoparticles. These nanoparticles are known to convert the incident energy into the activation energy of a photosensitizer, which leads to the generation of reactive oxygen species. Since not all photosensitizers are found to be suitable for the currently used scintillating nanoparticles, it is necessary to find the most effective biocompatible combination of these two agents. The most successful combinations of nanoparticles for XPDT are presented. Nanomaterials such as metal-organic frameworks having properties of photosensitizers and scintillation nanoparticles are reported to have been used as XPDT agents. The role of metal-organic frameworks for applying XPDT as well as the mechanism underlying the generation of reactive oxygen species are discussed.

A Flexi-PEGDA Upconversion Implant for Wireless Brain Photodynamic Therapy.

Near-infrared (NIR) activatable upconversion nanoparticles (UCNPs) enable wireless-based phototherapies by converting deep-tissue-penetrating NIR to visible light. UCNPs are therefore ideal as wireless transducers for photodynamic therapy (PDT) of deep-sited tumors. However, the retention of unsequestered UCNPs in tissue with minimal options for removal limits their clinical translation. To address this shortcoming, biocompatible UCNPs implants are developed to deliver upconversion photonic properties in a flexible, optical guide design. To enhance its translatability, the UCNPs implant is constructed with an FDA-approved poly(ethylene glycol) diacrylate (PEGDA) core clad with fluorinated ethylene propylene (FEP). The emission spectrum of the UCNPs implant can be tuned to overlap with the absorption spectra of the clinically relevant photosensitizer, 5-aminolevulinic acid (5-ALA). The UCNPs implant can wirelessly transmit upconverted visible light till 8 cm in length and in a bendable manner even when implanted underneath the skin or scalp. With this system, it is demonstrated that NIR-based chronic PDT is achievable in an untethered and noninvasive manner in a mouse xenograft glioblastoma multiforme (GBM) model. It is postulated that such encapsulated UCNPs implants represent a translational shift for wireless deep-tissue phototherapy by enabling sequestration of UCNPs without compromising wireless deep-tissue light delivery.

A continuous stimuli-responsive system for NIR-II fluorescence/photoacoustic imaging guided photothermal/gas synergistic therapy.

Nanosystems responsive to a tumor microenvironment (TME) have recently attracted great attention due to their potential in precision cancer theranostics. However, theranostic nanosystems with a TME-activated consecutive cascade for the accurate diagnosis and treatment of cancer have rarely been exploited. Herein, an activatable theranostic nanosystem (Bi2S3-Ag2S-DATS@BSA-N3 NYs) is designed and constructed on the basis of a one-pot biomineralization method and surface functional modification to improve second near-infrared (NIR-II) fluorescence/photoacoustic (PA) imaging-guided photothermal therapy (PTT)/gas therapy (GT). Based on enhanced penetration and retention (EPR) effect-mediated tumor accumulation, the tumor-overexpressed glutathione (GSH) can accelerate hydrogen sulfide (H2S) generation from the nanoparticles by reacting with the encapsulated diallyl trisulfide (DATS). Meanwhile, the in situ released H2S can be used not only for gas therapy, but also to start the reduction of -N3(-) to -NH2(+), thereby enhancing the tumor-specific aggregation of NYs. As a result, the activatable nanosystems with excellent tumor accumulation and biodistribution could achieve an accurate NIR-II/PA dual-modality imaging for guiding the synergistic anticancer efficacy (PTT/GT). Thus, this work provides a promising TME-mediated continuously responsive strategy for efficient anticancer therapy.

Plasma enabled devices for the selective capture and photodynamic identification of prostate cancer cells.

Prostate cancer is the second most common cancer in men and the second leading cause of male cancer deaths. The current blood test for detecting prostate cancers measures prostate-specific antigen. It has many limitations including a very high rate of false positives. Herein, prostate-specific membrane antigen (PSMA) based immunocapture and hexaminolevulinate (HAL) based photodetection are integrated into a new diagnostic device designed to selectively identify whole prostate cancer cells from voided urine with the aim of providing an accurate noninvasive alternative to current diagnosis methods. Prestained, prostate cancer cells spiked in urine samples at concentrations ranging from 1500 to 2000 cells/ml were captured with 89% sensitivity and 95% specificity. HAL, a cancer specific photosensitizer, was then used to circumvent the need for prestaining. Optimum HAL incubation conditions were identified (50 µM at 37 °C for 2 h) where the mean HAL-induced fluorescence intensity of LNCaP cells was three times that of healthy PNT2 cells, thus providing an independent way to discriminate captured cancer cells from background metabolites. Combining anti-PSMA immunocapture with HAL-induced fluorescent detection, 86% sensitivity and 88% selectivity were achieved, thereby proving the validity of the dual-method for the selective photospecific detection of prostate cancer cells.

A Dual Functional Nanoreactor for Synergistic Starvation and Photodynamic Therapy.

The combination of photodynamic therapy (PDT) and enzyme therapy is a highly desirable approach in malignant tumor therapies as it takes advantage of the spatial-controlled PDT and the effective enzyme-catalyzed bioreactions. However, it is a challenge to co-encapsulate hydrophilic enzymes and hydrophobic photosensitizers, and these two agents often interfere with each other. In this work, a protocell-like nanoreactor (GOx-MSN@MnPc-LP) has been designed for synergistic starvation therapy and PDT. In this nanoreactor, the hydrophilic glucose oxidase (GOx) is loaded in the pore of mesoporous silica nanoparticles (MSNs), while the hydrophobic manganese phthaleincyanide (MnPc) is loaded in the membrane layer of liposome. This spatial separation of two payloads protects GOx and MnPc from the cellular environment and avoids interference with each other. GOx catalyzes the oxidation of glucose, which generates hydrogen peroxide and gluconic acid, leading to the starvation therapy via glucose consumption in cancer cells, as well as the disruption of cellular redox balance. MnPc produces cytotoxic singlet oxygen under 730 nm laser irradiation, achieving PDT. The antitumor effects of the nanoreactor have been verified on tumor cells and tumor-bearing mice models. GOx-MSN@MnPc-LP efficiently inhibits tumor growth in vivo with a single treatment, indicating the robust synergy of starvation therapy and PDT treatment. This work also offers a versatile strategy for delivering hydrophilic enzymes and hydrophobic photosensitizers using a protocell-like nanoreactor for effective cancer treatment.

Biomineralization-inspired nanozyme for single-wavelength laser activated photothermal-photodynamic synergistic treatment against hypoxic tumors.

Hypoxia, one of the features of most solid tumors, can severely impede the efficiency of oxygen-dependent treatments such as chemotherapy, radiotherapy and type-II photodynamic therapy. Herein, a catalase-like nanozyme RuO2@BSA (RB) was first prepared through a biomineralization strategy, and a high efficiency near-infrared photosensitizer (IR-808-Br2) was further loaded into the protein shell to generate the safe and versatile RuO2@BSA@IR-808-Br2 (RBIR) for the imaging-guided enhanced phototherapy against hypoxic tumors. RB not only acts like a catalase, but also serves as a photothermal agent that speeds up the oxygen supply under near-infrared irradiation (808 nm). The loaded NIR photosensitizer could immediately convert molecular oxygen (O2) to cytotoxic singlet oxygen (1O2) upon the same laser irradiation. Results indicated that RBIR achieved enhanced therapeutic outcomes with negligible side effects. Features such as a simple synthetic route and imaging-guided and single-wavelength-excited phototherapy make the nanozyme a promising agent for clinical applications.