The Current Status of Photodynamic Therapy in Cancer Treatment.

Although we have made great strides in treating deadly diseases over the years, cancer therapy still remains a daunting challenge. Among numerous anticancer methods, photodynamic therapy (PDT), a non-invasive therapeutic approach, has attracted much attention. PDT exhibits outstanding performance in cancer therapy, but some unavoidable disadvantages, including limited light penetration depth, poor tumor selectivity, as well as oxygen dependence, largely limit its therapeutic efficiency for solid tumors treatment. Thus, numerous strategies have gone into overcoming these obstacles, such as exploring new photosensitizers with higher photodynamic conversion efficiency, alleviating tumor hypoxia to fuel the generation of reactive oxygen species (ROS), designing tumor-targeted PS, and applying PDT-based combination strategies. In this review, we briefly summarized the PDT related tumor therapeutic approaches, which are mainly characterized by advanced PSs, these PSs have excellent conversion efficiency and additional refreshing features. We also briefly summarize PDT-based combination therapies with excellent therapeutic effects.

State-of-the-Art Advances of Nanomedicine for Diagnosis and Treatment of Bladder Cancer.

Bladder cancer is a common malignant tumor of the urinary system. Cystoscopy, urine cytology, and CT are the routine diagnostic methods. However, there are some problems such as low sensitivity and difficulty in staging, which must be urgently supplemented by novel diagnostic methods. Surgery, intravesical instillation, systemic chemotherapy, and radiotherapy are the main clinical treatments for bladder cancer. It is difficult for conventional treatment to deal with tumor recurrence, progression and drug resistance. In addition, the treatment agents usually have the defects of poor specific distribution ability to target tumor tissues and side effects. The rapid development of nanomedicine has brought hope for the treatment of bladder cancer in reducing side effects, enhancing tumor inhibition effects, and anti-drug resistance. Overall, we review the new progression of nano-platforms in the diagnosis and treatment of bladder cancer.

Overexpression of BIRC6 driven by EGF-JNK-HECTD1 signaling is a potential therapeutic target for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. The lack of targeted therapies and poor patient outcome have fostered efforts to discover new molecular targets to treat patients with TNBC. Here, we showed that baculoviral IAP repeat containing 6 (BIRC6) is overexpressed and positively correlated with epidermal growth factor (EGF) receptor (EGFR) in TNBC cells and tissues and that BIRC6 overexpression is associated with poor patient survival. Mechanistic studies revealed that BIRC6 stability is increased by EGF-JNK signaling, which prevents ubiquitination and degradation of BIRC6 mediated by the E3 ubiquitin ligase HECTD1. BIRC6 in turn decreases SMAC expression by inducing the ubiquitin-proteasome pathway, thereby antagonizing apoptosis and promoting the proliferation, colony formation, tumorsphere formation, and tumor growth capacity of TNBC cells. Therapeutically, the PEGylated cationic lipid nanoparticle (pCLN)-assisted delivery of BIRC6 small interfering RNA (siRNA) efficiently silences BIRC6 expression in TNBC cells, thus suppressing TNBC cell growth in vitro and in vivo, and its antitumor activity is significantly superior to that of the EGFR inhibitor gefitinib. Our findings identify an important regulatory mechanism of BIRC6 overexpression and provide a potential therapeutic option for treating TNBC.

Nitazoxanide impairs mitophagy flux through ROS-mediated mitophagy initiation and lysosomal dysfunction in bladder cancer.

Bladder cancer is one of the most common malignancy in the urinary tract with high recurrence and drug resistance in clinics. Alternative treatments from existing drugs might be a promising strategy. Nitazoxanide (NTZ), an FDA-approved antiprotozoal drug, has got increasingly noticed because of its favorable safety profile and antitumor potential, yet the effects in bladder cancer and underlying mechanisms remain poorly understood. Herein, we find that NTZ induces mitochondrial damage and mitophagy initiation through PINK1-generated phospho-ubiquitin(pS65-Ub) and autophagy receptor-mediated pathway even in the absence of Atg5/Beclin1. Meanwhile, NTZ inhibits lysosomal degradation activity, leading to mitophagy flux impairment at late stage. Mitochondrial reactive oxygen species (ROS) production is critical in this process, as eliminating ROS with N-acetylcysteine (NAC) efficiently inhibits PINK1 signaling-mediated mitophagy initiation and alleviates lysosomal dysfunction. Co-treatment with NTZ and autophagy inhibitor Chloroquine (CQ) to aggravate mitophagy flux impairment promotes NTZ-induced apoptosis, while alleviation of mitophagy flux impairment with ROS scavenger reduces cell death. Moreover, we also discover a similar signaling response in the 3D bladder tumor spheroid after NTZ exposure. In vivo study reveals a significant inhibition of orthotopic bladder tumors with no obvious systemic toxicity. Together, our results uncover the anti-tumor activities of NTZ with the involvement of ROS-mediated mitophagy modulation at different stages and demonstrate it as a potential drug candidate for fighting against bladder tumors.

Fluorinated Chitosan To Enhance Transmucosal Delivery of Sonosensitizer-Conjugated Catalase for Sonodynamic Bladder Cancer Treatment Post-intravesical Instillation.

Sonodynamic therapy (SDT) is a noninvasive ultrasound-triggered therapeutic strategy for site-specific treatment of tumors with great depth penetration. The design of nano-sonosensitizers suitable for SDT treatment of bladder cancer (BCa) post-intravesical instillation has not yet been reported. Herein, a transmucosal oxygen-self-production SDT nanoplatform is developed to achieve highly efficient SDT against BCa. In this system, fluorinated chitosan (FCS) is synthesized as a highly effective nontoxic transmucosal delivery carrier to assemble with meso-tetra(4-carboxyphenyl)porphine-conjugated catalase (CAT-TCPP). The formed CAT-TCPP/FCS nanoparticles after intravesical instillation into the bladder cavity exhibit excellent transmucosal and intratumoral penetration capacities and could efficiently relieve hypoxia in tumor tissues by the catalase-catalyzed O2 generation from tumor endogenous H2O2 to further improve the therapeutic efficacy of SDT to ablate orthotopic bladder tumors under ultrasound. Our work presents a nano-sonosensitizer formulation with FCS to enhance transmucosal delivery and intratumoral diffusion and CAT to improve tumor oxygenation, promising for instillation-based SDT to treat bladder tumors without the concern of systemic toxicity.

Rapid and quantitative detection of urinary Cyfra21-1 using fluorescent nanosphere-based immunochromatographic test strip for diagnosis and prognostic monitoring of bladder cancer.

Bladder cancer is a common malignant tumour with high recurrence rate. Cytokeratin 19 fragments (Cyfra21-1) in urine has been regarded as a promising biomarker for the prognosis and diagnosis of bladder cancer due to the relevance of its high urinary level to the bladder cancer patients. However, currently detection methods of Cyfra21-1 have their limits, such as complicated steps, limited sensitivity or unsatisfying specificity. In this study, we developed a novel time-resolved fluoroimmuno test strip by using europium chelate microparticle (Eu-CM). Detection was performed in simple steps by carrying drops of sample into the well of the test strip, waiting for 15 min and inserting the strip into a fluorescence strip reader for quantitation. The standard curve equation of the test strip was y = 0.0177x + 0.01 (R2 = .9993). In the analysis of human urine samples (n = 115), it demonstrated a good performance (accuracy: CV < 10%, AUC: 0.989). With the cut-off value of 81 ng/mL, the sensitivity and specificity for bladder cancer were 92.86 and 100%, respectively. In comparison to ELISA and electrochemiluminescence methods, the Eu-CM based time-resolved fluoroimmuno test strip provided a rapid, sensitive and reliable method for monitoring bladder cancer. It may be applied as a non-invasive approach for in point-of-care for bladder cancer detection.

Fluorinated Polymer Mediated Transmucosal Peptide Delivery for Intravesical Instillation Therapy of Bladder Cancer.

Surgical intervention combined with intravesical instillation of chemotherapeutics to clear residual cancer cells after operation is the current standard treatment method for bladder cancer. However, the poor bioavailability of active pharmaceutical ingredients for bladder cancer cells on account of the biological barriers of bladder mucosa, together with significant side effects of currently used intravesical medicine, have limited the clinical outcomes of localized adjuvant therapy for bladder cancer. Aiming at improved intravesical instillation therapy of bladder cancer, a fluorinated polyethylenimine (F-PEI) is employed here for the transmucosal delivery of an active venom peptide, polybia-mastoparan I (MPI), which shows selective antiproliferative effect against various bladder cancer cell lines. Upon simple mixing, MPI and F-PET would coassemble to form stable nanoparticles, which show greatly improved cross-membrane and transmucosal penetration capacities compared with MPI alone or nonfluorinated MPI/PEI nanoparticles. MPI/F-PEI shows higher in vivo tumor growth inhibition efficacy for local treatment of a subcutaneous tumor model. More excitingly, as further demonstrated in an orthotopic bladder cancer model, MPI/F-PEI offers remarkably improved therapeutic effects compared to those achieved by free MPI or the first-line bladder cancer drug mitomycin C. This work presents a new transmucosal delivery carrier particularly promising for intravesical instillation therapy of bladder cancer.

In silico target fishing and pharmacological profiling for the isoquinoline alkaloids of Macleaya cordata (Bo Luo Hui).

BACKGROUND: Some isoquinoline alkaloids from Macleaya cordata (Willd). R. Br. (Bo Luo Hui) exhibited antibacterial, antiparasitic, antitumor, and analgesic effects. The targets of these isoquinoline alkaloids are undefined. This study aims to investigate the compound-target interaction network and potential pharmacological actions of isoquinoline alkaloids of M. cordata by reverse pharmacophore database screening. METHODS: The targets of 26 isoquinoline alkaloids identified from M. cordata were predicted by a pharmacophore-based target fishing approach. Discovery Studio 3.5 and two pharmacophore databases (PharmaDB and HypoDB) were employed for the target profiling. A compound-target interaction network of M. cordata was constructed and analyzed by Cytoscape 3.0. RESULTS: Thirteen of the 65 predicted targets identified by PharmaDB were confirmed as targets by HypoDB screening. The targets in the interaction network of M. cordata were involved in cancer (31 targets), microorganisms (12 targets), neurodegeneration (10 targets), inflammation and autoimmunity (8 targets), parasitosis (5 targets), injury (4 targets), and pain (3 targets). Dihydrochelerythrine (C6) was found to hit 23 fitting targets. Macrophage migration inhibitory factor (MIF) hits 15 alkaloids (C1-2, C11-16, C19-25) was the most promising target related to cancer. CONCLUSION: Through in silico target fishing, the anticancer, anti-inflammatory, and analgesic effects of M. cordata were the most significant among many possible activities. The possible anticancer effects were mainly contributed by the isoquinoline alkaloids as active components.