Prediction of T staging in PI-RADS 4-5 prostate cancer by combination of multiparametric MRI and 68Ga-PSMA-11 PET/CT.

BACKGROUND: In this study, we explored the diagnostic performances of multiparametric magnetic resonance imaging (mpMRI), 68 Ga-PSMA-11 PET/CT and combination of 68 Ga-PSMA-11 PET/CT and mpMRI (mpMRI + PET/CT) for extracapsular extension (ECE). Based on the analyses above, we tested the feasibility of using mpMRI + PET/CT results to predict T staging in prostate cancer patients. METHODS: By enrolling 75 patients of prostate cancer with mpMRI and 68 Ga-PSMA-11 PET/CT before radical prostatectomy, we analyzed the detection performances of ECE in mpMRI, 68 Ga-PSMA-11 PET/CT and mpMRI + PET/CT on their lesion images matched with their pathological sample images layer by layer through receiver operating characteristics (ROC) analysis. By inputting the lesion data into Prostate Imaging Reporting and Data System (PI-RADS), we divided the lesions into different PI-RADS scores. The improvement of detecting ECE was analyzed by net reclassification improvement (NRI). The predictors for T staging were evaluated by using univariate and multivariable analysis. The Kappa test was used to evaluate the prediction ability. RESULTS: One hundred three regions of lesion were identified from 75 patients. 50 of 103 regions were positive for ECE. The ECE diagnosis AUC of mpMRI + PET/CT is higher than that of mpMRI alone (ΔAUC = 0.101; 95% CI, 0.0148 to 0.1860; p < 0.05, respectively). Compared to mpMRI, mpMRI + PET/CT has a significant improvement in detecting ECE in PI-RADS 4-5 (NRI 36.1%, p < 0.01). The diagnosis power of mpMRI + PET/CT was an independent predictor for T staging (p < 0.001) in logistic regression analysis. In patients with PI-RADS 4-5 lesions, 40 of 46 (87.0%) patients have correct T staging prediction from mpMRI + PET/CT (κ 0.70, p < 0.01). CONCLUSION: The prediction of T staging in PI-RADS 4-5 prostate cancer patients by mpMRI + PET/CT had a quite good performance.

In Situ Vaccination with Mitochondria-Targeting Immunogenic Death Inducer Elicits CD8+ T Cell-Dependent Antitumor Immunity to Boost Tumor Immunotherapy.

In situ vaccination can elicit systemic antitumor immunity to potentiate immune checkpoint blockade (ICB) in poorly immunogenic tumors. Herein, an immunogenic cell death (ICD) inducer for in situ vaccination, which is based on a mitochondria-targeting modification of fenofibric acid (FFa), a lipid-lowering drug with potential inhibitory efficacy of respiratory complex I is developed. Mitochondria-targeting FFa (Mito-FFa) inhibits complex I efficiently and increases mitochondrial ROS (mtROS) generation, which further triggers endoplasmic reticulum (ER) stress with unprecedented calreticulin (CRT) exposure on tumor cellular membranes. Moreover, the generated mtROS also oxidizes mitochondrial DNA (mtDNA) and promotes it leakage into the cytoplasm for cGAS-STING-dependent type I interferon (IFN-I) secretion. The synchronous CRT exposure and IFN-I secretion successively improve the uptake of tumor antigens, maturation of dendritic cells (DCs) and cross-priming of CD8+ T cells. In a poorly immunogenic 4T1 tumor model, a single intratumoral (i.t.) Mito-FFa injection turns immune-cold tumors into hot ones and elicits systemic tumor-specific CD8+ T cells responses against primary and metastatic tumors. Furthermore, the synergistic effect with PD-L1 blockade and good bio-safety of i.t. Mito-FFa administration suggest the great translational potential of Mito-FFa in tumor immunotherapy.

Clinical features and outcomes of patients with chronic granulomatous disease in Taiwan.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by defective neutrophil killing of microbial pathogens and recurrent infections. We aimed to investigate the clinical, genetic features, treatment, and outcomes in patients with CGD. METHODS: Pediatric patients diagnosed with CGD from a medical center in Taiwan were enrolled from January 1999 to Oct 2021. RESULTS: Nine pediatric patients with CGD were enrolled: six X-linked (XL) CGD with CYBB gene mutations, three autosomal recessive (AR) CGD with two NCF1 and one CYBA gene mutations. The median age of onset and age of diagnosis was 0.92 and 2.64 years, respectively. Patients with XL-CGD had a younger age of onset (4.6 months vs. 1.83 years, P = 0.06) and age of diagnosis (1.71 vs. 8.86 years, P = 0.024) than AR-CGD patients. The most common sites of infections were skin and soft tissue abscesses. The most common pathogens were Staphylococcus, Serratia, and Salmonella spp. Prophylactic antibiotics, anti-fungal agents, and interferon-gamma (IFN-γ) were given in 9 (100%), 7 (77.8%), and 8 (88.9%) patients, respectively. The mean duration of IFN-γ usage was 5.15 years. One male patient with XL-CGD was successfully treated with hematopoietic stem cell transplantation at 2.2 years. The mortality rate was 11.1%, and the estimated overall survival at 20 years was 66.7%. CONCLUSION: Staphylococcus aureus, Serratia marcescens, and Salmonella infections are important in Taiwanese CGD patients. Patients with XL-CGD have early disease onset. IFN-γ prophylaxis and prophylactic anti-microbial agents might have an effect on alleviating the infection episodes in CGD patients.

Allosteric activation of the metabolic enzyme GPD1 inhibits bladder cancer growth via the lysoPC-PAFR-TRPV2 axis.

BACKGROUND: Bladder cancer is the most common malignant tumor of the urinary system. Surgical resection and chemotherapy are the two mainstream treatments for bladder cancer. However, the outcomes are not satisfactory for patients with advanced bladder cancer. There is a need to further explore more effective targeted therapeutic strategies. METHODS: Proteomics were performed to compare protein expression differences between human bladder cancer tissues and adjacent normal tissues. The function of GPD1 on bladder cancer cells were confirmed through in vivo and in vitro assays. Transcriptomics and metabolomics were performed to reveal the underlying mechanisms of GPD1. Virtual screening was used to identify allosteric activator of GPD1. RESULTS: Here, we used proteomics to find that GPD1 expression was at low levels in bladder cancer tissues. Further investigation showed that GPD1 overexpression significantly promoted apoptosis in bladder cancer cells. Based on transcriptomics and metabolomics, GPD1 promotes Ca2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. Finally, we performed a virtual screening to obtain the GPD1 allosteric activator wedelolactone and demonstrated its ability to inhibit bladder tumor growth in vitro and in vivo. CONCLUSIONS: This study suggests that GPD1 may act as a novel tumor suppressor in bladder cancer. Pharmacological activation of GPD1 is a potential therapeutic approach for bladder cancer.

Lysosomal protein transmembrane 5 promotes lung-specific metastasis by regulating BMPR1A lysosomal degradation.

Organotropism during cancer metastasis occurs frequently but the underlying mechanism remains poorly understood. Here, we show that lysosomal protein transmembrane 5 (LAPTM5) promotes lung-specific metastasis in renal cancer. LAPTM5 sustains self-renewal and cancer stem cell-like traits of renal cancer cells by blocking the function of lung-derived bone morphogenetic proteins (BMPs). Mechanistic investigations showed that LAPTM5 recruits WWP2, which binds to the BMP receptor BMPR1A and mediates its lysosomal sorting, ubiquitination and ultimate degradation. BMPR1A expression was restored by the lysosomal inhibitor chloroquine. LAPTM5 expression could also serve as an independent predictor of lung metastasis in renal cancer. Lastly, elevation of LAPTM5 expression in lung metastases is a common phenomenon in multiple cancer types. Our results reveal a molecular mechanism underlying lung-specific metastasis and identify LAPTM5 as a potential therapeutic target for cancers with lung metastasis.

Mass cytometry reveals immune atlas of urothelial carcinoma.

Immunotherapy has emerged as a robust clinical strategy for cancer treatment. PD1/PD-L1 inhibitors have been used as second-line therapy for urothelial carcinoma due to the high tumor mutational burden. Despite the efficacy of the treatment is significant, the response rate is still poor. The tumor immune microenvironment plays a key role in the regulation of immunotherapeutic efficacy. However, a comprehensive understanding of the intricate microenvironment in clinical samples remains unclear. To obtain detailed systematic tumor immune profile, we performed an in-depth immunoassay on 12 human urothelial carcinoma tissue samples and 14 paratumor tissue samples using mass cytometry. Among the large number of cells assayed, we identified 71 T-cell phenotypes, 30 tumor-associated macrophage phenotypes. T cell marker expression profiles showed that almost all T cells in the tumor tissue were in a state of exhaustion. CD38 expression on tumor-associated macrophages (TAMs) was significantly higher than PDL1, and CD38+ TAMs were closely associated with immunosuppression. CD38 may be a more suitable target for immunotherapy in urothelial carcinoma compared to PD1/PDL1. This single-cell analysis of clinical samples expands our insights into the immune microenvironment of urothelial carcinoma and reveals potential biomarkers and targets for immunotherapy development.

Crosstalk between IL-15Rα+ tumor-associated macrophages and breast cancer cells reduces CD8+ T cell recruitment.

BACKGROUND: Interleukin-15 (IL-15) is a promising immunotherapeutic agent owing to its powerful immune-activating effects. However, the clinical benefits of these treatments are limited. Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance. Herein, this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression. METHODS: T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15. Western blotting, histological analysis, CRISPR-Cas9 knockout, multi-parameter flow cytometry, and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα+ tumor-associated macrophages (TAMs) regulate breast cancer cell resistance to IL-15. RESULTS: We found that macrophages contributed to the resistance of tumor cells to IL-15, and tumor cells induced macrophages to express high levels of the α subunit of the IL-15 receptor (IL-15Rα). Further investigation showed that IL-15Rα+ TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1 (CX3CL1) in tumor cells to inhibit the recruitment of CD8+ T cells by releasing the IL-15/IL-15Rα complex (IL-15Rc). Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti- programmed cell death protein 1 (PD-1) antibody immunotherapy. Interestingly, Granulocyte-macrophage colony-stimulating factor (GMCSF) induced γ chain (γc) expression to promote tumor cell-macrophage crosstalk, which facilitated tumor resistance to IL-15. Additionally, we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha (HIF-1α) was essential for IL-15Rc to regulate CX3CL1 expression in tumor cells. CONCLUSIONS: The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumor microenvironment of breast cancer. Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.

Biomechanical Evaluation and Factorial Analysis of the 3-Dimensional Printing Self-Designed Metallic Reconstruction Plate for Mandibular Segmental Defect.

PURPOSE: Reconstruction plates are frequently used to treat mandibular segmental defects. The aim of this study is to compare the biomechanical performance of a 3-dimensional-printed self-designed titanium alloy reconstruction plate with that of the traditional reconstruction plate in mandible reconstruction. The analyzed parameters of the self-designed reconstruction plate, including plate length (100 mm and 125 mm), plate thickness (2.1, 2.4, and 2.7 mm), and bone mass (100, 75, and 50%), were also evaluated. METHODS: An artificial mandible with anatomical geometry was used to develop the self-designed reconstructed plate. Both in vitro experiments and finite element simulations were performed for the biomechanical comparison of the self-designed and traditional reconstruction plates. In finite element analysis, 3 major muscle forces of mandible movement were set as the loading condition, and the displacement of the condyle was fixed in all directions as the boundary condition. RESULTS: The biomechanical performances (stresses in the plate and strains in bone) of the self-designed reconstruction plate were superior to those of the traditional plate. Factorial analysis indicated that plate length and thickness had significant effects on decreasing stresses of the plate and mandibular bone. CONCLUSIONS: The self-designed reconstruction plate might have a benefit to reduce the stresses/strains in plate itself and surrounding bone.

Synergy of Tumor Microenvironment Remodeling and Autophagy Inhibition to Sensitize Radiation for Bladder Cancer Treatment.

Tumor hypoxia, acidosis, and excessive reactive oxygen species (ROS) were the main characteristics of the bladder tumor microenvironment (TME), and abnormal TME led to autophagy activation, which facilitated cancer cell proliferation. The therapeutic efficacy of autophagy inhibitors might also be impeded by abnormal TME. To address these issues, we proposed a new strategy that utilized manganese dioxide (MnO2) nanoparticles to optimize the abnormal TME and revitalize autophagy inhibitors, and both oxygenation and autophagy inhibition may sensitize the tumor cells to radiation therapy. Methods: By taking advantage of the strong affinity between negatively charged MnO2 and positively charged chloroquine (CQ), the nanoparticles were fabricated by integrating MnO2 and CQ in human serum albumin (HSA)-based nanoplatform (HSA-MnO2-CQ NPs). Results: HSA-MnO2-CQ NPs NPs efficiently generated O2 and increased pH in vitro after reaction with H+/H2O2 and then released the encapsulated CQ in a H+/H2O2 concentration-dependent manner. The NPs restored the autophagy-inhibiting activity of chloroquine in acidic conditions by increasing its intracellular uptake, and markedly blocked hypoxia-induced autophagic flux. In vivo studies showed the NPs improved pharmacokinetic behavior of chloroquine and effectively accumulated in tumor tissues. The NPs exhibited significantly decreased tumor hypoxia areas and increased tumor pH, and had remarkable autophagy inhibition efficacy on bladder tumors. Finally, a significant anti-tumor effect achieved by the enhanced autophagy inhibition and radiation sensitization. Conclusions: HSA-MnO2-CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers.

Investigation of a Modified Novel Technique in Bilateral Sagittal Splitting Osteotomy Fixation: Finite Element Analysis and In Vitro Biomechanical Test.

PURPOSE: To evaluate the biomechanical properties of the modified novel 2-hole monocortical plate fixation (2HMCPf) and traditional 4-hole monocortical plate fixation (4HMCPf) techniques in bilateral sagittal splitting osteotomy (BSSO) synthesis using a finite element analysis (FEA) and an in vitro biomechanical test with the application of a shearing loading force on a sawbone mandible model. MATERIALS AND METHODS: A three-dimensional mandible models were generated using the geometry obtained from the computerized tomography image of a sawbone mandible. Plates and screws were generated and combined with the mandible in a CAD environment. The 2HMCPf and traditional 4HMCPf techniques for BSSO osteosynthesis were then analyzed under the occlusal load using the FEA. An in vitro biomechanical test was executed to verify the result of FEA. The force on fixation failure and pattern of failure were recorded. RESULTS: The results revealed that the von Mises Stress on the mandible cortical bone (75.98 MPa) and the screw/plate (457.19 MPa) of the 2HMCPf group was lower than that of the 4HMCPf group (987.68 MPa, 1781.59 MPa). The stress concentrated on the central region of the 4HMCPf group and the distal set of the 2HMCPf group. In vitro study using the sawbone mandible model showed mechanical failure at the region of the proximal segment near the osteotomy site with the 4HMCPf group (average 32.198 N) but no failure on the fixation sites with the 2HMCPf group. Instead, the mandible sawbone fractured on the condyle neck region (average 44.953 N). CONCLUSION: From the biomechanical perspective, we proved that the 2HMCPf method was able to withstand a higher shearing loading force than the 4HMCPf fixation method in BSSO osteosynthesis.

Comparisons of the safety and effectiveness of robot-assisted versus laparoscopic partial nephrectomy for large angiomyolipomas: a propensity score-matched analysis.

OBJECTIVE: To compare the safety and effectiveness of robot-assisted partial nephrectomy (RAPN) versus laparoscopic partial nephrectomy (LPN) for large angiomyolipomas (AMLs). MATERIALS AND METHODS: We retrospectively evaluated 150 patients who were treated with either RAPN or LPN for large angiomyolipomas from 2014 to 2018. Propensity score matching was performed on age, gender, BMI, Charlson Comorbidity Index, tumour side and size, preoperative eGFR and RENAL score. RESULTS: In total, 63 and 87 patients underwent RAPNs and LPNs, respectively. There were more large and complex AMLs in the RAPN cohort, with the median tumour maximal diameters and RENAL scores differing between the two groups (8 versus 7 cm and 9 versus 8, P = 0.01). After matching, the median warm ischemic time was significantly shorter in the RAPNs versus the LPNs (17 versus 22 min, P = 0.001). The rate of intraoperative complications in the RAPNs appeared lower than the LPNs (3.2% versus 8.1%). The median postoperative length of stay was significantly shorter in the RAPN cohort than the LPNs (P = 0.001). Twelve months after surgery, RAPNs received a 94.6% renal function prevention; while this was 90.8% in LPNs (P = 0.001). Subgroup analysis indicated that prior selective arterial embolization (SAE) was related to better renal function preservation in the RAPN cohort (P = 0.01). No recurrence occurred in either of the two cohorts. CONCLUSIONS: RAPN is a safe and effective alternative to LPNs for large AMLs with a shorter warm ischemic time and higher renal preservation rate. Recurrence was equivalent in both RAPNs and LPNs.

Comparison of perioperative outcomes in robot-assisted radical cystectomy and laparoscopic radical cystectomy.

OBJECTIVE: To report perioperative outcomes in robot-assisted radical cystectomy and laparoscopic radical cystectomy. PATIENTS AND METHODS: Between January 2010 and July 2019, 298 patients with bladder cancer underwent robotic-assisted radical cystectomy (RARC) (n = 172) and laparoscopic radical cystectomy (LRC) (n = 126) at our institution were enrolled in the retrospective study. The demographic, perioperative, and complication data were collected and analyzed. RESULTS: The RARC group had less operative duration (P < .001), less blood loss (P < .001), lower transfusion rate (P < .05), and shorter hospital stay (P < .001) than the LRC group. The 90-day readmission rate between the RARC and LRC group had no significant differences (P = .401). The 90-day overall complication rates in the RARC group was much lower than the LRC group (P = .009). The 90-day minor complication rates (Clavien-Dindo grade ≤ IIA) between the RARC and LRC groups were similar (P = .274). The 90-day major complication rates (Clavien-Dindo grade ≥ IIIA) in the LRC group was higher than the RARC group (P = .022). CONCLUSIONS: The RARC approach appears to offer some operative and perioperative benefits compared with the LRC approach. Larger, randomized studies are required to confirm these findings.

Size and temporal-dependent efficacy of oltipraz-loaded PLGA nanoparticles for treatment of acute kidney injury and fibrosis.

Acute kidney injury (AKI) is associated with high mortality and morbidity with no effective treatment available at present, which greatly escalates the risk of chronic kidney disease. Nanotechnology-based drug delivery for targeting renal tubules offers a new strategy for AKI treatment but remains challenging due to the glomerular filtration barrier. To tackle this challenge, here we demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of 100 nm diameter could selectively accumulate in mouse injury kidneys in correlation to the degree of kidney injury and administration time during the initial phase of renal ischemia-reperfusion injury. The NPs were located in renal tubular epithelial cells confirmed by immunofluorescence, which is critical for the progression of AKI. Taking advantage of the high accumulation and renal tubule targeting of the PLGA NPs in the ischemia-reperfusion (IR) kidney, we designed PLGA NPs loaded with Oltipraz (PLGA-Oltipraz NPs) to treat IR-induced AKI and renal fibrosis. In vitro results showed that compared to free Oltipraz, PLGA-Oltipraz NPs displayed a higher antioxidation effect with improved cell viability, lower contents of malondialdehyde, and higher activity of superoxide dismutase. The therapeutic efficacy of PLGA-Oltipraz NPs was further investigated in vivo. Mice with AKI treated with PLGA-Oltipraz NPs exhibited significantly reduced tubular necrosis, less collagen deposition, and better renal function at the initial phase as well as improved renal fibrosis at the recovery phase. This study establishes a promising approach for AKI and fibrosis treatment with PLGA-Oltipraz NPs. It also reveals the importance of size-selective NPs and drug administration time window to nanotherpeutics.

O2-generating MnO2 nanoparticles for enhanced photodynamic therapy of bladder cancer by ameliorating hypoxia.

Photodynamic therapy (PDT) is an emerging effective treatment for cancer. However, the great promise of PDT for bladder cancer therapy has not yet been realized because of tumor hypoxia. To address this challenge, we fabricated O2-generating HSA-MnO2-Ce6 NPs (HSA for human serum albumin, Ce6 for chlorin e6, and NPs for nanoparticles) to overcome tumor hypoxia and thus enhance the photodynamic effect for bladder cancer therapy. Methods: The HSA-MnO2-Ce6 NPs were prepared. We investigated the O2 generation of NPs in vitro and in vivo. The orthotopic bladder cancer model in C57BL/6 mice was established for in vivo study, and dual-modal imaging of NPs were demonstrated. Therapeutic efficacy of NPs for bladder cancer was evaluated. Results: HSA-MnO2-Ce6 NPs had an excellent performance in generating O2in vitro upon reaction with H2O2 at endogenous levels. Moreover, 1O2 generation was increased two-fold by using HSA-MnO2-Ce6 NPs instead of HSA-Ce6 NPs in the presence of H2O2 under 660 nm laser irradiation. In vitro cell viability assays showed that HSA-MnO2-Ce6 NPs themselves were non-toxic but greatly enhanced PDT effects on bladder cancer cells under laser irradiation. In vivo near-infrared (NIR) fluorescence and magnetic resonance (MR) imaging suggested the excellent bladder tumor-targeting property of HSA-MnO2-Ce6 NPs. O2 content in orthotopic bladder cancer was increased 3.5-fold after injection of HSA-MnO2-Ce6 NPs as compared with pre-injection. Given the excellent tumor-targeting ability and negligible toxicity, HSA-MnO2-Ce6 NPs were then used to treat orthotopic bladder cancer by PDT. The PDT with HSA-MnO2-Ce6 NPs showed remarkably improved therapeutic efficacy and significantly prolonged lifetime of mice as compared with controls. Conclusion: This study not only demonstrated the great potential of HSA-MnO2-Ce6 NPs for bladder cancer photodynamic ablation but also provided a new therapeutic strategy to overcoming tumor hypoxia.

miR34a/GOLPH3 Axis abrogates Urothelial Bladder Cancer Chemoresistance via Reduced Cancer Stemness.

Rationale: Chemoresistance and subsequent recurrence of human urothelial bladder cancer (UBC) is partially driven by a subpopulation of tumor initiating cells, namely cancer stem cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment and following chemoresistance and recurrence remains largely unclear. Methods: Gemcitabine and cisplatin (GC) chemoresistant cell lines (T24 GC 3rd and 5637 GC 3rd cells) and the chemo-sensitive UBC cell lines T24 and 5637 were established in vivo for the investigation of acquired resistance mechanisms. The role of miR34a/GOLPH3 axis in regulating UBC chemoresistance and recurrence was evaluated in cell and animal models. The expression levels of miR34a/GOLPH3 axis and CSCs markers were assayed in specimens of UBC. The association of GOLPH3 with clinicopathologic features and prognosis was analysed. Results: RT-PCR and western blotting confirmed that the expression levels of miR34a were decreased and GOLPH3 were increased in GC chemoresistant UBC cell lines. Downregulation of miR34a resulted in the overexpression of GOLPH3, which is a target gene of miR34a confirmed by luciferase experiment. The ectopic expression of miR34a decreased the stem cell properties of chemoresistant UBC cells and re-sensitized these cells to GC treatment in vitro and in vivo. Moreover, miR34a/GOLPH3 axis has obvious clinical relevance with prognosis and recurrence in human UBC patients with standard GC chemotherapy. Conclusion: Our results suggest that miR34a/GOLPH3 axis exert key role in CSCs involved UBC drug resistance and recurrence and warrant further development as a promising therapeutic approach in treating drug-resistant UBC.

Drug delivery system based on dendritic nanoparticles for enhancement of intravesical instillation.

Intravesical instillation of antitumor agents following transurethral resection of bladder tumors is the standard strategy for the treatment of superficial bladder cancers. However, the efficacy of current intravesical instillation is limited partly due to the poor permeability of the urothelium. We therefore aimed to develop a high-penetrating, target-releasing drug delivery system to improve the efficacy of intravesical instillation. PAMAM, a dendrimer, were conjugated with polyethylene glycol (PEG) to form PEG-PAMAM complex as a nanocarrier. Doxorubicin (DOX) was then encapsulated into PEG-PAMAM to generate DOX-loaded PEG-PAMAM nanoparticles (PEG-PAMAM-DOX). Our results indicated that the PEG-PAMAM was a stable nanocarrier with small size and great biosafety. The release of DOX from PEG-PAMAM-DOX was sluggish but could be effectively triggered in an acid microenvironment (pH =5.0). As a drug carrier, PEG-PAMAM could penetrate mice bladder urothelium effectively and increase the amount of DOX within the bladder wall after intravesical instillation. The antitumor effect of PEG-PAMAM-DOX was evaluated using an orthotopic bladder cancer model in mice. Compared to free DOX, PEG-PAMAM-DOX showed significantly improved efficacy of DOX for intravesical instillation with limited side effects. In conclusion, we successfully developed a PEG-PAMAM-based drug delivery system to enhance the antitumor effect of intravesical instillation.

Boosting the Peroxidase-Like Activity of Nanostructured Nickel by Inducing Its 3+ Oxidation State in LaNiO3 Perovskite and Its Application for Biomedical Assays.

Catalytic nanomaterials with intrinsic enzyme-like activities, called nanozymes, have recently attracted significant research interest due to their unique advantages relative to natural enzymes and conventional artificial enzymes. Among the nanozymes developed, particular interests have been devoted to nanozymes with peroxidase mimicking activities because of their promising applications in biosensing, bioimaging, biomedicine, etc. Till now, lots of functional nanomaterials have been used to mimic peroxidase. However, few studies have focused on the Ni-based nanomaterials for peroxidase mimics. In this work, we obtained the porous LaNiO3 nanocubes with high peroxidase-like activity by inducing its 3+ oxidation state in LaNiO3 perovskite and optimizing the morphology of LaNiO3 perovskite. The peroxidase mimicking activity of the porous LaNiO3 nanocubes with Ni3+ was about 58~fold and 22~fold higher than that of NiO with Ni2+ and Ni nanoparticles with Ni0. More, the porous LaNiO3 nanocubes exhibited about 2-fold higher activity when compared with LaNiO3 nanoparticles. Based on the superior peroxidase-like activity of porous LaNiO3 nanocubes, facile colorimetric assays for H2O2, glucose, and sarcosine detection were developed. Our present work not only demonstrates a useful strategy for modulating nanozymes' activities but also provides promising bioassays for clinical diagnostics.

Highly effective photothermal chemotherapy with pH-responsive polymer-coated drug-loaded melanin-like nanoparticles.

Dopamine is a neurotransmitter commonly used in clinical treatment. Polydopamine (PDA) has excellent histocompatibility and biosafety and can efficiently convert near-infrared reflection (NIR) to thermal energy. In this study, PDA was used as a promising carrier, and pH-responsive polymer-coated drug-loaded PDA nanoparticles (NPs; doxorubicin@ poly(allylamine)-citraconic anhydride [Dox@PAH-cit]/PDA NPs) were developed. As expected, the Dox@PAH-cit/PDA NPs exhibited excellent photothermal efficiency. In addition, at a low pH condition, the loaded Dox was released from the NPs due to the amide hydrolysis of PAH-cit. Upon NIR exposure (808 nm), the temperature of the NP solution rapidly increases to kill tumor cells. Compared with unbound chemotherapy drugs, the NPs have a stronger cell uptake ability. In vivo, the PDA NPs were able to efficiently accumulate at the tumor location. After intravenous administration and NIR exposure, tumor growth was significantly inhibited. In summary, the present investigation demonstrated that the Dox@PAH-cit/PDA NPs presented highly effective photothermal chemotherapy for prostate cancer.

Self-assembled tumor-targeting hyaluronic acid nanoparticles for photothermal ablation in orthotopic bladder cancer.

Bladder cancer is one of the most frequent malignancies in the urinary system. Radical cystectomy is inevitable when bladder cancer progresses to a muscle-invasive disease. However, cystectomy still causes a high risk of death and a low quality of life (such as ureter-abdomen ostomy, uroclepsia for ileal-colon neobladder). Therefore, more effective treatments as well as bladder preservation are needed. We developed self-assembled tumor-targeting hyaluronic acid-IR-780 nanoparticles for photothermal ablation in over-expressing CD44 (the receptor for HA) bladder cancer, which show high tumor selectivity, high treatment efficacy, good bioavailability, and excellent biocompatibility. The nanoparticles demonstrated a stable spherical nanostructure in aqueous conditions with good mono-dispersity, and their average size was 171.3±9.14nm. The nanoparticles can be degraded by hyaluronidase when it is over-expressed in bladder cells; therefore, they appear to have a hyaluronidase-responsive "OFF/ON" behavior of a fluorescence signal. HA-IR-780 NPs also showed high photothermal efficiency; 2.5, 5, 10 and 20µg/mL of NPs had a maximum temperature increase of 11.2±0.66°C, 18.6±0.75°C, 26.8±1.11°C and 32.3±1.42°C. The in vitro cell viability showed that MB-49 cells could be efficiently ablated by combining HA-IR-780 NPs with 808nm laser irradiation. Then, in vivo biodistribution showed the HA-IR-780 NPs are targeted for accumulation in bladder cancer cells but have negligible accumulation in normal bladder wall. The photothermal therapeutic efficacy of HA-IR-780 NPs in the orthotopic bladder cancer model showed tumors treated with NPs had a maximum temperature of 48.1±1.81°C after 6min of laser irradiation. The tumor volume was approximately 65-75mm3 prior to treatment. After 12days, the tumor sizes for the PBS, PBS plus laser irradiation and HA-IR-780 NPs-treated groups were 784.75mm3, 707.5mm3, and 711.37mm3, respectively. None of the tumors in the HA-IR-780 NPs plus laser irradiation-treated group were visible to the naked eye. A toxicity study showed HA-IR-780 NPs (2.5-20mg/kg, i.v.) were nontoxic and safe for in vivo applications. HA-IR-780 nanoparticles address current clinical challenges, treating locally aggressive lesions and preserving the bladder. They have enormous potential to improve the bladder cancer treatment strategies in clinic. STATEMENT OF SIGNIFICANCE: 1) Bladder cancer is one of the most frequent malignancies in the urinary system. Radical cystectomy is inevitable while bladder cancer progress to muscle-invasive disease. 2) We developed self-assembled tumor-targeting hyaluronic acid-IR-780 nanoparticles for photothermal ablation in over-expressing CD44 (the receptor for HA) bladder cancer. 3) Photothermal therapeutic efficacy of HA-IR-780 NPs in orthotopic bladder cancer model showed tumors were completely ablated. 4) HA-IR-780 nanoparticles address current clinical challenges, treating locally aggressive lesions as well as for bladder preservation.