Functional Nanomedicines for Targeted Therapy of Bladder Cancer

Bladder cancer is one of most common malignant urinary tract tumor types with high incidence worldwide. In general, transurethral resection of non-muscle-invasive bladder cancer followed by intravesical instillation of chemotherapy is the standard treatment approach to minimize recurrence and delay progression of bladder cancer. However, conventional intravesical chemotherapy lacks selectivity for tumor tissues and the concentration of drug is reduced with the excretion of urine, leading to frequent administration and heavy local irritation symptoms. While nanomedicines can overcome all the above shortcomings and adhere to the surface of bladder tumors for a long time, and continuously and efficiently release drugs to bladder cancers. The rapid advances in targeted therapy have led to significant improvements in drug efficacy and precision of targeted drug delivery to eradicate tumor cells, with reduced side-effects. This review summarizes the different available nano-systems of targeted drug delivery to bladder cancer tissues. The challenges and prospects of targeted therapy for bladder cancer are additionally discussed.

The Role of PIEZO1 in Urinary Bladder Function and Dysfunction in a Rodent Model of Cyclophosphamide-Induced Cystitis

In the urinary bladder, mechanosensitive ion channels (MSCs) underlie the transduction of bladder stretch into sensory signals that are relayed to the PNS and CNS. PIEZO1 is a recently identified MSC that is Ca2+ permeable and is widely expressed throughout the lower urinary tract. Recent research indicates that PIEZO1 is activated by mechanical stretch or by pharmacological agonism via Yoda1. Aberrant activation of PIEZO1 has been suggested to play a role in clinical bladder pathologies like partial bladder outlet obstruction and interstitial cystitis/bladder pain syndrome (IC/BPS). In the present study, we show that intravesical instillation of Yoda1 in female Wistar rats leads to increased voiding frequency for up to 16 hours after administration compared to vehicle treatment. In a cyclophosphamide (CYP) model of cystitis, we found that the gene expression of several candidate MSCs (Trpv1, Trpv4, Piezo1, and Piezo2) were all upregulated in the urothelium and detrusor following chronic CYP-induced cystitis, but not acute CYP-induced cystitis. Functionally with this model, we show that Ca2+ activity is increased in urothelial cells following PIEZO1 activation via Yoda1 in acute and intermediate CYP treatment, but not in naïve (no CYP) nor chronic CYP treatment. Lastly, we show that activation of PIEZO1 may contribute to pathological bladder dysfunction through the downregulation of several tight junction genes in the urothelium including claudin-1, claudin-8, and zona occludens-1. Together, these data suggest that PIEZO1 activation plays a role in dysfunctional voiding behavior and may be a future, clinical target for the treatment of pathologies like IC/BPS.

TP7.2.3 The effect of immediate versus early instillation of mitomycin C after transurethral resection of bladder cancer: Is timing everything?

Introduction and Aims Almost three quarters of patients diagnosed with bladder cancer have non-muscle invasive disease. The European Association of Urology (EAU) guidelines recommend the use of intravesical instillation of Mitomycin C (MMC) to reduce the rate of recurrence. Methods A retrospective cohort analysis was carried out of all patients who underwent a TURBT between January 2016 and January 2019 in our Trust. A comparison of recurrence outcomes was investigated between patients who had immediate instillation of MMC (within 1 hours post-TURBT) versus early instillation (within 24 hours post-TURBT). Recurrence was assessed at 3 months cystoscopy and at 1 year follow-up. Results 201 patients were included. 100 underwent immediate MMC instillation (75% male, 25% female); 101 early instillation (72% male, 28% female). There was 11% recurrence (immediate) versus 13% (early) in instillation groups at 3 months. At first year, recurrence was seen in 12% (immediate) versus 14% (early) groups. Of these recurrences, there was an upstaging of tumour in 27% (immediate) versus 31% (early) at the 3 monthly follow-up and 25% (immediate) versus 28% (early) at the 1st year. The mean period of post-operative stay following initial TURBT was 0.8 days in the immediate versus 1.1 days in the early instillation groups. Conclusion Although no statistical differences were seen in this study, the results appear to favour immediate instillation of MMC after TURBT with respect to reduction in recurrence and upstaging rates. Post-operative length of stay in hospital was also shorter in patients who had an immediate MMC instillation.

Role of Aminophylline Intravesical Instillation on Enhancing Ureteral Dilatation prior to Ureteroscopy

Background Semi-rigid uretroscopy (URS) is a common intervention approach for lower ureteric stones. Ureteral dilatation is frequently needed before URS to enable ureter accessing. Aminophylline is known by its muscle relaxant effect and has been suggested to be effective in ureteral dilation. Objectives To evaluate the effect of intravesical administration of aminophylline on ureteroscopy and to measure intraureteral pressure Methods This prospective randomized controlled study included 50 before and after aminophylline injection. patients with lower ureteral calculi. In group A, the ureter was dilated by intravesical aminophylline whereas in group B balloon dilator was used. Intraureteral pressure was measured using pressure transducer connected to invasive pressure monitor. Results No statistically significant difference was noticed between both groups in operative time, intra operative complication, need for ureteral stenting or stone free rate. However, post-operative pain and haematuria were statistically significantly higher among balloon group compared to aminophylline group. In group A, there was statistically significant decrease in intraureteral pressure after injection of aminophylline (7.80 ± 1.71) compared to before injection (12.2 ± 1.85) with p-value < 0.001. Conclusion Aminophylline is effective in ureteral dilatation when intravesically injected with less frequent post-operative pain and hematuria.

Efficacy of Intra-Arterial Plus Intravesical Chemotherapy for High-Risk Non-Muscle-Invasive Bladder Cancer: A Pooled Analysis

Background: The treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) remains highly debated for its high recurrence and progression risk. This work aimed to verify the efficacy and toxicity of intra-arterial chemotherapy (IAC) plus intravesical chemotherapy (IVC) in high-risk NMIBC.Methods: A comprehensive online literature search was conducted in three databases to select researches related to IAC + IVC for high-risk NMIBC. All data were analyzed using the Review Manager software version 5.3. And we used the Cochrane Risk of Bias tool to assessed the quality of these enrolled researches.Results: Seven eligible original publications were enrolled in our studies with a total of 1,247 patients. Compared with the intravesical instillation, IAC + IVC therapy showed a better therapeutic effect. The total odds ratio for tumor recurrence rate, tumor progression rate, survival rate, and tumor-specific death rate was calculated as 0.51 (95% CI: 0.36–0.72; p < 0.05), 0.51 (95% CI: 0.36–0.72; p < 0.05), 1.75 (95% CI: 1.09–2.81; p < 0.05), and 0.48 (95% CI: 0.28–0.84; p < 0.05), respectively. In patients who received IAC, most of the adverse events (AEs)in the treatment were Grade I and II.Conclusion: IAC + IVC regimen for high-risk NMIBC could effectively reduce recurrence and progression and provide a better prognosis than intravesical instillation. The adverse events of IAC were mild and acceptable.

Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer

Azacitidine, an inhibitor of DNA methylation, shows therapeutic effects against several malignancies by inducing apoptosis and inhibiting tumor cell proliferation. However, the anti-tumor effects of azacitidine on urinary bladder urothelial carcinoma (UBUC), especially following intravesical instillation (IVI), are not established. Here, UBUC cell lines were used to analyze the in vitro therapeutic effects of azacitidine. Potential signaling pathways were investigated by antibody arrays and Western blotting. The N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat UBUC model was used for in vivo quantitative analysis of tumor burden. Azacitidine significantly inhibited DNMT expression in UBUC cell lines and reduced cell viability and clonogenic activity, as determined by MTT and colony formation assays, while also inducing significant cytotoxic effects in the form of increased sub-G1 and Annexin V-PI populations (all p < 0.05). Antibody arrays confirmed the in vitro suppression of TNF-R1 and the induction of TRAIL-R2 and their downstream signaling molecules. TNF-R1 suppression reduced claspin and survivin expression, while TRAIL-R2 activation induced cytochrome C and caspase 3 expression. Rats with BBN-induced bladder cancer had a significantly reduced tumor burden and Ki67 index following IVI of azacitidine (p < 0.01). Our study provides evidence for a reduction in BBN-induced bladder cancer by IVI of azacitidine through alterations in the TRAIL-R2 and TNF-R1 signaling pathways. These findings might provide new insights for further clinical trials.

Effectiveness of Steroid Pulse Therapy for Systemic Side Effects after Bacillus Calmette-Guérin Intravesical Instillation Therapy: A Series of Five Cases

Introduction. Bacillus Calmette-Guérin (BCG) instillation is an established therapy for the treatment of carcinoma in situ (CIS) of the bladder and prevention of recurrence after transurethral resection of bladder tumor noninvasive bladder cancer. However, serious systemic side effects may occur in less than 5% of patients with BCG intravesical instillation. Systemic side effects can sometimes be fatal and require early and accurate treatment. We describe five cases wherein steroid pulse therapy was effective for treating the systemic side effects after BCG intravesical instillation. Case Presentations. BCG intravesical instillation was used to prevent the recurrence of nonmuscle invasive bladder cancer and treat CIS of the bladder; the dose used was 40–80 mg each time, and the Tokyo strain was used. The patients developed fever, impaired consciousness, arthralgia, conjunctival hyperemia, and symptoms of cystitis. The median time from installation to side effect manifestation was 6 days (0–8). One to two courses of steroid pulse therapy were administered (1 course in 3 days), and the dose of methylprednisolone was 500–1000 mg/day. BCG sepsis was observed in one case; however, in the other four cases, one course of steroid pulse therapy showed a rapid improvement in symptoms. In the case of BCG sepsis, hemodialysis and mechanical ventilation were required because of septic shock and acute renal failure. Antituberculosis drugs (isoniazid, rifampicin, and ethambutol) were started promptly; however, no improvement was noticed. Two courses of steroid pulse therapy improved the patient’s general condition, and hemodialysis and mechanical ventilation were no longer required. All patients survived without relapse of symptoms. Conclusion. Our cases suggest that early steroid pulse therapy may be effective for rapid symptom improvement of the systemic side effects of BCG instillation therapy.