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Delivery of Multifunctional Microspheres via Intravesical Instillation for Bladder Carcinoma: Therapeutic Potential
Zhaoxiang Lu1,2, Wentie Yang2, Youzhi Hong3
1Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Abstract:
Despite the use of standard intravesical instillation after surgery for non-muscle invasive bladder cancer (NMIBC), current drugs fail to eradicate residual tumor cells and are associated with high recurrence rates. To address this unmet clinical need, we synthesized tumor-targeted poly(1-carboxy-3,3,3-trimethylpropyl methacrylate) (PCTM) microspheres for intravesical delivery using microfluidic and click chemistry. Systematic in vitro and in vivo evaluations demonstrated that the PCTM microspheres exhibit excellent bladder mucosal adhesion, deep tissue penetration, and tumor-specific targeting. Notably, PCTM exerted potent antitumor activity in a variety of bladder cancer cell lines and in orthotopic and ectopic models of urinary bladder cancer, with no serious side effects detected in the peripheral vital organs of mice. Mechanistic studies integrating RNA sequencing, flow cytometry, and western blot analysis showed that PCTM inhibited the proliferation and progression of bladder cancer cells by downregulating CDC42 and HCFC1 and indirectly inhibiting the expression of the cell-cycle protein A1, which subsequently induced S-phase arrest of mitosis. Taken together, these findings suggest that the PCTM microspheres may be a promising intravesical therapeutic agent for bladder cancer tumor eradication, thus providing a transformative strategy to significantly improve the prognosis of patients with NMIBC.
Insights
New poly(1-carboxy-3,3,3-trimethylpropyl methacrylate) (PCTM) microspheres show promise for treating non-muscle invasive bladder cancer (NMIBC). These targeted microspheres effectively eradicate bladder tumors with minimal side effects, offering a potential new therapy.
Area of Science:
- Biomaterials Science
- Oncology
- Drug Delivery Systems
Background:
- Standard intravesical instillation for non-muscle invasive bladder cancer (NMIBC) has limitations in eradicating residual tumor cells, leading to high recurrence rates.
- There is a significant unmet clinical need for more effective intravesical therapies for NMIBC.
Purpose of the Study:
- To develop and evaluate novel tumor-targeted poly(1-carboxy-3,3,3-trimethylpropyl methacrylate) (PCTM) microspheres for intravesical delivery in bladder cancer.
- To assess the efficacy and safety of PCTM microspheres in preclinical models of bladder cancer.
Main Methods:
- PCTM microspheres were synthesized using microfluidic and click chemistry techniques.
- In vitro and in vivo studies were conducted to evaluate bladder mucosal adhesion, tissue penetration, tumor targeting, antitumor activity, and safety.
- Mechanistic investigations involved RNA sequencing, flow cytometry, and western blot analysis.
Main Results:
- PCTM microspheres demonstrated excellent bladder mucosal adhesion, deep tissue penetration, and specific tumor targeting.
- PCTM exhibited potent antitumor activity against various bladder cancer cell lines and in orthotopic/ectopic mouse models.
- No significant side effects were observed in the vital organs of treated mice.
- PCTM inhibited bladder cancer cell proliferation and progression by downregulating CDC42 and HCFC1, inducing S-phase arrest.
Conclusions:
- PCTM microspheres represent a promising intravesical therapeutic agent for bladder cancer eradication.
- This novel approach offers a transformative strategy to potentially improve outcomes for patients with NMIBC.
