Speaker
Description
The effective delivery of anticancer drugs remains a critical clinical challenge due to factors such as degradation in biological environments, limited tumor penetration, and poor targeting of cancer cells. Specifically, in non-muscle invasive bladder cancer (NMIBC), the efficacy of intravesical therapies is further compromised by drug sedimentation and rapid elimination from the bladder via urination, leading to high recurrence rates and poor long-term survival in patients.
Urease-powered nanomotors (NMs), self-propelled nanoparticles that harness urea for autonomous motion, have emerged as a promising strategy to overcome these limitations. By utilizing the urea present in the bladder, these NMs can actively navigate toward tumor sites, enhance drug local retention, and improve drug delivery compared to standard therapies and passive particles. However, current NM designs often rely on inorganic materials and are loaded with conventional chemotherapies, underscoring the need for more biocompatible and personalized formulations.
Here, we introduce a novel formulation of urease-powered nanobots composed of poly(lactic-co-glycolic acid) (PLGA) loaded with a selective inhibitor of fibroblast growth factor receptor 3 (FGFR3), commonly altered in NMIBC. NMs were synthetized, loaded with FGFR3 inhibitor and functionalized with urease to enable self-propulsion in urea-rich environments. NM motility, cellular uptake, therapeutic efficacy and mechanisms of action were evaluated using NMIBC mice cells (MB49 cells). Finally, we performed in vivo experiments in which NMs were administered intravesical and survival and tumor volume were evaluated over 2 months.
Our results demonstrate that the NMs exhibit robust propulsion in the presence of urea and significantly enhanced cellular uptake compared to passive particles. In addition, drug delivery via NMs resulted in a 10-fold reduction in the IC₅₀ of free drug. In vitro studies revealed that the NMs induced S-phase cell cycle arrest and rapid apoptosis, consistent with the known mechanisms of FGFR3 inhibitor. In a murine model of bladder cancer, intravesical administration of the NMs led to effective tumor suppression, prevention of recurrence, and an 83% survival rate, with complete tumor eradication observed in treated animals.
Collectively, these findings demonstrate the potential of our biocompatible, urease-powered nanobots as an effective and targeted intravesical therapy platform for NMIBC.
