Intravesical therapy for the treatment of superficial urinary bladder tumors is promising. However, it is also challenging, due to bladder contraction and relaxation and drug elimination via urination or dilution by urine production. They developed a biodegradable drug-eluting device positioned in the renal pelvis as an alternative strategy for bladder instillation. The urine drains from the renal pelvis into the ureter, collects the eluted drug, and transports it into the bladder. The combination of the renal pelvis and the bladder creates a two-compartment system. The drug is administered into the depot compartment, the renal pelvis, and is instantly and homogeneously distributed into the central compartment, the bladder. This results in an increase in its residence time and in gradual adsorption into the urothelium. The device is inserted through the ureter, followed by upset bulging after reaching the renal pelvis in order to guarantee fixation, while preventing urinary obstruction. The device is made of electrospun poly(lactic-co-glycolic acid) (PLGA) fibers that encapsulate a chemotherapeutic drug, cisplatin (1.17–2.34% w/w). Experimental studies of the stresses developed during the bulging and simulations of the urine flow interaction with the device demonstrated structural longevity and operational safety of the device. Sustained release of 94% of the device content was demonstrated after 1 week in vitro with a flow rate of 30 mL/h. They believe that the drug-eluted device may offer a significant advantage over existing therapies for treatment of nonmuscle invasive bladder cancer.
(a) Scanning electron microscopy images of layers I–III. (b) Schematic illustration of the fabrication steps of the device: (i) A tube made of electrospun fibers with longitudinal cuts; (ii) application of axial compression force and bulging of the tube; (iii) the bulged tube is coated with electrospun fibers encapsulating cisplatin and finally coated using air-spraying. (c) Images of the manufactured device: (i) after bulging of the tube; (ii) the final device.
Bladder cancer is one of the most common forms of cancer worldwide. It is more prevalent in men than in women and represents the sixth most common cancer in men worldwide. Current treatment of superficial bladder tumors, which do not invade the muscle tissue, includes transurethral resection of the bladder tumor (TURBT) followed by immediate intravesical drug delivery (IDD) via urinary catheterization.The most common intravesical approach is Bacillus Calmette–Guerin (BCG) immunotherapy, which is considered a first-line treatment for superficial bladder cancer. Combinations of chemotherapeutic drugs such as mitomycin C (MMC) are used as adjuvant therapy in order to reduce the potential risk of tumor recurrence.
(a–d) SEM images of layer II containing different concentrations of encapsulated cisplatin in the PLGA fibers: (a) 0%, (b) 1.17%, (c) 1.76%, and (d) 2.34% w/w. (e–h) Data generated by EDS of (e) 0%, (f) 1.17%, (g) 1.76%, and (h) 2.34% w/w concentrations of cisplatin in the PLGA fibers.
However, IDD is hindered by the low permeability of the bladder wall as well as by the short residence time of the drug in the bladder due to urination and dilution over time as the bladder fills up, leading to a decrease in its concentration. Multiple efforts have been invested in recent years for enhancing IDD efficacy by prolonging the residence time of drugs in the bladder and slowing the drug diffusion in a sustained manner. These efforts are mainly directed toward improving the bioadhesion by controlling the binding interaction of the polymer and/or administered drug to the urothelium, applying hyperthermia to enhance drug efficacy,incorporating therapeutic agents into thermosensitive hydrogels, or floating hydrogels for sustained release.Also, drug-eluting ureteral stents were developed allowing for the facile incorporation of drugs, that can then be locally released.
(a) Compression test (absolute values) of layer I (n = 3). (b) Deflection of the blister at the center, w0, and the boundary conditions: the moment M at the clamp and the stress σ at the cross section. (c) Images of compression experiments. (d) Experimentally measured deflection normalized by the initial length vs the engineering strain. (e) Simulated layer I, prestressed position in the lower image (stretched tube) and compressed position at the top, showing the level of deformation.
Cisplatin is considered to be the most effective chemotherapeutic treatment for advanced bladder cancer, and it has been suggested as an efficient alternative treatment for nonmuscle invasive bladder cancer (NMIBC).Horn et al. showed the efficacy of cisplatin as a local agent for treatment of superficial bladder tumors. Hadaschik et al. demonstrated that use of cisplatin as an intravesical agent significantly inhibits bladder tumor growth. Delivery of cisplatin using particles was suggested by Huxford et al. and was demonstrated by functionalized PLGA/PEG nanoparticles to prostate cancer cells. In order to control the burst release from nanoparticles, Xie et al. encapsulated cisplatin in PLA/PLGA nanofibers and demonstrated release of 20–70% of the encapsulated drug over 30 days. Kaplan et al. showed the use of cisplatin-loaded super hydrophobic nanofiber meshes for reducing lung cancer recurrence postresection.
Numerical simulation of the velocity field of urine within and around the device when it bulges in the renal pelvis under two flow rates, (a) 5 and (b) 30 mL/h, and the wall shear stresses under a flow rate of 30 mL/h (c) inside and (d) outside the stent surface.
In this work, they present a drug-eluting biodegradable device capable of releasing cisplatin in a controlled manner from the renal pelvis via the ureter to the bladder. The work concept resembles a two-compartment model, where the drug enters through the renal pelvis (depot compartment) to the bladder (central compartment) and is then distributed to the urothelium. In classical intravesical drug installation via urinary catheterization (a single compartment), drug elimination can be considered as concentration-dependent, which results in first-order kinetics. Pharmacokinetic parameters are therefore not affected by the dose. The proposed two-compartment model provides a means for tuning the drug concentration over time and thus extends the drug’s residence time in the bladder. The drug-eluting device acts like an “actuator” that can adjust its release over time and control the supply to the renal pelvis (the depot compartment). The suggested cisplatin’s indirect supply will therefore help to overcome the uncertainties inherent to the bladder dynamics. Moreover, positioning a biodegradable device in the renal pelvis will prevent the need for frequent administration in order to maintain the desired therapeutic effects via urinary catheterization.
(a) Schematic illustration of the drug-eluted device. The device is inserted through the ureter (A) up into the renal pelvis, followed by upset bulging (B) to ensure proper positioning and urine flow through the device and around it (yellow arrows). The cross section of the device wall is composed of three-layers (layers I–III), where cisplatin (red dot) is encapsulated in the middle layer in electrospun PLGA fibers. (b) Two-compartment model, where the drug enters through the renal pelvis (depot compartment) to the bladder (central compartment).
Considerable challenges need to be addressed for achieving this goal. For example, the drug-eluting device must possess mechanical stability, must be resistant to erosion arising from the urine flow and pH effects, and must be biodegradable. The device is designed to be inserted through the ureter into the renal pelvis and then inflated through upset bulging. The device’s scaffold is made of several layers of PLGA fibers and particles, where the inner layer is based on cisplatin-encapsulated fibers at varying concentrations. Experimental studies and simulations of the stresses developed during the device insertion and upset bulging demonstrated structural longevity and operational safety of the device. The drug release results demonstrated a controlled release of cisplatin for 1 week, which depends on the degree of loading. They envision that this biodegradable renal drug-eluting device allows more effective treatment of NMIBC by increasing the urothelium’s exposure to the drug while minimizing systemic side effects1.
Experimental results of drug release tests of devices containing varying concentrations of cisplatin. Cumulative release of cisplatin from devices containing: 1.17, 1.76, and 2.34% w/w cisplatin for 1 week, 2.34% w/w cisplatin in layer II only without layers III and I, and 2.34% w/w cisplatin under convective flow conditions.
Kabha, A. et al. (2021). Biodegradable Controlled-Release Device for Localized Chemotherapeutic Treatment of Bladder Cancer. ACS biomaterials science & engineering. doi:10.1021/acsbiomaterials.1c00339