In Situ Floating Hydrogel for Intravesical Delivery of Adriamycin Without Blocking Urinary Tract

Purpose: Poloxamer 407 (P407) thermo-sensitive hydrogel formulations were developed to enhance the retention time in the urinary bladder after intravesical instillation. Materials and Methods: P407 hydrogels (P407Gels) containing 0.2 w/w% fluorescein isothiocyanate dextran (FD, MW 4 kDa) as a fluorescent probe were prepared by the cold method with different concentrations of the polymer (20, 25, and 30 w/w%). The gel-forming capacities were characterized in terms of gelation temperature (G-Temp), gelation time (G-Time), and gel duration (G-Dur). Homogenous dispersion of the probe throughout the hydrogel was observed by using fluorescence microscopy. The in vitro bladder simulation model was established to evaluate the retention and drug release properties. P407Gels in the solution state were administered to nude mice via urinary instillation, and the in vivo retention behavior of P407Gels was visualized by using an in vivo imaging system (IVIS). Results: P407Gels showed a thermo-reversible phase transition at 4°C (refrigerated; sol) and 37°C (body temperature; gel). The G-Temp, G-Time, and G-Dur of FD-free P407Gels were approximately 10°C-20°C, 12-30 seconds, and 12-35 hours, respectively, and were not altered by the addition of FD. Fluorescence imaging showed that FD was spread homogenously in the gelled P407 solution. In a bladder simulation model, even after repeated periodic filling-emptying cycles, the hydrogel formulation displayed excellent retention with continuous release of the probe over 8 hours. The FD release from P407Gels and the erosion of the gel, both of which followed zero-order kinetics, had a linear relationship (r 2 =0.988). IVIS demonstrated that the intravesical retention time of P407Gels was over 4 hours, which was longer than that of the FD solution (＜1 hour), even though periodic urination occurred in the mice. Conclusions: FD release from P407Gels was erosion-controlled. P407Gels represent a promising system to enhance intravesical retention with extended drug delivery.

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“…To mimic the human urinary bladder, an in vitro bladder simulation model was established from slight modifications of an earlier report. 26…”

Section: In Vitro Bladder Simulation Studymentioning

confidence: 99%

Poloxamer 407 Hydrogels for Intravesical Instillation to Mouse Bladder: Gel-Forming Capacity and Retention Performance

Kim

Yoon

et al. 2017

Korean J Urol Oncol

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“…In this floating hydrogel system, the hydrogel could float immediately due to the whole hydrogel was full of micro-bubbles at the beginning by shaking the P407 solution. However, the time to float of hydrogels we previously developed were several minutes, because chemical reaction took time [7,8]. …”

Section: Discussionmentioning

confidence: 99%

“…As hydrogels attach to the bladder wall, another problem is serious bladder irritation symptoms, such as blood clots in bladder [6]. The two floating hydrogel drug delivery systems we developed before were able to overcome these two shortcomings and prolonged the resident time of drug in the bladder [7,8]. The first floating hydrogel system consisted of thermo-sensitive polymer (Poloxamer 407) and NaHCO 3 , which was liquid at low temperature while forming gel at body temperature (37 °C).…”

Section: Introductionmentioning

confidence: 99%

Floating Hydrogel with Self-Generating Micro-Bubbles for Intravesical Instillation

et al. 2016

Self Cite

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Intravesical instillation is the main therapy for bladder cancer and interstitial cystitis. However, most drug solutions are eliminated from bladder after the first voiding of urine. To solve this problem, we proposed a floating hydrogel with self-generating micro-bubbles as a new delivery system. It floated in urine, avoiding the urinary obstruction and bladder irritation that ordinary hydrogels caused. In this study, we abandoned traditional gas-producing method like chemical decomposition of NaHCO3, and used the foamability of Poloxamer 407 (P407) instead. Through simple shaking (just like shaking SonoVue for contrast-enhanced ultrasound in clinical), the P407 solution will “lock” many micro-bubbles and float in urine as quickly and steadily as other gas producing materials. In vivo release experiments showed that drug was released continually from hydrogel for 10 h during the erosion process. Thus, the residence time of drug in bladder was prolonged and drug efficacy was improved. In vivo efficacy study using rabbit acute bladder injury model showed that prolonged drug residence time in bladder increased the efficiency of heparin in the protection of bladder mucosal permeability. Therefore, our floating hydrogel system with self-generating micro-bubbles was single-component, simply prepared and efficacy enhancing, successfully exempting users from worries on safety and clinical efficiency from bench to bedside.

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“…Human studies to characterize the safety, pharmacodynamics, and pharmacokinetics of intraperitoneal P407 have not yet been performed, but animal studies suggest that intraperitoneal injections of P407 have a half life of approximately 21 h based on urinary excretion [28]. P407 is currently Food and Drug Administration-approved for clinical use in vascular anastomosis [4] and is under active preclinical investigation for many additional novel applications [23, 36]. …”

Section: Discussionmentioning

confidence: 99%

Evaluation of a Thermoprotective Gel for Hydrodissection During Percutaneous Microwave Ablation: In Vivo Results

Moreland

Lubner

Ziemlewicz

et al. 2014

Cardiovasc Intervent Radiol

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In Situ Floating Hydrogel for Intravesical Delivery of Adriamycin Without Blocking Urinary Tract

Cited by 49 publications

References 24 publications

Poloxamer 407 Hydrogels for Intravesical Instillation to Mouse Bladder: Gel-Forming Capacity and Retention Performance

Poloxamer 407 Hydrogels for Intravesical Instillation to Mouse Bladder: Gel-Forming Capacity and Retention Performance

Floating Hydrogel with Self-Generating Micro-Bubbles for Intravesical Instillation

Evaluation of a Thermoprotective Gel for Hydrodissection During Percutaneous Microwave Ablation: In Vivo Results

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