Preparation of silane-dispersed graphene crosslinked vinyl carboxymethyl chitosan temperature-responsive hydrogel with antibacterial properties.
Kang Wanwen,Liang Jiacheng,Liu Ting,Long Hui,Huang Langhuan,Shi Qingshan,Zhang Jingxian,Deng Suiping,Tan Shaozao
International journal of biological macromolecules
We synthesized a temperature-sensitive antibacterial hydrogel, defined as NIPAM-CG/GM hydrogel. First, vinyl carboxymethyl chitosan (CG) was synthesized as a crosslinking carrier and silane dispersed graphene (GM) was synthesized as a reinforcer. Then, the N-isopropylacrylamide (NIPAM) monomer was free-radical polymerized with the vinyl groups of CG and GM to form a NIPAM-CG/GM hydrogel without any crosslinking agent. The influences of different hydrogel compositions on the microstructure, compressive properties, swelling, drug loading, and drug release properties of the hydrogels were discussed, and its temperature sensitivity was also demonstrated. The results showed that the lower critical solution temperature (LCST) and mechanical properties of the hydrogel could be adjusted by controlling the amount of CG and GM. Next, its biocompatibility was characterized, and its antibacterial performance was tested against Escherichia coli and Staphylococcus aureus. The antibacterial mechanism was explained by measuring the difference in the ion concentration outside the membrane and changes in the morphology of live/dead bacteria. NIPAM-CG/GM had a high drug loading and nearly complete drug release at a physiological temperature of 37 °C. Its moderate mechanical properties, excellent biocompatibility, and antibacterial effects give NIPAM-CG/GM great potential applications as a wound dressing.
10.1016/j.ijbiomac.2021.12.050
Floating Hydrogel with Self-Generating Micro-Bubbles for Intravesical Instillation.
Lin Tingsheng,Zhao Xiaozhi,Zhang Yifan,Lian Huibo,Zhuang Junlong,Zhang Qing,Chen Wei,Wang Wei,Liu Guangxiang,Guo Suhan,Wu Jinhui,Hu Yiqiao,Guo Hongqian
Materials (Basel, Switzerland)
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.
10.3390/ma9121005
Novel Applications of OnabotulinumtoxinA in Lower Urinary Tract Dysfunction.
Jhang Jia-Fong,Kuo Hann-Chorng
Toxins
OnabotulinumtoxinA (BoNT-A) was first used to treat neurogenic lower urinary tract dysfunction (LUTD) 30 years ago. Recently, application of BoNT-A in LUTD have become more common since the approval of intravesical BoNT-A injection for patients with both overactive bladders (OAB) and neurogenic detrusor overactivity (NDO) by regulatory agencies in many countries. Although unlicensed, BoNT-A has been recommended to treat patients with interstitial cystitis/bladder pain syndrome (IC/BPS) under different guidelines. BoNT-A delivery with liposome-encapsulation and gelation hydrogel intravesical instillation provided a potentially less invasive and more convenient form of application for patients with OAB or IC/BPS. BoNT-A injections into the urethral sphincter for spinal cord injury patients with detrusor-sphincter dyssynergia have been used for a long time. New evidence revealed that it could also be applied to patients with non-neurogenic dysfunctional voiding. Previous studies and meta-analyses suggest that BoNT-A injections for patients with benign prostate hyperplasia do not have a better therapeutic effect than placebo. However, new randomized and placebo-controlled trials revealed intraprostatic BoNT-A injection is superior to placebo in specific patients. A recent trial also showed intraprostatic BoNT-A injection could significantly reduce pain in patients with chronic prostatitis. Both careful selection of patients and prudent use of urodynamic evaluation results to confirm diagnoses are essential for successful outcomes of BoNT-A treatment for LUTD.
10.3390/toxins10070260
Efficacy and Safety of Noninvasive Intravesical Instillation of Onabotulinum Toxin-A for Overactive Bladder and Interstitial Cystitis/Bladder Pain Syndrome: Systematic Review and Meta-analysis.
Lee Hyun Young,Doo Seung Whan,Yang Won Jae,Song Yun Seob,Sun Hwa Yeon,Nho Eli Jongchan,Lee Bora,Kim Jae Heon
Urology
OBJECTIVE:To investigate the efficacy and safety of noninvasive intravesical instillation of onabotulinum toxin-A (OBTX-A) through systematic review and meta-analysis. Recently, several studies of noninvasive intravesical instillation of OBTX-A have been published. However, its efficacy is not well validated yet compared to well-known efficacy of minimally invasive intravesical injection of OBTX-A. METHOD:Systematic review and meta-analysis were performed to evaluate the efficacy of noninvasive intravesical instillation of OBTX-A in patients with overactive bladder and interstitial cystitis/bladder pain syndrome by measuring outcomes such as urgency episode per 72 hours, frequency per 72 hours, urgency urinary incontinence, voided volume (VV), postvoided residual volume, maximum flow rate, and patient perception of bladder condition. RESULT:Six trials in 4 studies that compared instillation of OBTX-A and placebo involving 248 patients (121 experimental and 127 controls) were included for final data extraction. Instillation of OBTX-A significantly increased VV, with a mean difference of 38.48 (95% confidence interval: 76.05, 0.92) compared to the placebo group. However, other outcomes showed statistically insignificant changes. Major adverse events were not reported in the group receiving intravesical instillation of OBTX-A. CONCLUSION:Intravesical instillation of OBTX-A showed limited efficacy with improvement of VV for treatment of overactive bladder or interstitial cystitis/bladder pain syndrome. More studies are needed to overcome the efficacy of current noninvasive bladder instillation of OBTX-A regarding effective drug transport.
10.1016/j.urology.2018.11.037
Hyaluronic acid improves pain symptoms more than bladder storage symptoms in women with interstitial cystitis.
Hung Man-Jung,Tsai Ching-Pei,Lin Yi-Hao,Huang Wen-Chu,Chen Gin-Den,Shen Pao-Sheng
Taiwanese journal of obstetrics & gynecology
OBJECTIVE:Intravesical hyaluronic acid (HA) therapy is one of acceptable methods to treat bladder pain and storage symptoms (i.e., urgency, frequency and nocturia) of interstitial cystitis/bladder pain syndrome (IC/BPS). We aim to assess the impacts of intravesical HA on bladder pain and storage symptoms, respectively, and to investigate their associated factors in patients with IC/BPS. MATERIALS AND METHODS:In this prospective, multicenter study, 103 women with refractory IC/BPS undergoing a standard protocol of intravesical HA therapy were enrolled. A pain Visual Analog Scale (VAS) and the Interstitial Cystitis Symptom and Problem Index (ICSI & ICPI) were used to assess symptoms and bother associated with IC/BPS. The Scaled Global Response Assessment (GRA) was used to evaluate patients' perception of overall changes in bladder pain and storage symptoms, respectively, after treatment. RESULTS:Mean age of participants was 43.6 ± 11.8 years. The average duration of symptoms was 5.1 ± 5.0 years. Significant improvements in pain VAS, ICSI and ICPI scores were observed after treatment. However, patients reported significantly different rates of moderate/marked improvement in bladder pain and storage symptoms (73.8% vs. 47.6%; P < 0.001) on the GRA, respectively. "Lower pain VAS score" and "reduced functional bladder capacity" were found to be the factors that adversely affected the treatment responses of bladder pain and storage symptoms, respectively, after repeated statistical analyses. CONCLUSION:Bladder instillation of HA seemed more efficient in improving bladder pain than storage symptoms associated with IC/BPS. The persistence of bladder storage symptoms after treatment might result from a reduced functional bladder capacity.
10.1016/j.tjog.2018.11.033
SuperGAG biopolymers for treatment of excessive bladder permeability.
Pharmacology research & perspectives
Few therapeutic options exist for treatment of IC/BPS. A novel high MW GAG biopolymer ("SuperGAG") was synthesized by controlled oligomerization of CS, purified by TFF and characterized by SEC-MALLS and 1H-NMR spectroscopy. The modified GAG biopolymer was tested in an OVX female rat model in which bladder permeability was induced by a 10-minute intravesicular treatment with dilute (1 mg/ml) protamine sulfate and measured by classical Ussing Chamber TEER measurements following treatment with SuperGAG, chondroitin sulfate, or saline. The effect on abrogating the abdominal pain response was assessed using von Frey filaments. The SuperGAG biopolymer was then investigated in a second, genetically modified mouse model (URO-MCP1) that increasingly is accepted as a model for IC/BPS. Permeability was induced with a brief exposure to a sub-noxious dose of LPS and was quantified using contrast-enhanced MRI (CE-MRI). The SuperGAG biopolymer restored impermeability to normal levels in the OVX rat model as measured by TEER in the Ussing chamber and reduced the abdominal pain response arising from induced permeability. Evaluation in the URO-MCP1 mouse model also showed restoration of bladder impermeability and showed the utility of CE-MRI imaging for evaluating the efficacy of agents to restore bladder impermeability. We conclude novel high MW SuperGAG biopolymers are effective in restoring urothelial impermeability and reducing pain produced by loss of the GAG layer on the urothelium. SuperGAG biopolymers could offer a novel and effective new therapy for IC/BPS, particularly if combined with MRI to assess the efficacy of the therapy.
10.1002/prp2.709
Novel Applications of Non-Invasive Intravesical Botulinum Toxin a Delivery in the Treatment of Functional Bladder Disorders.
Jhang Jia-Fong,Kuo Hann-Chorng
Toxins
Although intravesical botulinum toxin type A (BoNT-A) injection for functional bladder disorders is effective, the injection-related problems-such as bladder pain and urinary tract infection-make the procedure invasive and inconvenient. Several vehicles have recently been developed to deliver BoNT-A without injection, thereby making the treatment less or non-invasive. Laboratory evidence revealed that liposome can carry BoNT-A across the uroepithelium and act on sub-urothelial nerve endings. A randomized placebo controlled study revealed that intravesical administration of liposome-encapsulated BoNT-A and TC-3 hydrogel embedded BoNT-A can improve urinary frequency, urgency, and reduce incontinence in patients with overactive bladders. A single-arm prospective study also revealed that intravesical administration of TC-3 hydrogel embedded BoNT-A can relieve bladder pain in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). We recently administered suprapubic energy shock wave (ESW) after BoNT-A intravesical administration in six patients with IC/BPS. Although pain reduction and symptom improvement were not significant, immunochemical staining showed cleaved synaptosome-associated protein 25 in the bladder after the procedure. This suggests that ESW can promote passage of BoNT-A across the uroepithelium. In conclusion, using vehicles to intra-vesically deliver BoNT-A for functional bladder disorders is promising. Further studies are necessary to confirm the efficacy and explore novel applications.
10.3390/toxins13050359
A Novel Intravesical Dextrose Injection Improves Lower Urinary Tract Symptoms on Interstitial Cystitis/Bladder Pain Syndrome.
Chen Chin-Li,Kao Chien-Chang,Yang Ming-Hsin,Fan Gang-Yi,Cherng Juin-Hong,Tsao Chih-Wei,Wu Sheng-Tang,Cha Tai-Lung,Meng En
Frontiers in pharmacology
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a painful recurrent condition characterized by the discomfort of the bladder, and current treatment options have limited effectiveness. Prolotherapy is a well-known treatment that involves the injection of non-biologic solutions to reduce pain and/or promote proliferation of soft tissue, and dextrose is the most common injectate. This study investigated the effects of dextrose prolotherapy in a rat model of IC/BPS and patients with IC/BPS. We used cyclophosphamide to induce IC/BPS in rats, and intravesical instillation of 10% dextrose solution was performed. After 1 week, we conducted a urodynamic test, bladder staining, and ECM-related gene expression analysis to examine the treatment's efficacy. We found that dextrose treatment could recover the instability of the bladder, reduce frequent urination, and improve the glycosaminoglycan layer regeneration and the bladder wall thickness along with a significant intense expression of CD44 receptors. Furthermore, we enrolled 29 IC/BPS patients with previous hyaluronic acid/Botox treatment for more than 6 months with remained unchanged condition. In this study, they received intravesical injections of 10% dextrose solution followed by assessments for up to 12 weeks. Patient characteristics and a 3-day voiding diary before treatment were recorded. Patient responses were examined using IC/BPS-related questionnaires. Moreover, expressions of growth factors and cytokines were analyzed. The results demonstrated that dextrose prolotherapy in patients with IC/BPS reduced the frequency of treatment over time, with the mean number of treatments being 3.03 ± 1.52, and significantly reduced the incidence of nocturia and questionnaire scores associated with symptoms. Dextrose prolotherapy significantly enhanced EGF level and, in contrast, reduced the level of HGF, PIGF-1, and VEGF-D after several weeks following treatment. The cytokine analysis showed that the expressions of IL-12p70 and IL-10 were significantly up-regulated after dextrose prolotherapy in IC/BPS patients. The levels of most growth factors and cytokines in IC/BPS patients had no significant difference and showed a similar tendency as time progressed when compared to healthy controls. Overall, the alteration of growth factors and cytokines exhibited safe treatment and potential stimulation of tissue remodeling. In summary, our study demonstrated that dextrose prolotherapy is a promising treatment strategy for IC/BPS disease management.
10.3389/fphar.2021.755615
An indirect comparison meta-analysis of noninvasive intravesical instillation and intravesical injection of botulinum toxin-A in bladder disorders.
Yunfeng Gao,Fei Lai,Junbo Liu,Dingyuan Yang,Chaoyou Huang
International urology and nephrology
BACKGROUND:Botulinum toxin type A (BTX-A) intravesical instillation and BTX-A intravesical injection are both effective treatments or overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS), but direct comparative studies of the two treatments are lacking. METHODS:We conducted a pairs-comparison meta-analysis and an adjusted indirect comparison meta-analysis extracting published data from randomized controlled trials in literature databases from the inception of each database to Aug. 31, 2021, evaluating efficacy and safety of BTX-A intravesical instillation and BTX-A intravesical injection. We also carried out a subgroup analysis. RESULTS:We identified 24 trials in 21 studies were included in our study, of which 18 trials in 17 studies were BTX-A intravesical injections, 6 trials in 4 studies were BTX-A intravesical instillation. Compared with the normal saline injection, BTX-A intravesical injections for patients with OAB and IC/ BPS can obviously improve the symptoms of urinary frequency, urgency episode, UI and UUI, but BTX-A significantly increased the rate of urinary retention and urinary tract infection and increased PVR (p < 0.05). Adjusted indirect comparison meta-analysis showed that BTX-A intravesical injections was more effective than BTX-A intravesical instillation (p > 0.05). Surprisingly, BTX-A intravesical instillation had fewer side effects than BTX-A intravesical injections (p < 0.05). CONCLUSIONS:Although BTX-A intravesical injections of OAB and IC/BPS has been significantly superior the BTX-A intravesical instillation, it has major side effects, but this needs to be confirmed by more large-scale, multicenter, direct comparison randomized controlled trials.
10.1007/s11255-022-03107-6
Low-Energy Shock Wave Plus Intravesical Instillation of Botulinum Toxin A for Interstitial Cystitis/Bladder Pain Syndrome: Pathophysiology and Preliminary Result of a Novel Minimally Invasive Treatment.
Jiang Yuan-Hong,Jhang Jia-Fong,Lee Yu-Khun,Kuo Hann-Chorng
Biomedicines
Low-energy shock wave (LESW) therapy is known to facilitate tissue regeneration with analgesic and anti-inflammatory effects. LESW treatment has been demonstrated to be effective in treating chronic prostatitis and pelvic pain syndrome as well as overactive bladder, and it has a potential effect on interstitial cystitis/bladder pain syndrome (IC/BPS) in humans. LESW reduces pain behavior, downregulates nerve growth factor expression, and suppresses bladder overactivity by decreasing the expression of inflammatory proteins. Previous rat IC models have shown that LESW can increase urothelial permeability, facilitate intravesical delivery of botulinum toxin A (BoNT-A), and block acetic acid-induced hyperactive bladder, suggesting that LESW might be a potential therapeutic module for relieving bladder inflammatory conditions, such as bladder oversensitivity, IC/BPS, and overactive bladder. A recent clinical trial showed that LESW monotherapy was associated with a significant reduction in pain scores and IC symptoms. BoNT-A detrusor injection or liposome-encapsulated BoNT-A instillation could also inhibit inflammation and improve IC symptoms. However, BoNT-A injection requires anesthesia and certain complications might occur. Our preliminary study using LESW plus intravesical BoNT-A instillation every week demonstrated an improvement in global response assessment without any adverse events. Moreover, an immunohistochemistry study revealed the presence of cleaved SNAP25 protein in the suburothelium of IC bladder tissue, indicating that BoNT-A could penetrate across the urothelial barrier after application of LESW. These results provide evidence for the efficacy and safety of this novel IC/BPS treatment by LESW plus BoNT-A instillation, without anesthesia, and no bladder injection. This article reviews the current evidence on LESW and LESW plus intravesical therapeutic agents on bladder disorders and the pathophysiology and pharmacological mechanism of this novel, minimally invasive treatment model for IC/BPS.
10.3390/biomedicines10020396
Intravesical Immunostimulatory Gel for Triple Therapy of Bladder Cancer.
Guo Pengyu,Wang Lu,Shang Wenting,Chen Jiuwei,Chen Ziyin,Xiong Feng,Wang Ziqi,Tong Zhichao,Wang Keliang,Yang Liming,Tian Jie,Xu Wanhai
ACS applied materials & interfaces
Bladder cancer displays multiple biological features aided in drug resistance; therefore, single therapy fails to induce complete tumor regression. To address this issue, various kinds of cell death of cancer cells as well as restoring tumor immune microenvironment need to be taken into consideration. Here, we introduce a gel system termed AuNRs&IONs@Gel, which target-delivers a combination of photothermal, ferroptotic, and immune therapy through intravesical instillation. AuNRs&IONs@Gel consists of a gel delivery platform, embedded gold nanorods (AuNRs), and iron oxide nanoparticles (IONs). The targeted delivery gel platform provides dextran aldehyde-selective adhesion with cancer collagen. In this condition, photothermal therapy can be performed by gold nanorods (AuNRs) under imaging-guided near-infrared radiation. Local high concentrations of IONs can be absorbed by cancer cell to induce ferroptosis. Moreover, tumor-associated macrophages which often display an immune-suppressive M2-like phenotype will be repolarized by IONs into the antitumor M1-like phenotype, exerting a direct antitumor effect and professional antigen presentation of dead cancer cells. This process triggers a potent immune response of innate and adapt immunities to protect tumor rechallenge in long terms. Our triple-therapy strategy employs FDA-approved nanoparticles to inhibit bladder cancer which may possess great potential for clinical translation.
10.1021/acsami.0c15176
Safety and Feasibility of Intravesical Instillation of Botulinum Toxin-A in Hydrogel-based Slow-release Delivery System in Patients With Interstitial Cystitis-Bladder Pain Syndrome: A Pilot Study.
Rappaport Yishai H,Zisman Amnon,Jeshurun-Gutshtat Michal,Gerassi Tami,Hakim Gil,Vinshtok Yuri,Stav Kobi
Urology
OBJECTIVE:To assess the feasibility and the safety of a mixture instillation of TC-3 gel, a novel reverse-thermal gelation hydrogel, and botulinum toxin-A (BTX-A) for the treatment of interstitial cystitis-bladder pain syndrome (IC/BPS). TC-3 gel-BTX-A mix is instilled into the bladder as liquid, solidifies because of body heat, and gradually dissolves to release BTX-A for several hours. METHODS:A single intravesical instillation of 200 U BTX-A premixed with 40 mL TC-3 gel was delivered to the bladder. Adverse events and preliminary efficacy outcome measures were assessed: bladder diary, visual analog scale (VAS) for pain, and Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI) at baseline and at 2, 6, and 12 weeks. RESULTS:A total of 15 severely symptomatic patients with IC/BPS (ICSI and ICPI score ranges 12-19 and 12-16, respectively; median VAS = 7) were enrolled (male and female = 4 and 11, ages 24-76). In terms of safety, no increase in VAS score was noted at instillation. All adverse events were transient and mild, the most common being temporary mild constipation (n = 4, 26%). The mean VAS at baseline vs week 12 was 6.6 ± 2.7 vs 5.3 ± 2.8 (P = .044). The mean ICSI and ICPI scores were reduced at week 12 compared with baseline (15.4 ± 2.4 vs 12.9 ± 4.3, P = .004, and 14.8 ± 1.4 vs 11.9 ± 4.0, P = .004, respectively). The mean number of voids per night at baseline decreased for 6 weeks (3.3 ± 2.1 vs 1.8 ± 0.9, P = .046) and then returned to baseline level at week 12. CONCLUSION:Intravesical instillation of a TC-3 gel-BTX-A mixture is safe and tolerable. Preliminary results suggest temporary efficacy lasting for a few weeks.
10.1016/j.urology.2017.12.028
Novel in-situ gel for intravesical administration of ketorolac.
Sherif Abdelrahman Y,Mahrous Gamal Mohamed,Alanazi Fars Kaed
Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society
The urinary bladder stores urine until the time of urination. Systemic administration of drugs to treat bladder diseases faces several limitations. Therefore, intravesical drug delivery is a promising alternative route of administration. An in-situ gel is used to form a gel inside the bladder cavity and ensure continuous release of the drug even after urination. The objective of the present study was to optimize an in-situ gel formulation of poloxamer and chitosan for intravesical delivery of ketorolac tromethamine. The gelling temperature of the prepared combinations ranged from 20.67 to 25.8 °C. In-vitro release of KT was sustained for up to 7 h using a poloxamer concentration ranging from 17% to 19% and a chitosan concentration ranging from 1% to 2%. Design-Expert® 10 was used to select the optimized formulation (poloxamer/chitosan 17/1.589% w/w) which significantly ( < 0.05) extended the drug release more than each polymer alone. An study showed the ability of the optimized formulation to sustain drug release after emptying two times to mimic urination. Furthermore, the formed gel adhered to the bladder tissue throughout the time period of the experiment. Intravesical administration of the optimized formulation to rabbits via catheter showed no obstruction of urine flow and continuous release of the drug for 12 h.
10.1016/j.jsps.2018.03.014
Gemcitabine hydrochloride microspheres used for intravesical treatment of superficial bladder cancer: a comprehensive in vitro/ex vivo/in vivo evaluation.
Drug design, development and therapy
INTRODUCTION:Bladder cancer is responsible for more than 130,000 deaths annually worldwide. Intravesical delivery of chemotherapeutic agents provides effective drug localization to the target area to reduce toxicity and increase efficacy. This study aimed to develop an intravesical delivery system of gemcitabine HCl (Gem-HCl) to provide a sustained-release profile, to prolong residence time, and to enhance its efficiency in the treatment of bladder cancer. MATERIALS AND METHODS:For this purpose, bioadhesive microspheres were successfully prepared with average particle size, encapsulation efficiency, and loading capacity of 98.4 µm, 82.657%±5.817%, and 12.501±0.881 mg, respectively. For intravesical administration, bioadhesive microspheres were dispersed in mucoadhesive chitosan or in situ poloxamer gels and characterized in terms of gelation temperature, viscosity, mechanical, syringeability, and bioadhesive and rheological properties. The cytotoxic effects of Gem-HCl solution, Gem-HCl microspheres, and Gem-HCl microsphere-loaded gel formulations were evaluated in two different bladder cancer cell lines: T24 (ATCC HTB4TM) and RT4 (ATCC HTB2TM). RESULTS:According to cell-culture studies, Gem-HCl microsphere-loaded poloxamer gel was more cytotoxic than Gem-HCl microsphere-loaded chitosan gel. Antitumor efficacy of newly developed formulations were investigated by in vivo studies using bladder-tumor-induced rats. CONCLUSION:According to in vivo studies, Gem-HCl microsphere-loaded poloxamer gel was found to be an effective and promising alternative for current intravesical delivery-system therapies.
10.2147/DDDT.S164704
Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel.
International journal of nanomedicine
PURPOSE:To develop an intravesical instillation system for the treatment of bladder cancer, rapamycin (Rap) was encapsulated into liposomes and then homogeneously dispersed throughout a poloxamer 407 (P407)-based hydrogel. METHODS:Rap-loaded conventional liposomes (R-CL) and folate-modified liposomes (R-FL) were prepared using a film hydration method and pre-loading technique, and characterized by particle size, drug entrapment efficiency, and drug loading. The cellular uptake behavior in folate receptor-expressing bladder cancer cells was observed by flow cytometry and confocal laser scanning microscopy using a fluorescent probe. In vitro cytotoxic effects were evaluated using MTT assay, colony forming assay, and Western blot. For in vivo intravesical instillation, Rap-loaded liposomes were dispersed in P407-gel, generating R-CL/P407 and R-FL/P407. Gel-forming capacities and drug release were evaluated. Using the MBT2/Luc orthotopic bladder cancer mouse model, in vivo antitumor efficacy was evaluated according to regions of interest (ROI) measurement. RESULTS:R-CL and R-FL were successfully prepared, at approximately <160 nm, 42% entrapment efficiency, and 57 μg/mg drug loading. FL cellular uptake was enhanced over 2-fold than that of CL; folate receptor-mediated endocytosis was confirmed using a competitive assay with folic acid pretreatment. In vitro cytotoxic effects increased dose-dependently. Rap-loaded liposomes inhibited mTOR signaling and induced autophagy in urothelial carcinoma cells. With gelation time of <30 seconds and gel duration of >12 hrs, both R-CL/P407 and R-FL/P407 preparations transformed into gel immediately after instillation into the mouse bladder. Drug release from the liposomal gel was erosion controlled. In orthotopic bladder cancer mouse model, statistically significant differences in ROI values were found between R-CL/P407 and R-FL/P407 groups at day 11 (=0.0273) and day 14 (=0.0088), indicating the highest tumor growth inhibition by R-FL/P407. CONCLUSION:Intravesical instillation of R-FL/P407 might represent a good candidate for bladder cancer treatment, owing to its enhanced retention and FR-targeting.
10.2147/IJN.S216432
Effects of poloxamer-based thermo-sensitive sol-gel agent on urethral stricture after transurethral resection of the prostate for benign prostatic hyperplasia: a multicentre, single-blinded, randomised controlled trial.
Chung Jae Hoon,Kim Kyu Shik,Choi Jae Duck,Kim Tae Hyo,Lee Ki Soo,Oh Cheol Young,Noh Joon Hwa,Kim Jun Seok,Kim Won Tae,Lee Seung Hwan,Kim Jae Heon,Kim Tae Nam,Huh Wan,Lee Seung Wook
BJU international
OBJECTIVE:To evaluate the effectiveness of poloxamer-based thermo-sensitive sol-gel instillation, after transurethral resection of the prostate (TURP), for preventing urethral stricture. PATIENTS AND METHODS:In all, 198 patients underwent TURP for benign prostatic hyperplasia. Recruited patients were randomly divided into two groups: groups A and B. Patients in Group A (100 patients, experimental group) received poloxamer-based thermo-sensitive sol-gel instillation and patients in the Group B (98 patients, control group) received lubricant instillation after TURP. Each patient was evaluated at 4 (V1), 12 (V2), and 24 weeks (V3) after TURP. The effectiveness of poloxamer-based thermo-sensitive sol-gel instillation was evaluated based on the International Prostate Symptom Score (IPSS), IPSS-Quality of Life (QoL), Overactive bladder questionnaire (OAB-q), maximum urinary flow rate (Q ), post-void residual urine volume (PVR), and cystoscopy. RESULTS:Amongst the initial 198 participants, 80 patients in Group A and 83 in Group B completed the study. There were no significant differences in IPSS-QoL and OAB-q between the groups. However, Q was significantly different between groups A and B, at a mean (SD) of 18.92 (9.98) vs 15.58 (9.24) mL/s (P = 0.028) at 24 weeks after TURP. On cystoscopic examination, urethral stricture after TURP was found in two of the 80 patients in Group A and 10 of 83 in Group B (P = 0.023). CONCLUSIONS:Poloxamer-based thermo-sensitive sol-gel instillation after TURP lowered the incidence of urethral stricture.
10.1111/bju.14902
UGN-101 (mitomycin gel): a novel treatment for low-grade upper tract urothelial carcinoma.
Therapeutic advances in medical oncology
Upper tract urothelial carcinoma (UTUC) is a rare malignancy. The standard treatment for localized high-risk disease is radical nephroureterectomy, which confers significant morbidity and is not appropriate for all patients. Patients harboring low-risk, non-invasive disease may be candidates for organ-sparing treatment, which includes endoscopic resection with or without intracavitary drug therapy. Successful administration of intracavitary chemotherapy to the upper tracts is impeded by rapid washout of the agent and short dwell times. This has limited the clinical utility of mitomycin C for treatment of upper tract tumors, despite the successful outcomes observed in low-grade urothelial carcinoma of the bladder. Currently, there is an unmet need for development of a technically feasible and oncologically sound intracavitary therapy for management of low-grade UTUC. UGN-101 (Jelmyto™) is a novel formulation of mitomycin C that uses a unique hydrogel designed to increase urinary dwell time, and thereby efficacy of treatment. Preclinical data demonstrated promising results regarding the safety and feasibility of this agent. Preliminary results of a phase III trial (OLYMPUS study) [ClinicalTrials.gov identifier: NCT02793128] demonstrated the efficacy of UGN-101 as a successful chemo-ablative agent for low-grade upper tract tumors. UGN-101 may represent a pivotal paradigm shift in the treatment of low-grade UTUC. Indeed, the drug has recently been granted approval by the US Food and Drug Administration as the first treatment for low-grade UTUC, which may lead to significant improvements in patient care and a long-awaited decrease in the burden of disease.
10.1177/1758835920937950
Co-Delivery of Cisplatin and Gemcitabine via Viscous Nanoemulsion for Potential Synergistic Intravesical Chemotherapy.
Chen Ting-Yu,Tsai Ming-Jun,Chang Li-Ching,Wu Pao-Chu
Pharmaceutics
Combined chemotherapy is an effective and safe treatment for cancers. Co-administration of cisplatin and gemcitabine produces a synergistic effect for bladder cancer treatment, so viscous microemulsions were developed for co-delivery of cisplatin and gemcitabine to extend the retention time and improve the permeability of chemotherapeutic drugs into the urothelium by intravesical administration. Results showed that the deposition amounts of cisplatin and gemcitabine significantly increased in in vitro and in vivo study. The penetration depth in bladder tissue samples increased from 60 to 120 μm. The dual-loaded formulation also showed thermodynamic and chemical stability, demonstrating that these gel-based microemulsions are promising drug delivery carriers for chemotherapy agents by intravesical administration.
10.3390/pharmaceutics12100949
Optimization of a floating poloxamer 407-based hydrogel using the Box-Behnken design: in vitro characterization and in vivo buoyancy evaluation for intravesical instillation.
Goo Yoon Tae,Yang Hee Mang,Kim Chang Hyun,Kim Min Song,Kim Hyeon Kyun,Chang In Ho,Choi Young Wook
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
Intravesical instillation of a poloxamer 407 (PLX)-based hydrogel offers advantages such as thermo-sensitivity and sol-to-gel transition, but its utility is limited by urinary obstruction and insufficient bladder residence time. To overcome these obstacles, a floating PLX-hydrogel (FPH) was developed using sodium bicarbonate (BC) as a floating agent and hyaluronic acid (HA) as a gel strength modulator. The FPH composition was optimized using the Box-Behnken design with three independent variables: X [PLX concentration, 23.91%], X [BC concentration, 5.15%], and X [HA concentration, 3.49%]. The quadratic model was the best fit (desirability function, 0.623), resulting in response parameters of Y [floating time, 53.7 s], Y [gelation temperature gap, 20.3°C], and Y [duration time of gel, 396.7 min]. Rheological observations revealed the mechanical rigidity (storage modulus > loss modulus at elevated temperature) of the optimized FPH (phase transition temperature, 15.08°C). Gel erosion and drug release studies were performed using the gravimetric method; the remaining FPH fraction decreased exponentially with time, and gemcitabine release was biphasic and surface erosion-controlled. In vivo buoyancy was evaluated in rats using ultrasonography; these results were similar to those of the in vitro floating behavior. Thus, optimized FPH for intravesical instillation is a prospective option for bladder cancer treatment.
10.1016/j.ejps.2021.105885
Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial.
Chevli K Kent,Shore Neal D,Trainer Andrew,Smith Angela B,Saltzstein Daniel,Ehrlich Yaron,Raman Jay D,Friedman Boris,D'Anna Richard,Morris David,Hu Brian,Tyson Mark,Sankin Alexander,Kates Max,Linehan Jennifer,Scherr Douglas,Kester Steven,Verni Michael,Chamie Karim,Karsh Lawrence,Cinman Arnold,Meads Andrew,Lahiri Soumi,Malinowski Madlen,Gabai Nimrod,Raju Sunil,Schoenberg Mark,Seltzer Elyse,Huang William C
The Journal of urology
PURPOSE:Low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG IR NMIBC) is a recurrent disease, thus requiring repeated transurethral resection of bladder tumor under general anesthesia. We evaluated the efficacy and safety of UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic alternative to transurethral resection of bladder tumor for patients with LG IR NMIBC. MATERIALS AND METHODS:This prospective, phase 2b, open-label, single-arm trial recruited patients with biopsy-proven LG IR NMIBC to receive 6 once-weekly instillations of UGN-102. The primary end point was complete response (CR) rate, defined as the proportion of patients with negative endoscopic examination, negative cytology and negative for-cause biopsy 3 months after treatment initiation. Patients with CR were followed quarterly up to 12 months to assess durability of treatment effect. Safety and adverse events were monitored throughout the trial. RESULTS:A total of 63 patients (38 males and 25 females 33-96 years old) enrolled and received ≥1 instillation of UGN-102. Among the patients 41 (65%) achieved CR at 3 months, of whom 39 (95%), 30 (73%) and 25 (61%) remained disease-free at 6, 9 and 12 months after treatment initiation, respectively. A total of 13 patients had documented recurrences. The probability of durable response 9 months after CR (12 months after treatment initiation) was estimated to be 73% by Kaplan-Meier analysis. Common adverse events (incidence ≥10%) included dysuria, urinary frequency, hematuria, micturition urgency, urinary tract infection and fatigue. CONCLUSIONS:Nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 resulted in significant treatment response with sustained durability. UGN-102 may provide an alternative to repetitive surgery for patients with LG IR NMIBC.
10.1097/JU.0000000000002186
Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Report.
The Journal of urology
PURPOSE:Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma. MATERIALS AND METHODS:In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS:Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs. CONCLUSIONS:Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease.
10.1097/JU.0000000000002350
Efficacy of instillation of MB49 cells and thermoreversible polymeric gel in urothelial bladder carcinoma immunization.
Laboratory animal research
BACKGROUND:Activating the immune system for therapeutic benefit has long been a goal in immunology, especially in cancer treatment, but the low immunogenicity of antitumor vaccines remains a limiting factor in the fight against malignant neoplasms. The increase in the immunogenicity of weak antigens using biodegradable polymers, such as chitosan, has been observed in the field of cancer immunotherapy. However, the effects of the vaccine using a combination of tumor cells and a thermoreversible delivery system based on chitosan in bladder cancer models, mainly using the intravesical route to stimulate the antitumor immune response, are unknown. We propose to evaluate the efficacy of a polymeric gel matrix (TPG) formed by poloxamer 407 and chitosan, associated with MB49 cells, as an intravesical antitumor vaccine using a C57BL/6 murine model of bladder urothelial carcinoma. The effectiveness of immunization was analyzed with the formation of three experimental groups: Control, TPG and TPG + MB49. In the vaccination phase, the TPG + MB49 group underwent a traumatic injury to the bladder wall with immediate intravesical instillation of the vaccine compound containing MB49 cells embedded in TPG. The TPG group was subjected to the same procedures using the compound containing the gel diluted in medium, and the control group using only the medium. After 21 days, the animals were challenged with tumor induction. RESULTS:In vitro tests showed loss of viability and inability to proliferate after exposure to TPG. In vivo tests showed that animals previously immunized with TPG + MB49 had higher cumulative survival, as well as significantly lower bladder weight and size in contrast to the other two groups that did not show a statistically different tumor evolution. In addition, the splenocytes of these animals also showed a higher rate of antitumor cytotoxicity in relation to the TPG and control groups. CONCLUSIONS:We can conclude that MB49 cells embedded in a polymeric thermoreversible gel matrix with chitosan used in the form of an intravesical vaccine are able to stimulate the immune response and affect the development of the bladder tumor in an orthotopic and syngeneic C57BL/6 murine model.
10.1186/s42826-022-00122-7