Despite being the fifth most common cancer in the United States, minimal progress has been made in the treatment of bladder cancer in over a decade. Intravesical instillation of Bacillus Calmette-Guerin (BCG) for the treatment of non-muscle invasive bladder cancer (NMIBC) has been in use for over 30 years and remains the standard treatment in cases of intermediate and high risk disease. Despite the relative success of intravesical BCG, unmet needs in the treatment of NMIBC persist. These challenges include disease recurrence and progression even with treatment with BCG, as well as issues regarding its availability and patient tolerability. The inherent properties of the bladder pose the biggest obstacle to developing effective intravesical treatments for NMIBC. Current research is now focusing on methods to improve the delivery of intravesical therapies. The objective of this review is to discuss novel intravesical drug delivery systems and how they are addressing these challenges in the treatment of NMIBC.
In the United States, approximately 76,960 new cases of bladder cancer and 16,390 bladder cancer related deaths are expected in 2016 . Approximately 70% of new cases present as non-muscle invasive bladder cancer (NMIBC), of which 70% are pTa (confined to bladder epithelium), 20% are pT1 lesions (invasion of lamina propria), and 10% are carcinoma in situ (CIS). As many as 80% of patients with pTa disease will experience disease recurrence, and up to 45% of patients with pT1 or CIS will experience disease progression without treatment .
Intravesical Bacillus Calmette-Guerin (BCG) is recommended as adjuvant therapy to reduce the risk of tumor recurrence and possibly disease progression in intermediate risk (multiple or recurrent low-grade tumors) and high risk patients (T1, CIS, high-grade disease or multiple recurrent >3 cm low-grade Ta tumors) [3–10]. Mitomycin C (MMC) is an alternative intravesical therapy and is most often given as a single, immediate postoperative instillation after transurethral resection of bladder tumor (TURBT) to decrease the risk of recurrence [3–5, 11]. MMC is also recommended as adjuvant treatment because of its ability to reduce the risk of disease recurrence, however several studies have demonstrated superior prevention of tumor recurrence with BCG maintenance therapy as compared to MMC [7–8, 12].
Despite treatment with BCG up to 39% of pTa or pT1 disease will recur and 8% will progress to muscle invasive disease [6, 12]. BCG also has known side effects which impact patient acceptance. There has been a worldwide supply shortage since 2012. In addition, the intrinsic properties of the bladder pose unique challenges in developing effective intravesical therapies. Intravesical drugs are constantly diluted by urine and are regularly removed from the bladder by voiding. In this review we will discuss novel intravesical drug delivery systems and how they address these challenges in the treatment of NMIBC.
HISTORY OF INTRAVESICAL THERAPY
The first intravesical therapies can be traced to the 11th century. The Persian physician and philosopher Avicenna described transurethral injection of drugs into the bladder to treat bladder inflammation in his Canon of Medicine, which was completed in 1025 AD . In the 1890 s bladder washings with iodoform and various acidic solutions were administered through a foley catheter or a glass nozzle inserted into the distal urethra to treat cystitis. Felix Guyon is often cited for his method of bladder instillation with a solution of bichloride mercury to treat cystitis . Intravesical therapy for the treatment of bladder tumors was described in the medical literature in the 1950 s. Walton and Sinclair instilled radioactive solutions of sodium and bromine in 1952, and Ellis and Oliver instilled radioactive colloidal gold in 1955 [15, 16]. Jones et al. introduced Thiotepa , which was the first FDA approved intravesical agent for NMIBC. Thiotepa was found to have significant side effects, most notably bone marrow suppression . In the 1970 s, intravesical BCG was first introduced in the treatment of bladder cancer when Morales demonstrated the success of BCG in treating carcinoma in situ .
ANATOMY AND PHYSIOLOGY, PHARMACODYNAMICS
The bladder is a muscular, hollow pelvic organ whose main functions include the storage and expulsion of urine. The bladder is relatively impermeable to prevent reabsorption of waste substances. This is accomplished by the bladder permeability barrier (BPB). The BPB includes the basal germinal cell layer (5–10 um), an intermediate layer (20 um), and the apical layer of umbrella cells (100–200 um). Umbrella cells are given their name for their hexagonal, umbrella shape and are able to change shape and surface area as the bladder fills and contracts. The umbrella cell apical surface consists of an asymmetrical unit membrane, which is composed of densely packed plaques made of uroplakins that cover 70–90% of the luminal surface and are surrounded by hinge membranes. Umbrella cells are then interconnected by tight junctions. These unique characteristics create a barrier between urine and plasma. In addition, a hydrophilic glycosaminoglycan (GAG) layer of mucin forms a thin aqueous layer on top of the umbrella cells that acts as an anti-adherent and prevents adhesion of foreign particles .
While the relative impermeability of the bladder minimizes the systemic absorption of the drug and the subsequent side effects, this also poses a challenge in achieving the desired effects of intravesical drugs. While urothelium is not completely impermeable and a small but finite passive permeability is present through transcellular and paracellular pathways, studies have shown that the permeability values of mammalian bladder epithelium are exceptionally low [21, 22].
More importantly, any drug instilled into the bladder is diluted as the bladder constantly receives urine from the kidneys and is quickly washed out during bladder emptying. This decreases both the concentration of the drug and the amount of time a drug is in contact with the targeted tissue. Au et al. studied the pharmacodynamics of Mitomycin C (MMC) in human bladder tumors and demonstrated that drug concentration and exposure time are paramount in determining tumor response to MMC. They determined that prolonging the exposure time leads to a proportional decrease in the drug concentration needed to achieve the same effect . Consequently, research has focused on increasing the dwell time and absorption of intravesical drugs with the development of novel intravesical drug therapy systems.
NOVEL INTRAVESICAL DRUG DELIVERY SYSTEMS
Intravesical drug delivery devices
To increase the dwell time of intravesical drugs, researchers are developing intravesical drug delivery devices that are implanted in the bladder and left in place for an extended period of time. This increases the amount of time the bladder mucosa is exposed to the drug.
One such novel technology is the Taris Biomedical Lidocaine Releasing Intravesical System (LiRIS®) device. This device consists of a water permeable silicone double lumen tube. Drug tablets are placed into one lumen with an orifice that acts as an osmotic drug pump to release the drug over time. The gross structure of the device resembles a pretzel and was designed to resist structural collapse and promote retention of the device within the bladder with minimal irritation. This device is inserted transurethrally into the bladder through a foley catheter (Fig. 1) and is subsequently removed during office cystoscopy . The original research for this device was performed at the Massachusetts Institute of Technology by Lee and Cima, where they demonstrated increased levels of lidocaine in the bladder tissue of rabbits after three days of exposure . This device is currently in Phase 2 trials for the intravesical delivery of lidocaine in interstitial cystitis patients. Future research will explore its application in bladder cancer treatments. A Phase 1 trial is planned to study the safety and tolerability of their Gemcitabine Releasing Intravesical System (GemRIS) (Table 1).
As a corollary to intravesical drug delivery devices, the field of ophthalmology has had success in intravitreal delivery of drugs to the eye. There are currently multiple products on the market which utilize similar principles of osmotic diffusion that the LiRIS® device utilizes. These include the FDA approved Vitrasert® and Retisert® implants which utilize a polyvinyl alcohol membrane to control sustained release of medications into the vitreous of the eye for the treatment of CMV retinitis and non-infectious retinitis, respectively [26, 27]. Newer devices include the biodegradable reservoir Durasert™, which is currently in Phase II trials for the treatment of high intraocular pressure with intravitreal latanoprost and the refillable Capsule Drug Ring delivery device that delivers bevacizumab after cataract surgery into the peripheral lens capsule . Utilizing similar concepts, the development of intravesical drug delivery devices may achieve similar success.
Nanocarriers can be used to optimize targeted drug delivery. Nanotechnology is a broad term comprising any structure on the nanometer scale. These nanocarriers come in many forms including metals, proteins, lipids, and polymers. Many of these technologies have been studied in animal models with the hope to translate their potential to the treatment of human disease.
Magnetic nanocarriers are composed of a magnetic component typically made of iron and an activated carbon containing Doxorubicin. These nanocarriers are delivered into the bladder and an external magnet is placed over the skin to target specific areas of the bladder. Leakakos et al. studied the use of magnetic targeted carriers (MTC) with Doxorubicin in swine bladder and found MTCs in the bladder wall predominantly at targeted areas and also at greater depths in the bladder tissue with undetectable plasma doxorubicin levels . The use of targeted local hyperthermia with magnetite nanoparticles and an alternating magnetic field is also being investigated in preclinical studies .
Nanoparticle albumin bound (NAB) particles increase the solubility of a drug to enhance transport across tumor epithelial cells by interacting with albumin receptors. McKiernan et al. completed Phase I and II trials with NAB Paclitaxel in patients with recurrent NMIBC who failed at least one prior BCG regimen. These investigators observed complete response in 10 out of 28 (36%) patients . McKiernan et al. also demonstrated decreased tumorigenesis and prevention of progression to muscle invasive disease after intravesical treatment with rapamycin in a murine model . Rapamycin is known to have antiproliferative effects by inhibiting the mammalian target of rapamycin (mTOR) pathway and is an otherwise water insoluble drug that becomes more soluble as an NAB. The use of NAB and Rapamycin (ABI-009) is currently undergoing recruitment for a combined Phase I and II study to establish its safety and efficacy in treating NMIBC (Table 1).
Liposome nanoparticles are spherical vesicles composed of phospholipid layers that surround an aqueous core. Liposomes are being studied for their ability to increase drug solubility and stability in urine, and a recent study confirmed that liposomes increase cellular uptake of drugs via endocytosis . Frangos et al. studied the effectiveness of IFN-alpha incorporated into liposomes against a human urothelial cell carcinoma line and found that the liposome-IFN complex demonstrated increased anti-proliferative activity compared to free IFN-alpha . Liposomes are also being studied for their use in the treatment of interstitial cystitis with intravesical capsaicin , as well as the use of empty liposomes which do not carry a drug but demonstrate benefits on their own in a rat model .
Efforts have been made to develop better methods to administer Paclitaxel intravesically with the use of polymers. Paclitaxel is water insoluble and the traditional preparation utilizes ethanol and Cremophor to improve its solubility, which can have significant side effects and drug interactions. A new water-soluble amphiphilic polymer PMB30 W composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and n-butyl methacrylate was developed to deliver Paclitaxel to rat bladder tumors. They demonstrated a significant reduction in bladder wet weight as a marker of bladder tumor burden reduction, higher Paclitaxel concentration in bladder tumor tissue, as well as no cytotoxicity in comparison to the traditional Paclitaxel/Cremophor group . Paclitaxel has also been studied with gelatin polymer nanoparticles and was found to maintain constant concentration in the urine regardless of urine volume. These investigators also demonstrated drug retention in bladder tissue up to 1 week, 360 times higher drug concentration in tumor tissue as compared to normal bladder tissue, and plasma Paclitaxel levels well below the threshold for systemic side toxicity .
Reverse thermosensitive hydrogels are being investigated for their ability to increase the dwell time of intravesical drugs. These polymer hydrogels exist in the liquid state at cold temperatures and solidify into a gel at body temperature. Urogen Pharma has developed a reverse thermosensitive hydrogel for multiple urologic uses. VesiGel™ contains high dose MMC and is inserted into the bladder through a foley catheter. The hydrogel then coats and adheres to the bladder epithelium as a solidified gel reservoir. The drug is slowly released from the gel and can increase drug dwell times to 6–8 hours. The gel completely dissolves and is removed with voided urine. Preclinical results show an increased level of MMC in bladder tissue at the same dose of MMC alone, higher concentration of MMC in the bladder for a longer period of time, and low plasma MMC levels . Clinical trials are currently ongoing, including the prospective Optimized Instillation of Mitomycin for Bladder Cancer (OPTIMA) study that will compare standard intravesical instillation of MMC versus instillation with VesiGel™ prior to TURBT in NMIBC (Table 1). Urogen Pharma has also developed MitoGel™, which utilizes a ureteral catheter to deliver hydrogel with MMC in the treatment of upper tract urothelial cancer. Preclinical trials have established safety and feasibility . Further clinical trials are underway, including the recruitment phase for the Optimized Delivery of Mitomycin for Primary Upper Tract Urothelial Carcinoma Study (OLYMPUS). They have also applied for the Investigational New Drug (IND) program for Vesimune™ for the treatment of carcinoma in situ (CIS). Vesimune utilizes a hydrogel with imiquimod, an immunotherapeutic toll-like receptor 7 (TLR7) agonist. Phase I studies demonstrated its safety for intravesical use for pTa and pT1 disease [41, 42]. Results from the Phase 2 pilot study for patients with CIS should be available soon. A separate group has also investigated the use of BackStop Gel®, a reverse thermosensitive hydrogel from Boston Scientific originally developed to prevent stone fragment retropulsion during ureteroscopy, in optimizing delivery of MMC to the upper tract of pigs . MMC was instilled into the upper tract using ureteroscopy, and BackStop was applied as a plug to prevent premature drainage of MMC and was subsequently washed out after 60 minutes. They monitored intrarenal pressures and concluded reverse thermosensitive polymer can safely retain MMC in the upper urinary tract .
A rat cyclophosphomide-induced cystitis model showed that PEG-PLGA-PEG polymer Poly- (ethylene glycol)-Poly[lactic acid-co-glycolic acid]-Poly(ethylene glycol) delivered Misoprostol in a sustained fashion for up to 24 hours after instillation with significantly reduced urinary frequency . Other thermosensitive hydrogels include OncoGel (PLGA-PEG-PLGA plus Pacitaxel), which has been studied in the treatment of esophageal cancer, brain cancer, and other solid tumors . The commercially available hydrogel Pluronic F127 is being studied in other oncologic settings, including its use in combination with nanoparticles to deliver hydrophobic chemotherapeutics in depot fashion .
Utilizing a similar concept, mucoadhesive carriers attach to the bladder epithelium to prolong dwell time. Chitosan is the main agent currently being investigated. Chitosan is a nontoxic, biodegradable, naturally occurring polysaccharide formed by cross-linking glucosamine and N-acetylglucosamine units by bi-functional glutaraldehyde. It has innate mucoadhesive properties and studies suggest the positively charged chitosan binds to negatively charged epithelial membrane and rearranges cellular junctions, thereby enhancing urothelial permeability .
Zaharoff et al. studied the effect of chitosan and Interleukin-12 on orthotopic bladder tumors in mice. They observed an 88–100% complete response (CR) rate in mice treated with chitosan/IL-12 compared to 30–68% CR rate in the IL-12 only group and 0% in the BCG group. Animals cured by chitosan/IL-12 administration were rechallenged with the same bladder tumor cell line and none developed new bladder tumors for at least one year. The chitosan/IL-12 group demonstrated increased immune response (increased urinary Th1 cytokines, increased T cell and macrophage infiltration of tumor) versus the IL-12 only and BCG groups, demonstrating the role of chitosan in enhancing the effects of IL-12 . By rejecting bladder cancer cell lines inoculated both intravesically and subcutaneously in mice after instillation of intravesical chitosan and IL-12, the same group more recently demonstrated tumor specific, systemic immunity against a bladder cancer cell line. These mice also demonstrated durable response months after the initial treatment . This therapy has the potential to decrease the number of intravesical treatments required and the downstream costs of frequent treatment and surveillance. This also demonstrates a novel intravesical to systemic transfer of immunity with the potential use for treatment of locally advanced or metastatic disease.
Zhang et al. studied the effect of a magnetic chitosan thermosensitive hydrogel in the delivery of BCG in rat bladders. Utilizing a combination of previously described concepts, they developed a chitosan and Beta-glycerophosphate based thermosensitive hydrogel and included Fe3O4 magnetic nanoparticles (Fig. 2). They demonstrated sustained release of BCG over 48 hours in the presence of a magnetic field. They also showed increased antitumor efficacy as demonstrated by smaller mean tumor volume and stronger Th1 immune response to BCG as demonstrated by increased urinary cytokines and T lymphocytes in the submucosal tissue . Chitosan is also being studied with gemcitabine . A recent study described the successful formulation of chitosan and thioglycolic acid nanoparticles that were loaded with gemcitabine and then suspended in chitosan gel or Polaxmer hydrogel. Results showed increased loss of the bioadhesive gelling ability of Polaxmer when diluted with artificial urine solution as compared to chitosan gel, which suggests chitosan gel as the superior system in delivery of chitosan-thioglycolic acid nanoparticles.
Chemohyperthermia and electromotive drug administration
Research in the early 2000 s investigated the use of chemohyperthermia (CHT) and electromotive drug administration (EMDA) to improve the delivery of intravesical therapies. CHT combines intravesical chemotherapy with hyperthermia. MMC is the most common chemotherapeutic agent used in CHT. Some studies have shown promising results with reported relative reduction in recurrence up to 59% when compared to MMC alone, however the same meta-analysis also concluded that definitive conclusions cannot be drawn because of the lack of randomized trials and heterogenous data .
EMDA utilizes the concepts of iontophoresis, electro-osmosis and electroporation to drive the movement of drugs across the urothelium with an electric current . Di Stasi et al. have studied EMDA extensively. Their initial randomized controlled trial in 2003 demonstrated significantly higher response rates at 3 and 6 months for the EMDA-MMC group as compared to the passive diffusion group (53% vs. 38%, p = 0.036; 58% vs. 31%, p = 0.012 respectively), as well as significantly higher peak plasma concentration of MMC following EMDA as compared to passive diffusion . More recently, combined BCG and EMDA with MMC have been studied. However, there are significant costs associated with EMDA and tolerability can be an issue.
Both CHT and EMDA are not widely used at this time. The European Association of Urology Guideline on NMIBC considers both CHT and EMDA as experimental based on limited evidence . In addition, the American Urologic Association Guideline on NMIBC does not recommend their use based on lack of evidence but does note CHT may be effective with the need for further studies . Neither CHT nor EMDA are approved for use in the United States. Ongoing trials hope to further evaluate the use of CHT and EMDA (Table 1).
Despite bladder cancer being the fifth most common cancer in the United States, there have been few advances in its treatment. Currently, the simple instillation of intravesical therapies is limited by the intrinsic properties of the bladder. This is changing in the face of our improved understanding of the pharmacodynamics of intravesical drug delivery with the development of novel intravesical drug delivery technologies. As our knowledge of the immunology of bladder cancer continues to progress, these technologies may also have the opportunity to converge with and exploit the parallel advances in systemic immunotherapy such as immune checkpoint inhibition.
CONFLICTS OF INTEREST
Coauthor Mark Schoenberg serves as an advisor to Urogen Pharma (Ra’anana, Israel).
American Cancer Society. Cancer Facts & Figures 2016. American Cancer Society; 2016.
van Rhijn BW , Burger M , Lotan Y , Solsona E , Stief GC , Sylvester RJ , Witjes JA , Zlotta AR . Recurrence and progression of disease in non-muscle-invasive bladder cancer: From epidemiology to treatment strategy. European Urology 2009;56(3):430–42.
Babjuk MM , Burger M , Zigeuner R , Shariat SF , van Rhijn BW , Comperat E , Sylvester R , Kaasinen E , Bohle A , Redorta JP , Roupret M . EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: Update 2013. European Urology 2013;64(4):639–53.
National Comprehensive Cancer Network. Bladder Cancer v2.2015. Available from http://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf.
Hall MC , Chang SS , Dalbagni G , Pruthi RS , Seigne JD , Skinner EC , Wolf JS , Schellhammer PF . Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. The Journal of Urology 2007;178(6):2314–30.
Böhle A , Bock PR . Intravesical bacille Calmette-Guérin versus mitomycin C in superficial bladder cancer: Formal meta-analysis of comparative studies on tumor progression. Urology (Ridgewood, NJ) 2004;63(4):682–6.
Shelley MD , Wilt TJ , Court J , Coles B , Kynaston H , Mason MD . Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: A meta-analysis of randomized trials. BJU International 2004;93(4):485.
Malmström PU , Sylvester RJ , Crawford De , Friedrich M , Krege S , Rintala E , Solson E , DisTasi SM , Witjes JA . An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer. European Urology 2009;56(2):247–56.
Sylvester RJ , van der Meijden AP , Lamm DL . Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: A meta-analysis of the published results of randomized clinical trials. The Journal of Urology 2002;168(5):1964.
Sylvester RJ , van der Meijden AP , Witjes JA , Kurth K . Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: A meta-analysis of the published results of randomized clinical trials. The Journal of Urology 2005;174(1):86–91.
Sylvester RJ , Oosterlinck W , van der Meijden AP . A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: A meta-analysis of published results of randomized clinical trials. The Journal of Urology 2004;171(6):2186.
Bohle A , Jocham D , Bock PR . Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: A formal meta-analysis of comparative studies on recurrence and toxicity. The Journal of Urology 2003;169(1):90–5.
Madineh SM . Avicenna’s Canon of Medicine and Modern Urology. Part III: Other bladder diseases. Urology Journal 2009;6(2):138.
Tillmanns H . A Text-Book of Surgery. Stimson L, editor. New York: D. Appleton and Company; 1899.
Walton RJ , Sinclair WK . Radioactive solutions (24 NA and 82Br) in the treatment of carcinoma of the bladder. British Medical Bulletin 1952;8(2-3):159.
Ellis F , Oliver R . Treatment of papilloma of bladder with radioactive colloidal gold Au198. British Medical Journal 1955;1(4906):136.
Jones H , Swinney J . Thiotepa in the treatment of tumours of the bladder. The Lancet (British edition) 1961;2(7203):615.
Watkins WE , Kozak JA , Flanagan MJ . Severe pancytopenia associated with the use of intravesical thio-TEPA. The Journal of Urology 1967;98(4):470.
Morales AA , Eidinger D , Bruce AW . Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. The Journal of Urology 1976;116(2):180.
Yoshimura N , Chancellor M . Physiology and Pharmacology of the Bladder and Urethra. In: LRKAlan J. Wein, Novick Andrew C., Partin Alan W. and Peters Craig A., editor. Campbell Walsh Urology. 1. 10th ed: Saunders; 2011. pp. 1786–98.
Lewis SA . Epithelial electrophysiology. In: Wills NK, Reuss L, Lewis SA, editors. Epithelial transport: A guide to methods and experimental analysis. London: Chapman & Hall; 1996. pp. 93–117.
Negrete HO , Lavelle JP , Berg J , Lewis SA , Zeidel ML . Permeability properties of the intact mammalian bladder epithelium. The American Journal of Physiology 1996;271(4):F886–94.
Schmittgen TD , Wientjes MG , Badalement RA , Au JL . Pharmacodynamics of mitomycin C in cultured human bladder tumors. Cancer Research (Chicago, Ill) 1991;51(15):3849.
Cima MJ . Single compartment drug delivery. Journal of Controlled Release 2014;190:150–71.
Lee HH , Cima MJ . An intravesical device for the sustained delivery of lidocaine to the bladder. Journal of Controlled Release 2011;149(2):133–9.
Sanborn GE , Anana R , Torti RE , Nightingale SD , Cal SX , Yates B , Ashton P , Smith T . Sustained-release ganciclovir therapy for treatment of cytomegalovirus retinitis. Use of an intravitreal device. Archives of Ophthalmology 1992;110(2):188.
Callanan DG , Jaffe GJ , Martin DF , Pearson PA , Comstock TL . Treatment of posterior uveitis with a fluocinolone acetonide implant: Three-year clinical trial results. Archives of Ophthalmology 2008;126(9):1191.
Molokhia SA , Sant H , Simonis J , Bishop CJ , Burr RM , Gale BK , Ambati BK . The capsule drug device: Novel approach for drug delivery to the eye. Vision Research (Oxford) 2010;50(7):680–5.
Leakakos T , Ji C , Lawson G , Petesron C , Goodwin S . Intravesical administration of doxorubicin to swine bladder using magnetically targeted carriers. Cancer Chemotherapy and Pharmacology 2003;51(6):445–50.
Oliveira TR , Stauffer PR , Lee CT , Landon CD , Etienne W , Ashcraft KA , McNerny KL , Mashal A , Nouls J , Maccarini PF , Beter WF , Inman B , Dewhirst MW . Magnetic fluid hyperthermia for bladder cancer: A preclinical dosimetry study. International Journal of Hyperthermia 2013;29(8):835–44.
McKiernan JM , Holder DD , Ghandour RA , Barlow LJ , Ahn JJ , Kates M , Badalato GM , Roychoudury A , Decastro GJ , Benson MC . Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure. The Journal of Urology 2014;192(6):1633–8.
Seager CM , Puzio-Kuter AM , Patel T , Jain S , Cordon-Cardo C , McKiernan J , Abate-Shen C . Intravesical delivery of Rapamycin suppresses tumorigenesis in a mouse-model of progressive bladder cancer. Cancer Prevention Research (Philadelphia) 2009;2(12):1008–14.
Rajaganapathy BR , Chancellor MB , Nirmal J , Dang L , Tyagi P . Bladder uptake of liposomes after intravesical administration occurs by endocytosis. PloS One 2015;10(3):e0122766.
Frangos DN , Killion JJ , Fan D , Fishbeck R , von Eschenbach AC , Fidler IJ . The development of liposomes containing interferon alpha for the intravesical therapy of human superficial bladder cancer. The Journal of Urology 1990;143(6):1252–6.
Tyagi PP , Chancellor MB , Li Z , DeGroat WC , Yoshimura N , Fraser MO , Huang L . Urodynamic and immunohistochemical evaluation of intravesical capsaicin delivery using thermosensitive hydrogel and liposomes. The Journal of Urology 2004;171(1):483–9.
Tyagi PP , Chancellor M , Yoshimura N , Huang L . Activity of different phospholipids in attenuating hyperactivity in bladder irritation. BJU International 2008;101(5):627–32.
Tamura KK , Kikuchi E , Konno T , Ishihara K , Matsumoto K , Miyajima A , Oya M . Therapeutic effect of intravesical administration of paclitaxel solubilized with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) in an orthotopic bladder cancer model. BMC Cancer 2015;15(10):317.
Lu ZZ , Yeh TK , Wang J , Chen L , Lyness G , Xin Y , Wjentjes MG , Bergdall V , Couto G , Alvarex Berger F , Kosarek CE , Au JL . Paclitaxel gelatin nanoparticles for intravesical bladder cancer therapy. The Journal of Urology 2011;185(4):1478–83.
Sagiv SP . Great Inventions that Trick Nature, New Delivery System Optimises Bladder Cancer Treatment by Increasing Dwell Time. ONdrugDelivery. 2013. http://www.ondrugdelivery.com/publications/44/TheraCoat.pdf
Meiron M , Chamie K , Lerner SP , Jeshurun M , Hakim G , Schoenberg MP , et al. Mitogel: Optimizing drug delivery to the upper urinary tract— a preclinical evaluation. Journal of Urology 2014;191(4):e914.
Falke JJ , Lammers RJ , Arentsen HC , Ravic M , Possi R , Cornel EB , Vergunst H , deReijke TM , Witjes JA . Results of a phase 1 dose escalation study of intravesical TMX-101 in patients with nonmuscle invasive bladder cancer. The Journal of Urology 2013;189(6):2077–82.
Arends TJ , Lammers RJ , Falke J , van der Heijden AG , Rustighini I , Pozzi R , Ravic M , Eisenhardt A , Vergunst H , Witjes JA . Pharmacokinetic, Pharmacodynamic, and Activity Evaluation of TMX-101 in a Multicenter Phase 1 Study in Patients With Papillary Non-Muscle-Invasive Bladder Cancer. Clinical Genitourinary Cancer 2015;13(3):204-9.e2.
Rane AA , Bradoo A , Rao P , Shivde S , Elhilali M , Anjdjar M , Pace K , D’A Honey JR . The use of a novel reverse thermosensitive polymer to prevent ureteral stone retropulsion during intracorporeal lithotripsy: A randomized, controlled trial. The Journal of Urology 2010;183(4):1417–23.
Wang AJ , Goldsmith ZG , Neisius A , Astroza GM , Oredein-McCoy O , Iqbal MW , SImmons WN , Madden JF , Preminger GM , Inman BA , Lipkin ME , Ferrandino MN . Increasing dwell time of mitomycin C in the upper tract with a reverse thermosensitive polymer. Journal of Endourology 2013;27(3):288–93.
Tyagi PP , Li Z , Chancellor M , De Groat WC , Yoshimura N , Huang L . Sustained intravesical drug delivery using thermosensitive hydrogel. Pharmaceutical Research 2004;21(5):832.
Elstad NL , Fowers KD . OncoGel (ReGel/paclitaxel)–clinical applications for a novel paclitaxel delivery system. Advanced Drug Delivery Reviews 2009;61(10):785–94.
Gou MM , Li X , Dai M , Gong C , Wang X , Xie Y , Deng H , Chen L , Zhao X , Qian Z , Wei Y . A novel injectable local hydrophobic drug delivery system: Biodegradable nanoparticles in thermo-sensitive hydrogel. International Journal of Pharmaceutics 2008;359(1-2):228–33.
Kerec MM , Bogataj M , Veranic P , Mrhar A . Permeability of pig urinary bladder wall: The effect of chitosan and the role of calcium. European Journal of Pharmaceutical Sciences 2005;25(1):113–21.
Zaharoff DA , Hoffman BS , Hooper HB , Benjamin CJ , Khurana KK , Hance KW , Rogers CJ , Pinto PA , Schlom J , Greiner GW . Intravesical immunotherapy of superficial bladder cancer with chitosan/interleukin-12. Cancer Research (Chicago, Ill.) 2009;69(15):6192–9.
Smith SG , Koppolu BP , Ravindranathan S , Kurtz SL , Yang L , Katz MD , Zaharoff DA . Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer. Cancer Immunology Immunotherapy 2015;64(6):689–96.
Zhang DD , Sun P , Li P , Xue A , Zhang X , Zhang H , Jin X . A magnetic chitosan hydrogel for sustained and prolonged delivery of Bacillus Calmette-Guérin in the treatment of bladder cancer. Biomaterials 2013;34(38):10258–66.
Şenyiğit ZA , Karavana SY , Ilem-Ozdemir D , Caliskan C , Waldner C , Sen S , Bernkop-Schburch A , Baloglu E . Design and evaluation of an intravesical delivery system for superficial bladder cancer: Preparation of gemcitabine HCl-loaded chitosan-thioglycolic acid nanoparticles and comparison of chitosan/poloxamer gels as carriers. International Journal of Nanomedicine 2015;10:6493.
Lammers RR , Witjes JA , Inman BA , Leibovitch I , Laufer M , Native O , Colombo R . The role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle invasive bladder cancer: A systematic review. European Urology 2011;60(1):81–93.
Di Stasi SS , Ridel C . Updates in intravesical electromotive drug administration of mitomycin-C for non-muscle invasive bladder cancer. World Journal of Urology 2009;27(3):325–30.
Di Stasi SS , Giannantoni A , Stephen RL , Capelli G , Navarra P , Massoud R , Vespasiani G . Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial blader cancer: A prospective randomized study. The Journal of Urology 2003;170(3):777–82.
Figures and Tables
|Trial||Drug Delivery System||Purpose|
|NCT01803295 (OPTIMA)||TC-3 hydrogel||Evaluate ablative effect and recurrence rate of MMC with TC-3 hydrogel compared to standard MMC on low risk NMIBC lesions|
|NCT02307487||TC-3 hydrogel||Evaluate the safety of escalating doses of MMC TC-3 hydrogel in high risk NMIBC prior to TURBT|
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