Bladder cancer is the second most common genitourinary malignancy. At initial diagnosis, approximately 70% of cases are non-muscle-invasive. Current treatment options for superficial disease include treating bladder cancer topically via intravesicular instillation of a chemotherapeutic agent into the bladder with a catheter. However, these treatment options are of limited efficacy. Despite intravesical chemotherapy and/or immunotherapy, up to 80% of patients with non-muscle-invasive bladder cancer develop recurrent tumours, of which 20-30% develop into more aggressive, potentially lethal tumours (Dalbagni, G. (2007) Nat. Clin. Pract. Urol. 4: 254-260).
Treatment failure is thought to be due in part to the short dwell-time of drugs active against bladder cancer cells in the bladder. For example, taxanes are generally not used for intravesicular instillation due to poor bioavailability of the current formulations in the bladder. Paclitaxel has documented antitumor activity in systemic bladder cancer therapy as it penetrates bladder tissues at a rate 20 times faster than that of water-soluble drugs such as mitomycin C, allowing for prolonged retention of therapeutic doses even after the instilled solution is removed. However, its intravesical use is hampered by the presence of Cremophor™-EL in the commercial formulation (Taxol™) as it entraps the drug in an aqueous environment and reduces paclitaxel penetration into the bladder wall (Mugabe, C., et al. (2008) British J. Urology Int. 102(7): 978-986).
While many active agents are hydrophobic or otherwise water insoluble, they are often needed in water-based or otherwise aqueous environments for effective treatment of numerous indications, including cancer (such as cancers of the bowel, lung, bladder and genitourinary system), infections (such as those of the digestive tract and the airways) and inflammatory or autoimmune diseases (such as irritable bladder, inflammatory bowel disease and chronic and acute inflammation). As such, multiple systems have been developed as delivery vehicles for such agents. One of these systems includes the use of polymeric micelles.
Polymeric micelles are amphiphilic, having a hydrophobic core and a hydrophilic shell, and as such, they can encapsulate hydrophobic molecules in the core due to hydrophobic interactions. The hydrophilic shell keeps the system soluble in water. However, these systems may be unstable in the bladder due to dilution effects or environmental factors.
Hyperbranched polyglycerols (“HPGs”) are one of the few hyperbranched polymers that can be synthesized in a controlled manner with pre-determined molecular weights and narrow polydispersity (Kainthan, R. K., et al. (2008) Biomacromolecules 9: 886-895). Hydrophobic molecules may be encapsulated in the hydrophobic core of an HPG (WO2006/130978).