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Intravesical Toll‐like receptor 7 agonist R‐837: Optimization of its formulation in an orthotopic mouse model of bladder cancer
Author(s) -
Hayashi Tomoko,
Crain Brian,
Corr Maripat,
Chan Michael,
Cottam Howard B,
Maj Roberto,
Barberis Alcide,
Leoni Lorenzo,
Carson Dennis A
Publication year - 2010
Publication title -
international journal of urology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.172
H-Index - 67
eISSN - 1442-2042
pISSN - 0919-8172
DOI - 10.1111/j.1442-2042.2010.02503.x
Subject(s) - medicine , poloxamer 407 , bladder cancer , poloxamer , systemic administration , tumor necrosis factor alpha , peripheral blood mononuclear cell , pharmacology , agonist , urology , cancer , cancer research , receptor , immunology , chemistry , in vivo , in vitro , biochemistry , microbiology and biotechnology , organic chemistry , copolymer , biology , polymer
Objective: To study the immune response caused by the intravesical administration of the immunomodulator R‐837 in various formulations and to estimate its therapeutic potential for bladder cancer. Methods: Female C57BL/6 mice were intravesically treated with different formulations of R‐837, a Toll‐like receptor 7 agonist used for treating genital warts and skin malignancy. The tested formulation mixtures contained different ratios of lactic acid, a thermosensitive poloxamer polymer (Lutrol F127) and 2‐(hydroxypropyl)‐β‐cyclodextrin (HPβCD). Induction of tumor necrosis factor α (TNFα) and keratinocyte‐derived chemokine (KC) was analyzed by Luminex microbeads assay. The therapeutic potential of intravesical administration of R‐837 was assessed in an orthotopic, syngeneic mouse model of bladder cancer using MB49 cells. Results: Intravesical administration of R‐837 in lactic acid alone induced systemic and bladder TNFα and KC in a dose‐dependent manner. Formulations including poloxamer decreased systemic absorption of R‐837 and significantly reduced systemic and local induction of KC. Addition of HPβCD in the poloxamer formulation particularly reversed levels of systemic and local levels of TNFα and KC. Histological examination showed that poloxamer‐HPβCD formulation allowed infiltration of mononuclear cells into urothelium and lamina propria. In studies using orthotopic mouse bladder cancer, the tumor loads in R‐837‐treated mice were significantly lower than those in vehicle‐treated or non‐treated mice. Conclusion: The optimized poloxamer‐HPβCD formulation of R‐837 shows therapeutic potential for bladder cancer while avoiding adverse side‐effects.