Shayak Samaddar1

1, Purdue University, West Lafayette, Indiana, United States

Bladder carcinoma is the most expensive tumor type to treat on a cost-per-patient basis from diagnosis to death. The majority of bladder carcinoma cases are categorized as superficial disease (nonmuscle invasive bladder cancer; NMIBC). Intravesical instillation of live Mycobacterium bovis Bacillus Calmette Guerin (BCG) is the adjuvant therapy of choice for the treatment of NMIBC. Unfortunately, BCG treatment suffers from drawbacks including frequent tumor relapse, resistance, and risk of sepsis. Recently, cyclic di-nucleotides have been reported as a potent immunostimulatory agent that works via stimulation of the STING (STimulator of INterferon Gene) pathway. Clinical translation of cyclic di-nucleotide therapy; however, faces two major challenges. First, the hydrophilic nature of the molecule prevents it from cross the cellular membrane to stimulate the STING pathway via binding with the cytosolic ATP dependent helicase. Second, there is no carrier system capable to deliver the cyclic di-nucleotides in a tumor specific manner. Here we describe a liposomal formulation that has been designed to overcome these two challenges. We have utilized a novel targeting ligand, fibronectin attachment peptide(FAP) to guide the liposomes to the fibronectin (FBN) rich extracellular matrix of the tumor microenvironment. Upon internalization by tumor and macrophagic cells, the pH responsive nature of the liposomes helps to escape the endosome and release the cargo into the cytosol, resulting in the release of a host of cytokines to induce the host innate immune system.