Sialic Acid Binding Liposome Nanoparticles for Targeted Bladder Cancer Therapy

Targeted delivery of therapeutics to bladder cancer is crucial for optimizing therapeutic efficacy and minimizing side effects. In this study, a novel targeted nanocarrier system was developed to enhance bladder cancer targeted therapy by modifying liposomes with 4-carboxyphenylboronic acid (CPBA), enabling selective binding with sialic acid residues overexpressed on bladder cancer cells. To further improve therapeutic outcomes, we employed a combination therapy based on chemotherapy and immunotherapy to both eliminate tumor cells and activate antitumor immune responses. We fabricated tumor-targeting liposome-chitosan-CPBA (LPCB) nanoparticles coloaded with doxorubicin (Dox), a chemotherapeutic agent, and resiquimod (R848), a toll-like receptor (TLR) 7/8 agonist that stimulates antitumor immunity. LPCB nanoparticles encapsulating Dox and R848 (LPCBDR) demonstrated enhanced binding to bladder tumor cells (T24, MB49) and cytotoxicity compared to nontargeted (non-CPBA incorporated) nanoparticles. LPCBDR nanoparticles also showed enhanced activation of murine dendritic cell (DC) populations characterized by the upregulation of costimulatory molecules. In vivo biodistribution studies with Cy7-labeled nanoparticles confirmed preferential tumor accumulation of LPCB NPs compared to nontargeted nanoparticles. Therapeutic efficacy using MB49 subcutaneous tumor model revealed that LPCBDR treatment group significantly reduces tumor volume compared to nontargeted nanoparticles and free drugs. Flow cytometric analysis of tumor and spleen samples further showed robust activation of Natural Killer (NK) cells, CD4⁺ T cells, and CD8⁺ T cell effector functions. Combined results demonstrate that sialic acid targeting LPCBDR nanoparticles offers a promising drug delivery platform for bladder cancer therapy.