(150g) Hierarchically Nano-Branched Particles for Sustained Adhesion and Drug Release to Bladder Tumors

In recent decades, engineered nanoparticles have garnered considerable attention for drug delivery due to their high surface area-to-volume ratios, tunable drug release rates, and ability to deliver drugs to target sites deep within the body. However, weak interactions between nanoparticles and epithelia often result in poor retention times, limiting their benefits in clinical settings. To address this challenge, we developed soft microparticles with chitosan-functionalized nanostructured branches that can be loaded with a wide range of FDA-approved chemotherapeutic drugs and be extruded onto epithelial tumor sites. We prepared soft dendritic particles using poly(lactic-co-glycolic acid) (PLGA), a copolymer that is widely used in therapeutic drug delivery applications due to its well-studied biocompatibility and biodegradability (i.e., into lactic acid and glycolic acid). In highly turbulent flows, precipitation of the PLGA in an antisolvent results in the formation of numerous branched nanofibers around the particle. The large surface area due to the dendritic morphology of the particles and chitosan functionalization allowed them to strongly adhere to tumor cells and epithelial tissues, gradually release drugs, and later degrade into biocompatible products under physiological conditions. We experimentally measured the amount of chitosan molecules bound to PLGA surfaces and investigated the effect of chitosan adsorption on the surface charge of PLGA for enhanced adhesion on cancer cells. We further demonstrate that the dendritic particles display better retention on epithelial tissues such as a mouse bladders and human bladder cancer cells compared to spherical nanoparticles. Finally, we show that dendritic particles can be precisely extruded on tumor sites using a biocompatible alginate gel. While alginate gel slowly dissolves in urine, the dendritic particles remain attached on epithelia and sustainably release chemotherapeutic drugs. We demonstrate the ability of this system to encapsulate and release gemcitabine, docetaxel, and methotrexate to effectively kill bladder cancer cells in vitro. Our work highlights an adhesive nano-branched particle-based drug delivery system that offers high retention at target tissues for sustained drug release.