Microfluidics analysis of cancer cell microenvironments and targeted destruction of cancer stem cells by nanomedicine

Tumor microenvironment (TME) of a mature solid tumor is made of three components: tumor cell clusters or nests, stroma and immune cells. Most of the microvessels are located in the stroma, which is made of extracellular matrix and tumor associated fibroblasts (TAF). Circulating nanoparticles (NP) extravasating through the leaky microvessels first encounter the stroma and are taken up by TAF. SomeNPwill also penetrate through the stroma and reach tumor nests, depending on the particle size. In a stroma rich bladder cancer model, TAF are themajor cells taken up small LPC NP which contain ~80% cisplatin. Genome damaged TAF secrete Wnt16 which in a paracrine manner activates tumor cells for drug resistance and for epithelial-to-mesenchymal transition. It also induces neighboring naive fibroblast to become drug resistance and the endothelial cells to undergo angiogenesis. After repeated LPC administration, the bladder tumor becomes highlyWnt16 positive and highly drug resistant. Tumor rapidly regrows soon after LPC dosing is completed. Delivery of Wnt16 siRNA by LPH NP to the tumor can down-regulate Wnt16, inhibit the development of tumor drug resistance and enhance tumor growth inhibition by LPC. In advancedmurine B16F10melanoma, tumor does not contain a lot of stroma, and is relatively resistant to a nano-vaccine. LPH delivery of TGFβ siRNA, PLGA NP delivery of CDDO-Me (an anti-inflammatory) or Sunitinib (a broad-spectrum kinase inhibitor), or PEGylated curcumin micelles, can all downregulate the Th2 type cytokines, inhibit Treg cells and myeloid-derived suppressor cells and enhance tumor infiltrating CD8+ T-cells in the treated tumor. These immune modulators significantly enhance the tumor growth inhibition by a nano vaccine designed to boost the CTL response against the melanoma. Thus, we conclude that both siRNA and small molecule inhibitors can be delivered to modulate TME to facilitate either chemo or immune therapy, or both. Work supported by NIH grants CA149363, CA151652, CA149387 and DK100664.