pH-sensitive hyaluronic acid nanomicelles for co-delivery of capsaicin and doxorubicin enhance the treatment of anaplastic thyroid carcinoma.

The cross-talk between cancer-associated fibroblasts (CAFs) and tumor cells has emerged as an important component in the development of anaplastic thyroid carcinoma (ATC). Herein, we prepared novel co-loaded galactose (Gal)-conjugated sulfated hyaluronic acid nanoparticles (CDHG) for co-delivery of capsaicin (CAP) and doxorubicin (DOX) by co-targeting CAFs and ATC cells simultaneously. To mimic the tumor microenvironment, we established novel "CAFs+8505c" 2D and 3D models for anti-ATC analyses in vitro. The results showed that, compared with ATC cells alone, the novel "CAFs+8505c" dual-cell model decreased drug sensitivity of tumor cells and promoted tumor migration. Notably, CDHG nanoparticles could be readily taken up by CAFs and ATC cells simultaneously, and efficiently permeate 3D tumor spheroids. Moreover, CDHG exhibited greater anti-proliferation and anti-migration effects than other formulations. The anti-ATC mechanisms revealed that CDHG could improve drug sensitivity of ATC cells, and inhibit tumor migration. In brief, the "CAFs+8505c" dual-cell system is a potential research model, and the combination therapy based on CDHG nanoparticles could obviously inhibit drug-resistance and migration of ATC cells.