CD-44 targeted nanoparticles for combination therapy in an in vitro model of triple-negative breast cancer: targeting the tumour inside out

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer defined by the lack of three key receptors: estrogen, progesterone, and HER2. This lack of receptors makes TNBC difficult to treat with hormone therapy or drugs, and so it is characterised by a poor prognosis compared to other kinds of breast cancer. This study explores photoactive Poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a potential therapeutic strategy for TNBC. The nanoparticles are functionalised with hyaluronic acid (HA) for targeted delivery to CD-44 receptors overexpressed in TNBC cells, especially under hypoxic conditions. Additionally, we co-loaded the nanoparticles with Doxorubicin (Dox) and Indocyanine Green (ICG) to enable combinatorial chemo-photothermal therapy. After carefully optimising the formulation, we propose an effortless and reproducible preparation of the nanodrugs. We demonstrate that HA-conjugated nanoparticles effectively target TNBC cells and inhibit their proliferation while the treatment efficiency is enhanced during near-infrared light irradiation. We also prove that our treatment is effective in a 3D cell culture model, highlighting the importance of tumour architecture and the metabolic stage of the cells in the tumour microenvironment. This approach is promising for a tumour-targeted theragnostic for TNBC with improved efficacy in hypoxic microenvironments.