The use of HA oligosaccharide-loaded nanoparticles to breach the endogenous hyaluronan glycocalyx for breast cancer therapy

Breast cancer is characterized by a stromal microenvironment consisting of highly abundant hyaluronan (HA). The role of the HA-coat as a 'fortress' fencing off tumor cells from drugs applied in the circulation has been largely neglected by previous research efforts. In this study we demonstrated that an unusually abundant secreted HA contributed to drug resistance in breast cancer. However, oligosaccharides of HA (oHA) treatment disrupted the cell-associated HA-coat and rendered breast cancer cells profoundly vulnerable to paclitaxel. Next the anti-tumor activity of self-assembled oHA-loaded nanoparticles was evaluated. Results showed that the nanoparticles induced an anti-tumor response both in vitro and in vivo. Systemic application of the nanoparticles dramatically increased the activity of chemotherapies and reduced tumor growth in breast tumor-bearing mouse model, possibly as a result of reduced accumulation of HA in the extracellular matrix surrounding xenografts tumor. We provided direct evidence suggesting that oHA possesses the advantages of ideal drug carrier and drug targeting, and oHA-loaded nanoparticles have great potential to overcome HA associated chemoresistance and improve cancer therapy.