Targeting Signaling Pathways of Hyaluronic Acid and Integrin Receptors by Synergistic Combination Nanocomposites Inhibits Systemic Metastases and Primary Triple Negative Breast Cancer

Abstract Triple negative breast cancer (TNBC) has a poor prognosis due to its aggressive nature, high incidence of distant metastasis, and lack of targets for effective therapy. Therefore, a novel multifunctional biopolymer‐anticancer drug combination nanomedicine is designed for the prevention of spontaneous metastasis while treating primary TNBC. Oligomeric hyaluronic acid (oHA) and doxorubicin (DOX) at a synergistic ratio against TNBC cells are co‐loaded in a polymer‐lipid hybrid nanoparticle (PLN) which is then functionalized with an internalizing cyclic peptide iRGD (iRGD‐DOX‐oHA‐PLN). iRGD conjugation enhances cellular uptake and cytotoxicity in vitro and nanoparticle (NP) accumulation in human TNBC tumors that overexpress integrins. NP‐delivered oHA inhibits cell migration and invasion in vitro via the intracellular release of oHA that interacts with the receptor for hyaluronan mediated motility and downregulates the phospho‐extracellular signal‐regulated kinase (p‐ERK) signaling pathway. Intravenously injected iRGD‐DOX‐oHA‐PLN significantly inhibits the growth of primary TNBC tumors in a mouse model and prevents spontaneous metastasis to the lungs and lymph nodes, superior to free solutions of DOX, oHA, or both and NP formulations loaded with DOX or oHA. These results suggest that iRGD‐DOX‐oHA‐PLN can be a promising bioactive polymer‐drug combination nanomedicine for the treatment of TNBC and prevention of its spontaneous metastasis.