Abstract

Triple-negative breast cancer (TNBC) metastasis is the cause of nearly 90% of breast cancer treatment failures as the side effects of clinical drugs and insufficient efficacy of single-modality therapy. Shikonin (SHK) is a naphthoquinone natural product from the herbal medicine Lithospermum erythrorhizon ., which is widely used for cancer therapy as one kind of Chinese medicine for its significant anti-tumor, anti-metastatic, and anti-inflammatory effects. However, passive targeting of SHK to tumor location in vivo and long-term high dose administration is likely to decrease heart rate and induce drug resistance, which accordingly results in therapeutic failure. Thus, we designed a biomimetic SHK-loading nano-system (Hybrid [email protected] / [email protected] @SHK nanoparticles, HMGPHS NPs) to achieve controlled release and reduced SHK dosage. The prolonged circulation time and higher targeting of the HMGPHS NPs allowed less drug leakage systemically with increased drug concentration at the tumor sites compared to naked ICG/ [email protected] @SHK (GPHS) NPs. Moreover, SHK could down-regulate the expression of COX-2, IL-6, and TNF-α to reduce the photothermal therapy-induced inflammatory response and improve the tumor microenvironment (TME), enabling HMGPHS NPs to significantly inhibit the growth and metastasis of TNBC. We propose that the combination of high efficacy, prolonged circulation, and high targeting of HMGPHS NPs could facilitate the conversion of SHK to clinical application for the effective treatment of TNBC.