Enhanced anti-tumor efficacy of hyaluronic acid modified nanocomposites combined with sonochemotherapy against subcutaneous and metastatic breast tumors

• Published in: Nanoscale 2019-06, Vol.11 (24), p.1147-11483
• Main Authors: Wu, Pengying, Sun, Yue, Dong, Wei, Zhou, Huige, Guo, Shifang, Zhang, Lei, Wang, Xiaobing, Wan, Mingxi, Zong, Yujin
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Apoptosis; Biocompatibility; Breast cancer; Chemotherapy; Doxorubicin; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Delivery Systems; Female; Hyaluronic acid; Hyaluronic Acid - chemistry; Hyaluronic Acid - pharmacology; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - therapy; Metastasis; Mice; Mice, Inbred BALB C; Nanocomposites; Nanocomposites - chemistry; Nanocomposites - therapeutic use; Neoplasm Metastasis; Toxicity; Tumors; Ultrasonic Therapy; Xenotransplantation
• ISSN: 2040-3364; 2040-3372
• DOI: 10.1039/c9nr01691k

Sonochemotherapy is a promising strategy for inhibiting tumor growth. However, achieving highly targeted and effective sonochemotherapy is still an enormous challenge. In this study, a novel chemotherapeutic-carrying nanocomposite (HPCID) was developed, which can effectively target metastatic cancer cells and provide an enhanced therapeutic effect. In detail, HPCID was composed of hyaluronic acid (HA), carboxyl-terminated PAMAM dendrimer, fluorochrome indocyanine green (ICG), and doxorubicin hydrochloride (Dox). The efficacy of this drug delivery system (DDS) in sonochemotherapy was assessed on the CD44-overexpressing metastatic breast cancer cell line 4T1 both in vitro and in vivo . The HA modification significantly improved the cellular internalization of HPCID, and the degradation of the HA shell by hyaluronidase that is abundant in the 4T1 cells resulted in enzyme-responsive drug release. Under ultrasound (US) stimulation, HPCID produced a high amount of reactive oxidant species (ROS), which induced significant cell apoptosis when combined with chemotherapy. In addition, the administration of HPCID in 4T1 xenograft-bearing mice combined with ultrasonic exposure significantly inhibited tumor growth and pulmonary metastasis, with no systemic toxicity. Taken together, the proposed HPCID-mediated sonodynamic therapy (SDT) is a novel strategy against breast cancer progression and metastasis. Schematic illustration of sonochemotherapy using HA-modified nanocomposites.