Enhanced manipulation of tumor microenvironments by nanomotor for synergistic therapy of malignant tumor

Abstract

Tumor microenvironments (TME) play critical roles in the growth and metastasis of tumor tissue, which provide a promising way to treat malignant tumor via manipulation of TME. However, developing proper strategy to effectively control TME is still a challenge. Herein, a Ce6@AT-PEG-MSN-Pt (CAPMP) nanomotor is fabricated to spontaneously move in tumor tissue and concurrently perform the enhanced manipulation of various tumor microenvironments including copper levels, hypoxia, local temperature and reactive oxygen species (ROS) for effective tumor therapy. The CAPMP nanomotor consists of a janus platinum-mesoporous silica core with acyl thioureas groups (copper chelator) conjugated polyethylene glycol on the surface and chlorin e6 (photosensitizer) in the pores. During therapy, the acyl thioureas groups on CAPMP would capture the over-expressed copper in tumor tissue and tumor cells to cause dramatic copper-deficiency of tumor. The chlorin e6 is in charge of the ROS (¹O₂) generation in tumor via photodynamic process, which would be triggered by 660 nm irradiation. The platinum layer of CAPMP served as both photothermal agent and O₂ producer. It rapidly raised the local temperature under 808 nm irradiation, meanwhile converted the over-expressed H₂O₂ in tumor tissue to O₂via catalytic reaction. The O₂ production not only drove the CAPMP for sustained movement to promote its efficiency of copper capture, but reversed the hypoxic environment of tumor tissue in large and deep area, which further promoted the ¹O₂ generation property of CAPMP. Both in vitro and in vivo experiments demonstrate that the raise of local temperature and enhanced ¹O₂ concentration performed significant damage of tumor tissue for primary tumor elimination, while the copper deficiency and hypoxia reversion further hindered the migration of tumor cells for metastasis inhibition, resulting in an effective strategy to treat malignant tumor.

Keywords: Metastasis inhibition; Primary tumor elimination; Self-driven nanomotor; Synergistic therapy; Tumor microenvironments manipulation.