Self-assembled multifunctional nanotheranostics against circulating tumor clusters in metastatic breast cancer

摘要

Circulating tumor clusters(CTC)disseminating from the primary tumor are responsible for secondary tumor formation where the conventional treatments such as chemotherapy and radiotherapy does not prevent the metastasis at locally advanced stage of breast cancer.In this study,a smart nanotheranostic system has been developed to track and eliminate the CTCs before it can colonize at a new site,which would reduce metastatic progression and increase the five-year survival rate of the breast cancer patients.Targeted multiresponsive(magnetic hyperthermia and pH)nanomicelles incorporated with NIR fluorescent superparamagnetic iron oxide nanoparticles were developed based on self-assembly for dual modal imaging and dual toxicity for spontaneous killing of CTCs in blood stream.A heterogenous tumor clusters model was developed to mimic the CTCs isolated from breast cancer patients.The nanotheranostic system was further evaluated for the targeting property,drug release kinetics,hyperthermia and cytotoxicity against developed CTC model in vitro.In vivo model in BALB/c mice equivalent to stageⅢandⅣhuman metastatic breast cancer was developed to evaluate the biodistribution and therapeutic efficacy of micellar nanotheranostic system.Reduced CTCs in blood stream and low distant organ metastasis after treatment with the nanotheranostic system demonstrates its potential to capture and kill the CTCs that minimize the secondary tumor formation at distant sites.