Ultrasound-enhanced Tumor Penetration of Carrier-free Nanodrugs for High-efficiency Chemo-photodynamic Therapy of Breast Cancer

In recent years, the chemo-photodynamic combinational therapy has become increasingly popular in treating breast cancer. However, the limited accumulation of nanodrugs into tumor (less than 1% of injected dose) extremely impacts therapeutic efficacy. Herein, the photosensitizer Chlorin e6 (Ce6) and the chemotherapeutic drug rhein (Rhe) were self-assembled to form a carrier-free nanodrug (RC NPs) with good stability and high drug loading rate. Ultrasound (US) irradiation was applied to increase the permeability of tumor blood vessels thus greatly enhance the drug accumulation of RC NPs in tumor tissues. After uptake by tumor cells, Ce6 could produce a sig-nificant amount of reactive oxygen species (ROS) when exposed to laser irradiation, while rhein could inhibit tumor cell proliferation and affect mitochondrial membrane potential, inducing tumor cell apoptosis through the mitochondria-dependent apoptosis pathway, thus effectively realizing the combined effect of PDT and chemotherapy. Taken together, RC NPs have an enhanced EPR effect when exposed to US irradiation and exhibit better tumor suppression, which provides new insights into chemo-photodynamic combination treatment for clinical breast cancer.