Efficient Combination Chemo-Sonodynamic Cancer Therapy Using Mitochondria-Targeting Sonosensitizer-Loaded Polysorbate-Based Micelles.

Sonodynamic therapy (SDT), utilizing ultrasound (US) and sonosensitizers, holds immense potential as a noninvasive and targeted treatment for a variety of deep-seated tumors. However, the clinical translation of SDT is hampered by several key limitations in sonosensitizers, especially their low aqueous stability and poor cellular uptake. In this study, non-ionic polysorbate (Tween 80, T80) was adopted to formulate effective nanocarriers for the safe and efficient delivery of sonosensitizers to cancer cells. Mitochondria-targeting triphenylphosphonium (TPP)-conjugated chlorin e6 (Ce6) sonosensitizer was loaded into T80-based micelles for efficient SDT. Pro-oxidant piperlongumine (PL) was co-encapsulated with TPP-conjugated Ce6 (T-Ce6) in T80 micelles to enable combination chemo-SDT. T80 micelles substantially enhanced the cellular internalization of T-Ce6. As a result, T80 micelles loaded with T-Ce6 and PL [T80(T-Ce6/PL)] significantly elevated intracellular reactive oxygen species (ROS) generation in MCF-7 human breast cancer cells upon US exposure. Moreover, T-Ce6 exhibited selective accumulation within the mitochondria, leading to efficient cell death under US irradiation. Importantly, T80(T-Ce6/PL) micelles caused cancer-specific cell death by selectively triggering apoptosis in cancer cells through PL. This study demonstrated the feasibility of using T80(T-Ce6/PL) micelles for efficient and cancer-specific combination chemo-SDT.

Defining Integrin Tension Required for Chemotaxis of Metastatic Breast Cancer Cells in Confinement.

Cancer metastasis is affected by chemical factors and physical cues. From cell adhesion to migration, mechanical tension applied to integrin expresses on the cell membrane and physical confinement significantly regulates cancer cell behaviors. Despite the physical interplay between integrins in cells and ligands in the tumor microenvironment, quantitative analysis of integrin tension during cancer cell migration in microconfined spaces remains elusive owing to the limited experimental tools. Herein, a platform termed microconfinement tension gauge tether to monitor spatial integrin tension with single-molecule precision by analyzing the epithelial-growth-factor-induced chemotaxis of metastatic human breast cancer cells in microfluidic channels is developed. The results reveal that the metastatic cancer cells exert the strongest integrin tension in the range of 54-100 pN at the leading edges of cells during chemokinetic migration on a planar surface, while the cells exert the strongest integrin tension exceeding 100 pN at the cell rear when entering microconfinement. Further analysis demonstrates that cells undergo mesenchymal migration under high integrin tension and less confinement, which is converted to amoeboid migration under low integrin tension or high confinement. In summary, the results identify a basic mechanism underlying the mechanical interactions between integrin tension and microenvironment that determines cancer invasion and metastasis.