Hypoxia in a solid tumor microenvironment (TME) can lead to the overexpression of hypoxia-inducible factor-1α (HIF-1α), which correlates to tumor metastasis. Reactive oxygen species (ROS) induced tumor cell apoptosis is becoming a promising method in tumor treatment. Currently, the ROS generating systems, e.g., photodynamic treatment and sonodynamic treatment, highly depend on oxygen (O 2 ) in the tumor microenvironment (TME). However, the level of O 2 in TME is too low to produce enough ROS. Herein, we developed an ultrasmall DSPE-PEG 2000 coated barium titanate nanoparticle (P-BTO) for tumor treatment based on ultrasound triggered piezocatalysis and water splitting. Interestingly, irradiated by ultrasound, the surface of ultasmall P-BTO nanoparticles produced imbalance charges, which induced a cascade of redox reaction processes to simultaneously generate ROS and O 2 , the latter one was hardly generated in large-sized barium titanate nanoparticles. The assynthesized P-BTO reached the highest accumulation in the tumor site at 4 h after intravenous injection. The results showed that the produced O 2 significantly alleviated the hypoxia of TME to down-regulate the expression of HIF-1α, and the produced ROS can efficiently kill tumor cells. Moreover, the tumor metastasis was also inhibited, providing a different way to treat triple-negative breast cancer, which was easily metastatic and lacked effective treatments in the clinic.
Tumor immunotherapy based on immune checkpoint blockade (ICB) still suffers from low host response rate and non‐specific distribution of immune checkpoint inhibitors, greatly compromising the therapeutic efficiency. Herein, cellular membrane stably expressing matrix metallopeptidase 2 (MMP2)‐activated PD‐L1 blockades is engineered to coat ultrasmall barium titanate (BTO) nanoparticle for overcoming the immunosuppressive microenvironment of tumors. The resulting M@BTO NPs can significantly promote the BTO's tumor accumulation, while the masking domains on membrane PD‐L1 antibodies are cleaved when exposure to MMP2 highly expressed in tumor. With ultrasound (US) irradiation, M@BTO NPs can simultaneously generate reactive oxygen species (ROS) and O2 based on BTO mediated piezocatalysis and water splitting, significantly promoting the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and improving the PD‐L1 blockade therapy to the tumor, resulting in effective tumor growth inhibition and lung metastasis suppression in a melanoma mouse model. This nanoplatform combines MMP2‐activated genetic editing cell membrane with US responsive BTO for both immune stimulation and specific PD‐L1 inhibition, providing a safe and robust strategy in enhancing immune response against tumor.
Trastuzumab
combined with chemotherapy is the first-line treatment
for advanced HER2-positive gastric cancer, but it still suffers from
limited therapeutic efficiency and serious side effects, which are
usually due to the poor delivery efficiency and the drug resistance
of tumor cells to the chemotherapeutic drugs. Herein, a type of ultrasound
microbubble for simultaneous delivery of sonosensitizers and therapeutic
antibodies to achieve targeting combination of sonodynamic therapy
and antibody therapy of HER2-positive gastric cancer was constructed
from pyropheophorbide-lipid followed by trastuzumab conjugation (TP
MBs). In vitro and in vivo studies
showed that TP MBs had good biological safety, and their in
vivo delivery can be monitored by ultrasound/fluorescence
bimodal imaging. With ultrasound (US) located at the tumor area, TP
MBs can be converted into nanoparticles (TP NPs) in situ by US-targeted microbubble destruction; plus the enhanced permeability
and retention effects and the targeting effects of trastuzumab, the
enrichment of sonosensitizers and antibodies in the tumor tissue can
be greatly enhanced (∼2.1 times). When combined with ultrasound,
TP MBs can not only increase the uptake of sonosensitizers in HER2-positive
gastric cancer NCI-N87 cells but also efficiently generate singlet
oxygen to greatly increase the killing effect on cells, obviously
inhibiting the tumor growth in HER2-positive gastric cancer NCI-N87
cell models with a tumor inhibition rate up to 79.3%. Overall, TP
MBs combined with US provided an efficient way for co-delivery of
sonosensitizers and antibodies, greatly enhancing the synergistic
therapeutic effect on HER2-positive gastric cancer while effectively
reducing the side effects.
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