Targeting drug delivery remains a challenge in various disease treatment including cancer. The local drug deposit could be greatly enhanced by some external stimuli-responsive systems. Here we develop pluronic P123/F127 polymeric micelles (M) encapsulating curcumin (Cur) that are permeabilized directly by focused ultrasound, in which ultrasound triggers drug release. Tumor preferential accumulation and site-specific sonochemotherapy were then evaluated. Cur-loaded P123/F127 mixed micelles (Cur-M) exhibited longer circulating time and increased cellular uptake compared to free Cur. With the assistance of focused ultrasound treatment, Cur-M showed tumor-targeting deposition in a time-dependent manner following systemic administration. This was due to enhanced permeabilization of tumor regions and increased penetration of Cur-M in irradiated tumor cells by ultrasound sonoporation. Furthermore, Cur-M self-assembly could be regulated by ultrasound irradiation. In vitro Cur release from mixed micelles was greatly dependent on ultrasound intensity but not on duration, suggesting the cavitational threshold was necessary to initiate subsequent sonochemotherapy. In vivo site-specific drug release was demonstrated in dual-tumor models, which showed spatial-temporal release of entrapped drugs following intratumoral injection. The sonoporation-assisted site-specific chemotherapy significantly inhibited tumor growth and the decrease in tumor weight was approximately 6.5-fold more than without exposure to ultrasound irradiation. In conclusion, the established ultrasound-guided nanomedicine targeting deposit and local release may represent a new strategy to improve chemotherapy efficiency.

Schematic illustration of sonochemotherapy using HA-modified nanocomposites.

Sonodynamic therapy (SDT) not only has greater tissue‐penetrating depth compared to photo‐stimulated therapies, but also can also trigger rapid drug release to achieve synergistic sonochemotherapy. Here, reactive oxygen species (ROS)‐responsive IR780/PTL‐ nanoparticles (NPs) are designed by self‐assembly, which contain ROS‐cleavable thioketal linkers (TL) to promote paclitaxel (PTX) release during SDT. Under ultrasound (US) stimulation, IR780/PTL‐NPs produce high amounts of ROS, which not only induces apoptosis in human glioma (U87) cells but also boosts PTX released by decomposing the ROS‐sensitive TL. In the U87 tumor‐bearing mouse model, the IR780/PTL‐NPs releases the drug at the target sites in a controlled manner upon US irradiation, which significantly inhibits tumor growth and induces apoptosis in the tumor tissues with no obvious toxicity. Taken together, the IR780/PTL‐NPs are a novel platform for sonochemotherapy, and can control the spatio‐temporal release of chemotherapeutic drugs during SDT.

No abstract

A cancer cell membrane-based biomimetic strategy was developed by loading doxorubicin and icotinib to overcome drug-resistance of EGFR-mutation lung cancer.

Targeted delivery of drug-loaded nanoparticles to brain tumors is exceptionally difficult due to the blood-brain barrier (BBB). In addition, several chemotherapeutic drugs induce autophagy, which protects the cells from apoptosis and mitigates the therapeutic effect. A novel "all-in-one" nanoparticles (AMPTL) consisting of endogenous reactive oxygen species-cleavable thioketal linkers conjugated to paclitaxel (PTX) and autophagy inhibitor 3-methyladenine, and angiopep-2 peptide-modified DSPE-PEG 2K is developed. AMPTL inhibits autophagy in the C6 glioma cells, as indicated by fewer autophagic vesicles, lower LC3-II expression and accumulation of SQSTM1/ P62, and significantly upregulates p53 and the pro-apoptotic Bax and cleaved caspase-3 proteins. In addition, AMPTL treatment induces cell cycle arrest at the G2/M phase. Thus, inhibition of autophagy in the AMPTL-treated glioma cells sensitizes them to PTX-induced cell cycle arrest and apoptosis. Furthermore, focused pulse ultrasound and microbubbles enhances the delivery of AMPTL to intracranial glioma tissues by reversibly opening the BBB, which significantly inhibits xenograft growth and markedly improves survival rates of the tumor-bearing mice. Taken together, combining non-invasive BBB opening with autophagy inhibitors and chemotherapeutic drugs can achieve cascade-amplifying synergistic therapeutic effects against glioma.

Ferroptosis is an emerging form of programmed cell death, and its combination with sonodynamic therapy (SDT) for antitumor is gradually attracting attention. However, their application in against glioma has not...

The combination of checkpoint blockade with focused ultrasound (FUS) physical therapy can enhance antitumor immune response by improving the precision and efficiency of immunotherapy. However, one of the major disadvantages of conventional FUS treatment is the small lesion size, which prolongs treatment duration. We constructed a focused acoustic vortex (FAV) system with a hollow cylindrical focal region, which exhibited a larger focal region compared to conventional FUS of the same frequency. We developed an all-in-one synergistic therapy against metastatic breast cancer based on integrated FAV double combination sequence-regulated phase-transformation nanodroplets (CPDA@PFH) with checkpoint blockade immunotherapy. A single treatment with FAV + CPDA@PFH resulted in 2.25-fold higher inhibition of tumor growth compared to that with FUS + CPDA@PFH. In addition, FAV-regulated CPDA@PFH combined with ICB induced a systemic immune response that not only inhibited the growth of primary (98.41% inhibition rate) and distal (80.71%) 4T1 tumors but also reduced the progression of lung metastasis. In addition, the synergistic therapy achieved long-term immune memory that effectively prevented tumor growth and improved the survival time of mice. The long-term survival rate of 4T1 tumor-bearing mice treated with FAV + CPDA@PFH + Anti-PD-L1 was 57.14% on day 60 after treatment. Our study is a proof-of-concept of cascade-amplified synergistic tumor therapeutics based on ultrasonic-hyperthermia, cavitation, sonodynamic therapy (SDT), and checkpoint blockade immunotherapy through FAV-regulated CPDA@PFH phase-transformation nanodroplets.