Multiple stimuli-responsive nanosystem for potent,ROS-amplifying,chemo-sonodynamic antitumor therapy

Although sonodynamic therapy(SDT)is a promising non-invasive tumor treatment strategy due to its safety,tissue penetration depth and low cost,the hypoxic tumor microenvironment limits its therapeutic effects.Herein,we have designed and developed an oxygen-independent,ROS-amplifying chemo-sonodynamic antitumor therapy based on novel pH/GSH/ROS triple-responsive PEG-PPMDT nanoparticles.The formulated artemether(ART)/Fe_(3)O_(4)-loaded PEG-PPMDT NPs can rapidly release drug under the synergistic effect of acidic endoplasmic pH and high intracellular GSH/ROS levels to inhibit cancer cell growth.Besides,the ROS level in the NPs-treated tumor cells is magnified by ART via interactions with both Fe^(2+)ions formed in situ at acidic pH and external ultrasound irradiation,which is not affected by hypoxia tumor microenvironment.Consequently,the enriched intracellular ROS level can cause direct necrosis of ROS-stressed tumor cells and further accelerate the drug release from the ROS-responsive PEG-PPMDT NPs,achieving an incredible antitumor potency.Specifically,upon the chemo-sonodynamic therapy by ART/Fe_(3)O_(4)-loaded PEG-PPMDT NPs,all xenotransplants of human hepatocellular carcinoma(HepG2)in nude mice shrank significantly,and 40% of the tumors were completely eliminated.Importantly,the Fe3O4 encapsulated in the NPs is an efficient MRI contrast agent and can be used to guide the therapeutic procedures.Further,biosafety analyses show that the PEG-PPMDT NPs possess minimal toxicity to main organs.Thus,our combined chemo-sonodynamic therapeutic method is promising for potent antitumor treatment by controlled release of drug and facile exogenous generation of abundant ROS at target tumor sites.

Combining immune checkpoint blockade with ATP-based immunogenic cell death amplifier for cancer chemo-immunotherapy

Amplifying“eat me signal”during tumor immunogenic cell death(ICD)cascade is crucial for tumor immunotherapy.Inspired by the indispensable role of adenosine triphosphate(ATP,a necessary“eat me signal”for ICD),a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy.Doxorubicin(DOX),ATP and ferrous ions(Fe^(2+))were co-assembled into nanosized amplifier(ADO-Fe)throughπ‒πstacking and coordination effect.Meanwhile,phenylboric acid-polyethylene glycol-phenylboric acid(PBA-PEG-PBA)was modified on the surface of ADO-Fe(denoted as PADO-Fe)by the virtue of d-ribose unit of ATP.PADO-Fe could display active targetability against tumor cells via sialic acid/PBA interaction.In acidic microenvironment,PBA-PEG-PBA would dissociate from amplifier.Moreover,high H_(2)O_(2)concentration would induce hydroxyl radical(·OH)and oxygen(O_(2))generation through Fenton reaction by Fe^(2+).DOX and ATP would be released from the amplifier,which could induce ICD effect and“ICD adjuvant”to amplify this process.Together with programmed death ligands 1(PD-L1)checkpoint blockade immunotherapy,PADO-Fe could not only activate immune response against primary tumor,but also strong abscopal effect against distant tumor.Our simple and multifunctional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy.