Application Of ROS-responsive Nanomicelles In Tumor "Ferroptosis"-Sonodynamic Combined Therapy

Nanoparticles(NPs)have been shown to be effective in targeted drug delivery to tumors due to their enhanced permeability and retention(EPR effect).The study also found that large-diameter nanoparticles(>100 nm)can stay in the tumor site for a long time,but the ability to diffuse within the tumor is weak,mainly distributed in the location close to the blood vessel;small-diameter nanoparticles are easy to diffuse in the tumor,but the ability to stay within the tumor is weak.Therefore,simultaneously improving the retention capacity of the drug at the tumor site and the uniformity of the intratumoral distribution is an urgent problem to be solved.In view of this,we constructed an ultrasound(US)responsive smart micellar carrier to deliver the sonosensitizer hypocrellins(HC)and Fe₃O₄nanoparticles to achieve the"ferroptosis"-sonodynamic combined therapeutic effect.The constructed carrier can generate reactive oxygen species(ROS)under ultrasound excitation,which in turn triggers the disassembly of micelles and the rapid release of drugs,which increases the retention time of the drugs and promotes the uniformity of the drugs in the tumor.distributed.The loaded Fe₃O₄dissolves and releases Fe²⁺,which catalyzes the conversion of hydrogen peroxide(H₂O₂)into highly toxic hydroxyl radicals(·OH),which is synergistic with ROS such as singlet oxygen(¹O₂)produced by sonodynamic therapy(SDT)anti-tumor effect.This research will provide new strategies for the construction of smart drug delivery systems and efficient treatment of tumors.The specific content is as follows:1.A polyethylene glycol-polypropylene sulfide-HC(PEG-PPS-HC)micelle with ROS-response controlled release function was constructed.The constructed PEG-PPS-HC micelles are spherical,with a particle size of about 70 nm,and can successfully load HC.Under ultrasound triggering,HC can effectively generate ROS,trigger the disassembly of micelles,and accelerate the release of HC.Cell research results show that pure PEG-PPS-HC has no obvious toxicity;under ultrasound conditions,it can significantly inhibit the growth of tumor cells.When the HC concentration is 30?g/m L,the cell inhibition rate reaches 60%.2.Construction and in vitro evaluation of an ultrasound-responsive drug delivery system(PEG-PPS-Fe₃O₄-HC)containing Fe₃O₄nanoparticles.The constructed PEG-PPS-Fe₃O₄-HC has a particle size of about 150 nm,and the encapsulated Fe₃O₄nanoparticles can be clearly seen.After ultrasonic excitation,the micellar system disassembles and releases 4-8 nm Fe₃O₄NPs.In vitro ROS detection results show that Fe₃O₄NPs can significantly increase the yield of total ROS and·OH.Cell uptake experiments show that PEG-PPS-Fe₃O₄-HC is taken up into cells through the lysosomal pathway.Under ultrasound excitation,HC and Fe₃O₄NPs can be released into the nucleus.PEG-PPS-Fe₃O₄-HC combined with sonodynamic therapy can significantly reduce the cell survival rate.The intracellular ROS analysis results show that the PEG-PPS-Fe₃O₄-HC+US group has the highest ROS content,and the presence of Fe₃O₄can promote the production of·OH.3.Evaluation of the combined therapeutic effect of PEG-PPS-Fe₃O₄-HC with sonodynamics and"ferroptosis".The results of in vivo distribution showed that nanoparticles could be enriched in the tumor site 5 h and 10 h after injection.The anti-tumor effect in vivo showed that the combined treatment effect of PEG-PPS-Fe₃O₄-HC SDT and“Ferroptosis”was significantly better than the pure sonodynamic therapy group.After two weeks of treatment,the combined treatment group and the PEG-PPS-HC group the tumor suppression rates were 67%and 74%,respectively.The results of Prussian blue staining show that ultrasound can promote the diffusion of Fe₃O₄nanoparticles in the tumor site to achieve a more uniform distribution.