Self-assembled GSH-regulated Nanoparticles For Enhanced Radioisotope Therapy

For a long time,cancer has been a serious threat to human health.At present,clinical cancer treatment methods are mainly surgical treatment,radiation therapy and chemical drug treatment.In addition,in order to improve the efficacy,it is very common to combine several single treatment methods and apply new combination treatments to cancer treatment.Combination therapies such as chemotherapy and radiation therapy have been widely used clinically.The combination of multiple disciplines can provide new content for the treatment of cancer.In recent years,nanotechnology is rapidly developing and mature in the field of tumor diagnosis and treatment.Nanomaterials are shining in the biomedical field because of their unique and excellent properties.But at the same time,there are many limitations in many aspects,such as biosafety,radiotherapy tumor treatment efficiency and chemotherapy side effects.According to this situation,we had designed and developed a combination of radiotherapy and chemotherapy in this topic.And a multifunctional nano drug-loading system based on a biocompatible carrier(131I-HOPA-C18PMH-PEG/PL).HOPA was used for radiolabeling in this system,while PL(Piperlongumine)was used to reduce the level of high GSH(reduced glutathione)in tumors.C18PMH-PEG was a modified carrier with excellent biocompatibility.It is envisaged that after intravenous administration into the living b ody,after the blood was circulated and distributed throughout the body,based on the EPR effect,about 13 nm of nanoparticles can achieve passive enrichment at the tumor site.Due to the acidic conditions of the tumor microenvironment,the pH-stimulated responsive nanosystem released the drug PL and effectively improved the environment of high GSH in the tumor.When the level of reactive oxygen species(ROS)in the tumor had increased,the rate of 131I in the tumor would be greatly improved.We had conducted in-depth research on the physicochemical properties of synthetic nanoparticles.The results demonstrated that the nanosystem was not only well dispersed and stable in aqueous solution and serum,but also had high radioactivity stability(nuclear 131I/125I labeling).Then we carried out biomedical research of the nanosystem at two levels in vitro and in vivo.The correctness of the hypothesis was verified at the cellular level.The killing effect of 131I-HOPA-C18PMH-PEG/PL nanoparticles on tumors and the uptake of tumor cells were studied.Later,we constructed a breast cancer tumor model using balb/c mice.Through pharmacokinetic analysis,it was found that the blood circulation of the nanosystem was consistent with the atrioventricular two-compartment model,and the half-life value was larger(ti/2α:0.7±0.15 h),t1/2β:31.01±0.55 h).SPECT(single photon emission computed tomography imaging)imaging showed that HOPA-C18PMH-PEG/PL was highly enriched at the tumor site via tail vein injection in mice,which may be the reason for the size of the nanosystem.The tumor-bearing mice were then randomized and subjected to different combinations of radioisotope therapy(RIT)and chemotherapy us:ing PL.The results showed that the 131I-labeled HOPA-C18PMH-PEG/PL tumor treatment method achieved the synergistic effect of radiotherapy and chemotherapy and reflected the characteristics of diagnosis and treatment integration.In addition,our research showed that this strategy(depletion of GSH and increased ROS)did not produce significant toxicity to normal tissues.Therefore,this subject successfully produced a multi-drug drug delivery system for SPECT imaging guided tumor treatment.The system had the advantages of integrated diagnosis and treatment,efficient coordination of RIT and chemotherapy,and high biosafety.This research will further promote the use of polymer nanoparticle-based cancer RIT and is expected to be used for future clinical transformation.