| Breast cancer is a common malignant tumor in women.Compared with other tumors,its age at onset is younger,and it is more invasive and prone to metastasis.Therefore,early diagnosis and treatment of this tumor is important.The application of diagnostic and therapeutic integrated nanoparticles brings new hope for the early diagnosis and treatment of this tumor.On the one hand,such nanoparticles can provide not only structural information,such as tumor location,morphology and relationship with surrounding normal tissues,but also functional information,such as tumor oxygen content.On the other hand,this type of nanoparticle can achieve combined treatment of tumors through photodynamic therapy(PDT),photothermal therapy,sonodynamic therapy,and drug release stimulated by internal or external stimulation of the tumor.PDT is a non-invasive treatment method that has received extensive attention and in-depth research,but its limitations have also limited its development.Reactive oxygen species that have therapeutic effects during PDT are generated by consuming free oxygen in tumor tissues.However,the hypoxic environment caused by characteristics of heterogeneous growth of tumor tissues limits the antitumor effect of PDT.In addition,the oxygen in tumor tissue consumed by PDT exacerbates hypoxia in tumor tissue.The hypoxic tumor microenvironment limits the antitumor effects of chemotherapy,radiation therapy,PDT and PTT.To overcome the limitations of PDT,hypoxia-activated prodrugs are added to the nanoparticles;hypoxia-activated prodrugs can be activated in a hypoxic environment and converted into obviously cytotoxic drugs to kill tumor cells.In addition,in order to reduce the toxic and side effects of chemotherapeutic drugs and improve the effective utilization rate of chemotherapeutic drugs,solid-liquid phase change materials have been selected as the core of nano-drug-loading platforms,and drug release at tumor sites has been achieved through the photothermal effect.This topic provides new ideas and methods for the treatment of breast cancer.Objective To prepare mitochondria-targeted solid-liquid phase change nanoparticles(PCM @ Lip/IT),test their physical and chemical properties,study their photoacoustic imaging and fluorescence imaging capabilities,evaluate the distribution and targeting of nanoparticles in vivo,and investigate the relief and antitumor effects of the oxygen environment.Methods First,PCM@Lip/IT nanoparticles were prepared by an improved nano-sedimentation method,and the morphology,particle size,hydrated particle size,stability of the nanoparticles,encapsulation efficiency,and photoexcitation of the prodrug TPZ and photosensitizer IR780 were measured.Release of TPZ.To study the parameters of PCM@Lip/IT nanoparticles suitable for treatment,temperature changes caused by the photothermal effect,1O2 production rate,and cell hypoxia in PDT,and its mitochondrial targeting.An infrared imager was used to evaluate the photothermal effect of nanoparticles.A confocal microscope was used to detect the degree of reactive oxygen species and hypoxia produced by nanoparticles in 4T1 cells by the photodynamic effect.CCK8 was used to evaluate the effects of PCM@Lip/IT nanoparticles on 4T1 cell safety and the antitumor effect of nanoparticles on 4T1 cells under NIR irradiation.Confocal microscopy was also used to evaluate the antitumor effect of PCM@Lip/IT nanoparticles on 4T1 tumor cells,mitochondrial targeting of tumor cells by PCM@Lip/IT nanoparticles,and damage to mitochondria by PCM@Lip/IT nanoparticles.In vivo,biosafety of the nanoparticles was evaluated by analyzing whole blood cells,renal function,liver function and visceral H & E staining of the control group and the PCM @ Lip / IT nanoparticle group tumor-bearing mice.Fluorescence imager and photoacoustic imager in vivo were used to evaluate the distribution,mitochondrial targeting,and choose a suitable time period for illumination.Results The PCM@Lip/IT nanoparticles were successfully prepared.It can be seen under an electron microscope that they have a typical spherical shape and uniform distribution.The particle size was approximately 60 nm and hydrated particle size detected by Malvern is 70 ± 3.21 nm.After NIR irradiation,the particle size of the nanoparticles increased slightly,to approximately 73 nm,and hydrated particle size detected by Malvern is 85 ± 3.78 nm.The encapsulation rate of IR780 in PCM@Lip/IT nanoparticles was 81.5±4.2%,and the drug loading was 3.74±0.2%.The encapsulation rate of TPZ was 43.3±2.4%,and the drug loading was 1.98±0.1%.The structure of PCM @ Lip / IT nanoparticles is stable,and there is no obvious change of particle size during long-term storage and transportation in vivo.The obvious TPZ drug release after NIR stimulation PCM@Lip/IT nanoparticles shows better biological safety and obvious mitochondrial targeting.Under NIR irradiation,the nanoparticles can produce a large amount of 1O2 in the cell and cause the cell to be in an anoxic state.PCM@Lip/IT nanoparticles combined with NIR irradiation can cause obvious cell apoptosis,and PDT can also cause obvious mitochondrial damage.In vivo treatment showed that PCM@Lip/IT nanoparticles combined with the NIR group can cause significant damage to tumor cells and reduce cell proliferation.In addition,blood tests and H&E staining of major organs showed that the PCM@Lip/IT nanoparticle group was not significantly different from the control group.Photoacoustic imaging and fluorescence imaging show good tumor targeting.Conclusion In this study,the solid–liquid phase change nanoparticles PCM@Lip/IT carrying IR780 and TPZ were successfully prepared.The nanoparticles demonstrate obvious mitochondrial targeting and biological safety,and the TPZ carried by them can improve tumor outcomes.The state of the poor antitumor effect of PDT and chemotherapy caused by hypoxia greatly increases the antitumor effect of photochemotherapy.At the same time,the nanoparticles can also help to monitor the treatment process by photoacoustic and fluorescent imaging and assist in choosing an appropriate light time window to improve the anti-tumor treatment effect.Therefore,the combined treatment of PTT,PDT,and chemotherapy with PCM@Lip/IT nanoparticles can completely kill tumor cells,providing a new direction for the diagnosis and treatment of breast cancer. |
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