| BackgroundIn 2018,liver cancer in China accounted for more than 50%of new cases and deaths in the world.In 2019,there were 370,000 new confirmed cases of liver cancer and 326,000 deaths during the same period.Therefore,liver cancer is a major disease that seriously endangers the lives and health of people in China and all of the world.The main reason for the poor prognosis of liver cancer is the low diagnosis rate of early liver cancer.Therefore,early diagnosis of liver cancer is particularly important to improve the prognosis.Liver cancer with a diameter of less than 20mm is defined as micro-liver cancer,and traditional imaging examinations such as ultrasound,CT,and MRI have low specificity and sensitivity to diagnose liver cancer lesions below 10 mm.The new optical imaging technology photoacoustic imaging has the advantages of non-invasive,high sensitivity and high spatial resolution.It can effectively detect tumor lesions with a diameter of less than 10 mm in combination with active or passive targeting molecular probes.However,so far,most probes are derived from some inorganic materials,including transition metal nanoparticles,carbon nanoparticles,noble metal nanoparticles.These materials are poorly biocompatible and have potential toxicity,which limits their further clinical application.Moreover,previous studies of PTT often focused on the treatment for surface tumors due to shallow light penetration depth and attenuated efficacy by threshold laser power for skin tolerance.There are few reports of photothermal treatment for orthotopic liver cancer.In order to solve these two problems,we have synthesized a multi-modal molecular probe IR820@PEG-SPIO based on new indocyanine green IR820 and PEGylated superparamagnetic iron oxide(SPIO).Compared with ICG,IR820 has high more stability and longer clearance plasma half-life up to 35 hours,meanwhile has the ability to produce enough heat to kill cancer cells without damaging surrounding normal tissues under NIR laser irradiation.Hence IR820 can act as a potential candidate for these applications.The synthesized IR820@PEG-SPIO showed excellent multimodal imaging capacity and great PTT effect both in vitro and in vivo.In addition,we creatively try to use small animal laparoscopy to assist minimally invasive photothermal ablation to treat orthotopic liver cancer in nude mice,which provides another possibility for clinically effective minimally invasive and precise interventional treatment of liver cancer.ObjectiveThrough the synthesis of a multi-modal molecular probe IR820@PEG-SPIO and the use of fluorescence,photoacoustic,and magnetic resonance multi-modal imaging,preoperative detection of early minimal liver cancer was achieved.The feasibility,accuracy and effectiveness of laparoscopic-assisted photothermal ablation for liver cancer in situ were also investigated.MethodThe iron oxide cores were synthesized by thermo-decomposition of iron(?)acetylacetonate in a mixture of oleic and oleylamine.To make SPIO NPs hydrophilic,the hydrophobic iron cores were coated with DSPE-PEG 2000 using the dual solvent exchange method.The mixture was then placed on a magnetic stirrer and incubated overnight at room temperature.The removal of unloaded IR820 molecules were carried out by ultracentrifugation at 100,000 g.The particle size,morphology,potential,absorption peaks,multimodal imaging capability and photothermal effect were studied in vitro.The multimodal imaging potential of the probe and the effect of laparoscopic-assisted photothermal treatment were further verified on orthotopic HepG2 tumor-bearing mice,and compared with the control group,surgery(tumor resection dependent on visual margin between tumor and normal tissue)group and sorafenib-treated group.ResultThe novel probe IR820@PEG-SPIO synthesized in this study is spherical in shape with average diameter of 14.3nm.The obtained nanoparticles exhibited negligible cytotoxicity and good biocompatibility.The UV-visible-NIR spectrum of IR820@PEG-SPIO has peak absorption at 831 nm.Outstanding fluorescence,photoacoustic and magnetic resonance imaging potential as well as high photothermal conversion efficiency was observed in vitro.The accumulation of probe could be observed at the tumor region in orthotopic HCC bearing mice after intravenous injection of IR820@PEG-SPIO and reached a peak at 24 h,effectively detecting lesions smaller than?2 mm.The median survival time of laparoscopic-assisted photothermal therapy group was 54.5 days,which was significantly higher than that of the PBS control group(29 days),open surgery group(34 days),and sorafenib group(40 days),P<0.05.At the same time,the laparoscopic-assisted photothermal treatment group had the lowest weight loss and the most obvious tumor shrinkage.Extensive tumor necrosis in laparoscopic-assited photothermal therapy group was confirmed by Pathological examination,tumor recurrence was observed in surgery group but not in the laparoscopic-assited photothermal therapy group.ConclusionIR820@PEG-SPIO has good biocompatibility and excellent multi-modal imaging capabilities,and can effectively detect early-stage micro liver cancer with a diameter of 2mm.In addition,the use of this molecular probe for laparoscopic-assisted minimally invasive photothermal treatment of orthotopic hepatocellular carcinoma has achieved good therapeutic outcomes,showing the clinical application prospects of this probe and the technique of laparoscopic assisted photothermal treatment of liver cancer. |
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