| BackgroundPrimary liver cancer is a common malignant disease with an overall 5-year survival rate less the 20%.Most primary liver cancers occurring worldwide are hepatocellular carcinoma(HCC),accounting for 80%of all cases.Unfortunately,the inconspicuous signs and symptoms,as well as atypical imaging features make it difficult to diagnose HCC at the early stage.Most patients who are found to be in the advanced stage,when the outcomes of treatment are discouraging.Therefore,it is important and urgent to study the key time point during the development of liver cancer and explore new effective therapy.The occurrence and development of liver cancer involves complex changes of molecules,cells and microvessels.Visualization of key molecules at the molecular and cellular levels and the structures and functions of microvessels during the evolution of HCC is helpful for the early diagnosis of HCC.Traditional imaging techniques are limited in spatial resolution or sensitivity and cannot clearly display microcirculation information of suspicious lesions.Photoacoustic imaging is an emerging modality that possesses the advantages such as high sensitivity and contrast.It is able to provide precise imaging of HCC in molecular,cellular and micro vascular scales.Effective treatment is another important part of the management of HCCs.However,the clinical treatments of HCC have obvious limitations,such as surgical treatment is more dependent on the experience of the surgeons,chemotherapy and systemic treatment may lead to significant side effects.Compared with other treatment modalities,radiotherapy in the treatment of liver cancer possesses unique advantages.Production of reactive oxygen species(ROS)is the main mechanism of the anti-tumor effect of radiotherapy.However,the generated ROS is eventually converted to hydrogen peroxide(H2O2),thus limiting the therapeutic effect of radiotherapy.Fenton reaction can convert H2O2 into hydroxyl radicals(HO·),thus improve the curative effect of radiotherapy.In this work,we have synthesized a galvanic battery nanoprobe that integrates radio-sensitization and Fenton reaction in one platform.Also,the nanoprobe can be applied to photoacoustic and magnetic resonance imaging,providing great potentials to imaging-guided treatment of hepatocellular carcinoma.ObjectiveThe objective of this study is to synthesize a FePt-PEG galvanic battery nanoprobe which possesses radio-sensitization and Fenton catalysis as well as photoacoustic imaging and Magnetic Resonance Imaging ability,providing great potentials to imaging-guided Fenton enhanced radiotherapy of hepatocellular carcinoma.MethodsFePt-PEG nanoprobe is synthesized via a thermal reduction procedure.The morphology and lattice space of FePt-PEG nanoprobe were observed by a transmission electron microscopy and a high-resolution transmission electron microscopy.The hydration particle size the nanoprobe were measured by a Malvern sizer.The absorption spectrum of the nanoprobe was measured by a microplate reader.The MRI switching ability of the nanoprobe was verified in an acidic environment.Cell toxicity was evaluated by an MTT assay.Fluorescence microscopy and flow cytometry were utilized to observe ROS generation and apoptosis triggered by the nanoprobe.The concentration-dependent signal intensity of the nanoprobe under photoacoustic imaging and Magnetic Resonance Imaging were measured in vitro.For the in vivo experiments,the ability for photoacoustic imaging and Magnetic Resonance Imaging were verified,and the efficiency for Fenton enhanced radiotherapy of HCC was evaluated.Results1.Important time points during the development of liver cancer:72～144 h may be key time point of the development of liver cancer and 96 h was the time point of the formation of new blood vessels in the tumor.2.The characterization results showed that the particle size of the FePt-PEG nanoprobes was 3.4 nm.The nanoprobes were composed of two elements:Fe and Pt.The Fe mass accounted for approximately 18%and the Pt for 82%of the total mass.The crystal structure displayed the face-centered cubic structure.the hydration particle size was 7.7 nm.The dispersion of FePt-PEG in DI water,PBS,DMEM and FBS were stable.The absorption spectrum declined gradually in the range of 400-1000 nm.3.The results of acid dissociation in vitro indicated that the nanoprobe was acid sensitive and dissociated after acid incubation.The morphology changes under transmission electron microscopy and the ultrafiltrate turned blue after adding with potassium ferricyanide,indicating the release of ferrous ions.In acidic environment,the magnetic resonance signal was converted from T2 weighted to T1 weighted but not in normal tissues without an acidic environment.The nanoprobe could convert H202 into HO·ex-vivo.4.FePt-PEG nanoprobes toxicity test results indicated that FePt-PEG nanoprobes had excellent biocompatibility and showed no toxicity to normal cells.Also,it did not cause obvious serum biochemical changes and organs pathological damage.5.In vitro imaging properties of FePt-PEG nanoprobes showed the photoacoustic and magnetic resonance signals of the nanoprobes had a significant linear relationship with the concentration of the nanoprobes6.Photoacoustic and magnetic resonance imaging of hepatocellular carcinoma in vivo showed that the T2-weighted signal conversion to T1 signal in the tumor site in magnetic resonance imaging was observed,which can be used as a method for the detection of ferrous iron release in the tumor.Also,the nanoprobe also had an excellent photoacoustic imaging property,which showed the potential to be used in the imaging of hepatocellular carcinoma.7.For treatment experiments,FePt-PEG nanoprobes were used for Fenton enhanced radiotherapy of HCC in vivo.The treatment exhibited excellent therapeutic efficacy without obvious side effect.ConclusionWe have synthesized a FePt-PEG nanoprobe with excellent biocompatibility and acid microenvironment responsive ability,for selectively release of ferrous ions in the tumor area as well as radio-sensitive,providing great potentials to Fenton enhanced radiotherapy of hepatocellular carcinoma.Also,Iron and platinum elements enabled the FePt-PEG nanoprobes be utilized for magnetic resonance imaging(MRI)and photoacoustic imaging(PAI)of hepatocellular carcinoma.The MRI switching effect could be utilized to detect the release of ferrous iron at the tumor area,providing great potentials in imaging-guided Fenton enhanced radiotherapy. |
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