PET Imaging-guided Breast Cancer Theranostics Using High-efficient Clearable Nanomaterials

Breast cancer is the most common malignancy in women worldwide.Since it is highly heterogeneous and each subtype has its unique features,the curative effect of conventional treatment for breast cancer is limited.In recent years,nanomaterials which could bring a new opportunity for tumor diagnosis and treatment,provide a carrier of multimodal imaging characteristics.The ideal nanomaterials should accumulate in the target site,carry out their carrier platform function such as loading imaging agent or therapeutic drug for imaging diagnosis and treatment,and then ultimately be eliminated from the body.However,the unique enhanced permeability and retention effect(EPR effect)is significantly weakened in the case of renal-clearable nanomaterials.The underlying reason is attributed to the rapid excretion nature of renal-clearable nanomaterials and to the short blood circulation time,making it difficult to accumulate into the tumor.Therefore,how to balance the highly efficient renal-clearance and the short blood circulation time in healthy tissues/organs is the key of nanomaterials in clinical application.Moreover,accurate evaluation of nanomaterials in diagnosis and therapeutic effects on breast cancer is imperative.The development of micro-positron emission tomography(microPET)has greatly promoted in the cancer molecular imaging,and furthermore,it could provide the prerequisites of preclinical research for nanoparticles.The purpose of this study are:(1)to design and synthesize a novel renal-clearable nanocomposite which should not only have significant thereaputic effect of photothermal therapy(PTT),but also have high loading efficiency of antitumor drugs;(2)to evaluated the feasibility and efficiency of these nanocomposites by using micro-PET imaging combined with the other studies including blood tests and pathological studie.Part ?We developed a biodegradable and renal-clearable theranostic system,namely ultrasmall CuSNDs-sealed,doxorubicin(DOX)-loaded mesoporous silica nanoparticles(abbreviated as MDNs)for theranostic applications.High-resolution transmission electron microscope(TEM),energy-dispersive X-ray spectroscopy,the dynamic light scatting and the UV-vis-NIR spectrophotometer were used to observe the characterization of MDNs.The UV-vis-NIR spectra,IR thermal imaging system and ICP-MS measurement were performed to evaluate photothermal conversion,drug release profiles,degradation,metabolism of MDNs.To assess the value of application with MDNs in triple negative breast cancer cell(MDA-MB-231 breast cancer cells)in vitro,the CCK8 experiment and live-dead cell fluorescence staining were utilized.We found that the near infrared(NIR)light can be transformed to thermal energy mediated by MDNs rapidly and efficiently;the porous structure of MDN with high drug loading capability enabled photothermal sensitive drug release and pronounced chemo-photothermal synergetic effects.Ultimately,the MDNs could be rapidly degraded and excreted in a reasonable period(within 30 days in the nude mice bearing MDA-MB-231 xenografts)to avoid long-term toxicity.In the MDNs + Laser group,the proliferation of MDA-MB-231 cells were significantly eliminated,and confirmed by the CCK8 experiment and fluorescence imaging.Part ?All balb/c nude mice were randomly assigned to each of the six groups:Control,CuSNDs,DOX,MDNs,CuSNDs + Laser and MDNs + Laser group.To assess the diagnostic and thereapuetic effect of MDNs,64Cu-MDNs microPET/CT imaging(at 10min,4h,and 24h after iv.injection of 64Cu-MDNs),18F-FDG microPET imaging(at 0 day,7 days,and 21 days after laser treatment),and IR thermal imaging(during laser treatment)studies were performed.To determine the biosafety of the MDNs,H.E.staining were confirmed on the key organs(including heart,liver,spleen,lung and kidney),furthermore,blood hematological and biochemistical tests were done on the tumor-bearing nude mice.In the MDNs + Laser group,the radioactive accumulation in the tumor increased gradually from 10 min to 24 h after i.v.injection of 64Cu-MDNs,which demonstrated the continuous uptake of MDNs within the tumor.The 64Cu-MDNs could be successfully detected by the microPET/CT imaging which indicates that 64Cu-MDNs can be a suitable microPET/CT imaging agent for the diagnosis of breast cancer subtype of MDA-MB-231.Moreover,MDA-MB-231-bearing xenografts could be successfully detectd by the 18F-FDG microPET imaging at all the time points,and the tumor to muscle(T/M)ratios of 18F-FDG in the MDNs + Laser group were significant decreased at 21 days post-treatment uptake compared to the other groups(p<0.05).The hematology and blood biochemistry analysis showed no significant difference in mice among all the groups,and the histological staining demonstrated that normal tissue structures without any noticeable organ damage or inflammatory lesions in the treatment groups.These results demonstrate that the MDNs induce no obvious system toxicity in mice bearing MDA-MB-231 breast cancer xenografts.ConclusionWe have developed a new renal-clearable multifunctional theranostic nanoplatform for the bimodal imagingguided cancer combination therapy.The MDNs shows excellent appearance on bimodal imaging,including PET imaging and photoacoustic imaging.Moreover,the porous structure imparts the high drug loading capability of MDNs,and shows photothermal sensitive drug release and prolonged synergetic effects of chemo-photothermal combination therapy.High tumor uptake of the as-synthesized NPs was achieved due to the longer blood circulation time.A key feature of the proposed theranostic system is to take advantages of biodegradable MSNs with the critical feature of renal-clearable CuSNDs.Therefore,the MDNs could be rapidly degraded and excreted in a reasonable period in living body to avoid long-term toxicity.Such single-compartment theranostic agents applicable in highly integrated multimodal imaging and multiple therapeutic functions may have substantial potentials in clinical practice.