Functional Photothermal Nanoparticles For Photoacoustic Imaging Guided Tumor Precise Ablation

Liver cancer is a highly malignant digestive system tumor.Due to the large number of hepatitis B patients in China,the incidence of new liver cancer accounts for more than 55%of the worldwide incidence.Early liver cancer diagnosis remains a critical strategy for improving the cure rate.However,the hidden initial symptoms of liver cancer make it difficult to early diagnose.Liver cancer is often diagnosed in an advanced stage.Once the metastasis occurs at distant organs,it becomes largely incurable and fatal.At present,the treatments of liver cancer include surgery,radiotherapy and chemotherapy.For patients with advanced liver cancer,eradication rate of surgical is low and recurrence rate is high.Moreover,liver cancer resists in chemotherapy and radiotherapy.The 5-year survival rate is only 7%with poor prognosis in patients.Therefore,how to achieve the diagnosis and effective treatment of advanced liver cancer has become a clinical problem to be solved.Neovasculature is a necessary step in the uncontrolled proliferation,invasion,and metastatic dissemination of liver cancer.Neovasculature provides oxygen,nutrients and growth factor for liver cancer.The formation and survival of neovascularization depends on the expression of many proteins and enzymes.Integrin?_v?₃,a transmembrane receptor,is highly expressed on the surface of endothelial cells.It regulates the migration and proliferation of endothelial cells,and facilitates the growth and survival of tumor neovasculature.Matrix metalloproteinase 2?MMP-2?,a proteolytic enzyme,is over expressed in tumor metastasis cells.It degrades extracellular matrix which then exposes the integrin site,promoting the formation of neovascularization and metastasis of liver cancer.If?_v?₃ and MMP-2 are used as targets for developing a highly targeted,highly sensitive,safe and effective platform toward diagnosis and treatment,it is expected to improve the effect of diagnosis and treatment of advanced liver cancer in China.Recently,small molecules,polymers and protein drugs concerning?_v?₃ and MMP-2 have been synthesized for the diagnosis and treatment of tumor.Although these materials display the targeting ability,there are some inevitable drawbacks,such as poor water solubility,side effects,and poor stability.It is difficult to achieve the desired effect of diagnosis and treatment.The development of nanotechnology has the potential to solve these problems.Among them,photothermal nanomaterials not only have the advantages of good biocompatibility and easy modification of nanomaterials,but also can convert light energy into thermal energy,which increases temperature to kill tumors.In addition,photothermal nanomaterials can be used as photoacoustic imaging?PA?contrast agents to achieve imaging of tumor blood vessels.Based on photothermal nanomaterials,we have developed a new method for safe,targeted cancer diagnosis and therapy with photothermal nanomaterials,which achieves efficient tumor neovascularization ablation and imaging of liver cancer metastasis.In this study,firstly we review the recent research progress on the application of nanomaterials in cancer diagnosis and treatment,secondly use two kinds of photothermal nanomaterials,hollow copper sulfide nanoparticles?HCuS NPs?and melanin nanoparticles?Mel NPs?assembled to functionalized photothermal nanomaterials.We carried out the following work:1.Through integrin?_v?₃-expressing tumor vasculature endothelial cells,we have designed and constructed a functional“nanobomb”.This“nanobomb”is rationally fabricated via the encapsulation of vinyl azide?VA?into c?RGDfE?peptide-functionalized,HCuS nanoparticles.Upon 980 nm NIR irradiation,the local temperature increase triggered VA to release N₂ bubbles rapidly.Subsequently,these N₂ bubbles could instantly explode to destroy the neovasculature and further induce necrosis of the surrounding tumor cells.A single-dose injection of RGD@HCuS?VA?led to complete tumor regression after 14 days,with no tumor regrowth for30 days.More importantly,high-resolution photoacoustic angiography,combined with excellent biodegradability,facilitated the precise destruction of tumor neovasculature by RGD@HCuS?VA?without damaging normal tissues.Attacking the supportive vasculature network of a tumor offers an important new avenue for cancer therapy.This near-infrared laser-activated“nanobomb”is developed as a noninvasive and targeted physical therapeutic strategy to effectively disrupt tumor neovasculature in an accurate and expeditious manner,which provides a new method for the treatment of advanced liver cancer.2.We have developed reactive matrix metalloproteinases-sensitive Mel NPs for tumor metastasis photoacoustic imaging and effective photothermal therapy.Mel NPs are selected as the inner core,and functionalized with the azide?AZ?and alkyne?AK?as the intermediate functional layer.Finally,PEG linked with the MMP-responsive polypeptides?GC8?are used as the outer shielding layer which assembled into Mel-AK-GC8 and Mel-AZ-GC8.These nanoprobes could be efficiently targeted to the tumor metastatic site.In the presence of tumor metastases,GC8 is specifically cleaved,followed by the aggregation of Mel-AK-GC8 and Mel-AZ-GC8.The aggregation-induced amplification of the PA signal.At the same time,the photothermal effect of Mel NPs could be used for photothermal treatment after aggregation,which can effectively inhibit tumor metastasis.These MMP-responsive nanoprobes with high sensitivity and good biocompatibility can be used for photoacoustic imaging detection and targeted photothermal therapy,which provide a powerful tool for the diagnosis and treatment of advanced liver cancer.