Design Of A Dual Nano-sensitizer Based On Dendrimers And Its Application In Tumor Radiotherapy

The hypoxic tumor microenvironment causes radiotherapy(RT)resistance,which greatly reduces the therapeutic efficacy and even leads to the failure of RT.Therefore,it is essential for RT to develop an efficient sensitization system to improve the hypoxic environment and reduce the radiation resistance.Metal-based nanomaterials with high atomic number,such as gold nanoparticles(Au NPs),are widely used as exogenous radiotherapy sensitizers due to their enhanced photoelectric effect and Compton effect.On the other hand,literatures have shown that hypoxia-inducible factor-1?(HIF-1?)in tumors is a key inducement for radiotherapy resistance.So endogenous radiosensitization can be achieved by inhibiting expression of HIF-1?.Currently single sensitization through either endogenous or exogenous strategy is often used for RT.However,the sensitization effect is still not ideal.For example,the hypoxic microenvironment of tumors usually weakens the sensitization of Au NPs.Therefore,it is expected that using a suitable nanoplatform to combine endogenous and exogenous sensitizers simultaneously can achieve a better sensitization for RT.On account of the unique physical and chemical properties,dendrimers have been successfully utilized as a nanocarrier platform to integrate one or more imaging or/and therapeutic agents for tumor diagnosis,treatment or theranostics.In this study,zwitterionic 1,3-propane sultone-modified fifth-generation polyamidoamine(PAMAM)dendrimers were used as carrier platform to first encapsulate gold nanoparticles in interior cavity through in situ synthesis(Vector)and then electrostatically adsorb HIF-1? si RNA(Vector/si RNA)for tumor RT with endogenously and exogenously enhanced sensitization.On the one hand,due to enhanced photoelectric and Compton effect,Au DENPs can be used as exogenous RT sensitizers to produce more cytotoxic reactive oxygen species and cause DNA damage under X-ray stimulation.On the other hand,through serum-enhanced delivery,HIF-1?si RNA can be effectively conveyed to tumor site and down-regulate the expression of HIF-1?protein and downstream genes,endogenously sensitizing RT and effectively alleviating metastatic invasion of tumors.The in vitro results showed that zwitterion-modified vector demonstrate good colloidal stability and can maintain a size of 427.4 nm without significant changes for one week.The highest transfection efficiency up to 40.7 and the best silencing effect can be obtained when N/P of vector/si-HIF-1? polyplexes is 20.The relative ROS levels of single RT without any sensitizer,Vector/scramble si RNA(si-ctrl)+RT and Vector/si-HIF-1?+RT are 1.3,1.6 and 1.9,respectively.This indicates that introduction of Au NPs can sensitize radiotherapy,simultaneously induced Au NPs and HIF-1? si RNA can further promote ROS level and inhibit cell proliferation to a greater extent,leading to endogenous and exogenous dual sensitization for tumor RT.In vivo experimental results of A549 subcutaneous tumor model in nude mouse showed that zwitterion-modified vector/si-HIF-1? polyplexes can cause DNA damage and achieve endogenously and exogenously dually enhanced radiotherapy,and inhibit tumor growth and lung metastasis.In conclusion,the prepared zwitterion-modified vector/si-HIF-1? polyplexes in this study can be used as a nanosensitizer to successfully implement dually sensitized tumor radiotherapy.These findings will open up new ideas to develop novel nanosensitizers for radiotherapy with high therapeutic efficicacy.