PH/Thermo Sensitive Magnetic P123-PAMAM Nanoconmplex For Multi-Mode Imaging And GT/CT/PDT/PTT To Overcome MDR Breast Cancer

During conventional chemotherapy(CT)of breast cancer,multidrug resistance(MDR),systematic side effects,inefficient drug release have impeded radically therapy of breast cancer.Intelligent-response nanomedicine brings a possibility to decouple these constraints.Before this work,we profoundly considered about what are crucial rules for nanomedicine designing.The first cardinal rule is the medicine could only cause neglegible harm to our body.Besides,long circulation time,optimum drug release profiles,precise tumor accumulation as well as MDR reversal effect also play an important role in developing the next generation of antitumor nanomedicine.In the light of the above considerations,we integrated multiple therapy strategies into one nanomedicine to overcome the drawbacks of single therapeutic strategy.Gene therapy has gained a lot of interests,however,seldom research has focused on PAMAM based smart responsive theranostic gene delivery systems to overcome MDR.Herein,the first example of a pH/thermo responsive magnetic P123-PAMAM(MNP@P-PA/Sur/Cur-ZnPc),which links P123 with PAMAM via pH sensitive hydrazone bond,and then encapsulated the P123 functionalized magnetic.nanoparticles.The nanocomplex could converse light power to heat at 808 nm laser irradiation to exert its photothermal therapy(PTT)advantage.Cationic dendrimers were removed very quickly from blood circulation,conjugation of P123 to PAMAM could reduce the positive charge of PAMAM and hence prolong drug circulation time and decrease its toxicity in vivo.Upon acid pH environment,MNP@P-PA/Sur/Cur-ZnPc nanocomplex could exert a unique 'proton sponge effect',promoting nucleic acids escape from endosomal entrapment and its delivery to cell nucleus by PAMAM.Additionally,MNP@P-PA/Sur/Cur-ZnPc nanocomplex greatly reversed MDR via ATP depletion,mitochondria damage,and drug efflux transporters inhibition.Based on FI/MRI/ITI multi-mode imaging,the MNP@P-PA/Sur/Cur-ZnPc nanocomplex showed the highly efficient tumor accumulation,which is driven by EPR effect-mediated passive targeting and magnetic guidance.Moreover,808 nm laser irradiation induced a 6 ? increment at tumor compared with non-targeted nanocomplex,facilitating MNP@P-PA/Sur/Cur-ZnPc nanocomplex to be quickly internalized into MCF-7/MDR cells and synchronously release the dual-drug.In comparison with ordinary therapeutic nanoparticles depending merely on gene therapy,the MNP@P-PA/Sur/Cur-ZnPc nanocomplex exhibited higher tumor inhibition ratio for the treatment of multidrug resistant breast cancer.Together,our results demonstrate the safety and considerable advantages of tumor-selective PAMAM based GT/CT/PDT/PTT over traditional based gene therapy.