Fabrication Of Porphyrin-based Nano-drug Delivery Systems For Reversing Tumor Multidrug Resistance

Presently,the chemotherapy still is the normal strategy for clinical cancer treatment.However,these disadvantages of the small molecule drugs such as lacking specific target and severe toxic side effects result the therapeutic effect not effective as expected.Moreover,the prolonged medicine long-term can lead to multiple drug resistance?MDR?in tumor cells.How to reverse the MDR of tumors and improve the therapeutic effect is a hot spot in nanomedicine research.Generally,the nanomedicine can bypass the drug efflux protein P-gp,prolong the long circulation time of the drug in the blood,and deliver the targeted effects through EPR effect to enhance the efficacy.Many studies have suggested that the high concentrations of reactive oxygen species can destroy P-gp efflux,promote drug accumulation in tumor cells,reverse multidrug resistance,and improve tumor inhibition.In this thesis,porphyrin,a kind of photosensitizer has been chosen and combined with chemotherapeutic drugs to construct a multifunctional nano drug delivery systems?NDDS?for photodynamic-chemotherapy to reverse multi-drug resistance.Mainly include the fowling two parts:?1?We have constructed kind of pH-sensitive nano drug delivery system THDP@DOX through the supramolecular coordination between metalloporphyrin and histidine.THDP@DOX has an average size of 63 nm with excellent biocompatibility and stability in blood.Under intercellular acid environment,THDP@DOX will disassembly release loaded DOX and porphyrin,co-delivery and release of photosensitizers and DOX achieve the combination of photodynamic therapy and chemotherapy effectively enhance the inhibition of tumor proliferation.Importantly,the generated singlet oxygen by porphyrin under light irradiation not only induced apoptosis,but also significantly reversed the multidrug resistance of the tumor.?2?We have constructed selfassembly carrier-free nanoparticle H₂TPPS@DOX through the supramolecular action.H₂TPPS@DOX has an average size of 93 nm,uniformly distributed with excellent stability in blood.Under intercellular acid environment,H₂TPPS@DOX will disassembly release DOX and porphyrin,co-delivery and release of photosensitizers and DOX achieve the combination of photodynamic therapy and chemotherapy effectively enhance the inhibition of tumor proliferation.Under illumination,H₂TPPS effectively produced singlet oxygen?¹O₂?,it not only induced apoptosis,but significantly could block the DOX efflux,effectively reversed the multidrug resistance of the tumor.The nano drug delivery system H₂TPPS@DOX exhibits excellent inhibition of tumor proliferation and the ability of reversing MDR of tumor.