Synthesis Of PH-Responsive And Tumor-Targeting Hemoglobin-based Oxygen Carriers And Rerearch On Their Performance

Hypoxia,a characteristic feature of tumors,can lead to angiogenesis,tumor metastasis and mutation.Moreover,tumor hypoxia has a negative effect on most anti-cancer treatments.Therefore,two multifunctional hemoglobin-based oxygen nanocarrier,which were intended to promote the efficient co-delivery of oxygen and anti-cancer drugs and combine modulating tumor hypoxia microenvironment with chemotherapy,were studied in this thesis.(1)pH-responsive hemoglobin-based oxygen nanocarrierFirst,the amphiphilic copolymer polymethylacrylic acid-b-poly(butylmethacrylate)(PMAA-b-PBMA),was synthesized via reversible addition-fragmentation chain transfer(RAFT)polymerization,followed by the covalent conjugation of hemoglobin(Hb)onto the micelles to obtain Hb-PMAA-b-PBMA.Hb-PMAA-b-PBMA was demonstrated to retain the activity of Hb and hold excellent capacity of binding oxygen.In vitro drug release behavior of DOX-eco-Hb-PMAA-b-PBMA,as well as DLS and TEM,revealed that Hb-PMAA-b-PBMA is pH-responsive drug nanocarrier system.In addition,in vitro cytotoxicity study indicated that the Hb-PMAA-b-PBMA is biocompatible and DOX-eco-Hb-PMAA-b-PBMA is more harmful to tumor cells than free DOX(2)Tumor-targeting and pH-responsive hemoglobin-based oxygen nanocarrier(HCMs)First,the triblock copolymer poly[2-(methacrylamido)glucopyranose]-b-poly(metha-crylicacid)-b-poly(butylmethacrylate)(PMAG-b-PMAA-b-PBMA),was synthesized via RAFT polymerization.Then HCMs was obtained through the covalent conjugation of Hb onto the micelles.HCMs was demonstrated to retain the activity of Hb and hold excellent capacity of binding oxygen.In vitro drug release behavior of DOX-eco-HCMs revealed that HCMs is pH-responsive drug nanocarrier system.In addition,in vitro cytotoxicity study indicated that the HCMs is biocompatible and DOX-eco-HCMs is more harmful to tumor cells than free DOX.More importantly,cellular uptake indicated that HCMs shows specific recognition of cancer cells,which means HCMs can actively target tumor cells.Therefore,the above multitherapeutic and multifunctional hemoglobin-based oxygen nanocarriers might be applied in cancer therapy in the future.