Construction And Evaluation Of Multifunctional Antitumor Polymersome Nanomedicines

Antitumor nanomedicines with prolonged drug circulation time,improved drug bioavailability,and reduced side-effects,have exhibited a great potential in targeted tumor therapy.In the first chapter,nanomedicines are divided into five kinds according to their materials,and their preparation methods,properties and challenges are introduced.Then various new type functional nanomedicines in recent years are discussed.To obtain polymersome nanomedicines with high therapeutic index and low side-effects,in this thesis two kinds of reduction-sensitive reversible-crosslinked biodegradable polymersomes were conveniently prepared for targeted treatment of melanoma and leukemia,respectively.In chapter 2,nano-prodrug polymersome nanomedicines?cRGD-PS-DM1?were prepared by a“one-pot”method,with reactive drug loading,superb stability and triggered drug release for targeted melanoma therapy.The nano-prodrug platform with cRGD-decorated polymersomal mertansine prodrug?cRGD-PS-DM1?was readily fabricatedfromcRGD-functionalizedpoly?ethyleneglycol?-b-poly?trimethylene carbonate-co-dithiolane trimethylene carbonate?with simultaneous loading of mertansine?DM1?via thiol-disulfide exchange reaction and disulfide crosslinking of polymersomal membrane.cRGD-PS-DM1 exhibited a size of¹00 nm,robustness and little drug leakage?3%?,while fast DM1 release triggered by 2-10 mM glutathione.MTT and CLSM studies confirmed effective homing of cRGD-PS-DM1 to?_v?₃ over-expressing B16F10 cells,with a low half-maximal inhibitory concentration(IC₅₀)of 8.7 ng DM1 equiv./m L.Notably,the in vivo studies showed that cRGD-PS-DM1 had a greatly broadened therapeutic window and ca.5 fold improved toleration as compared with free DM1.More importantly,as compared to nontargeting PS-DM1 and free DM1,cRGD-PS-DM1 in B16F10melanoma-bearing mice could effectively inhibit tumor growth with tumor-inhibition-rate of over 90%,and the mouse median survival was significantly prolonged to 28 d vs.18 d and 14 d,respectively.In chapter 3,we prepared vincristine sulfate?VCR?loaded,leukemia cell homing cell penetrating peptide directed polymersome nanomedicines CPP44-PS-VCR for active targeting and effective treatment of leukemia.VCR was actively loaded into polymersome interior via a pH-gradient method,and drug loading efficiency was as high as 79.5%at a theoretical drug loading content of 16.7 wt.%.CPP44-PS-VCR with a size of 90¹00 nm could actively target to K562 and AML-2 cells,and the optimal CPP44 surface density was screened to be 10 mol%as revealed from FACS and CLSM studies.Moreover,MTT assays confirmed that CPP44-PS-VCR had higher toxicity than PS-VCR on AML-2 cells.In mice bearing subcutaneous AML-2 tumor,CPP44-PS-VCR had shown high efficacy?tumor inhibition rate⁷0%?and low side-effects.Moreover,the freeze-dried CPP44-PS-VCR powder using 7%mannitol and 7%sucrose as cryoprotectants could be rehydrated to polymersomes with a size of¹20 nm and drug leakage less than 2%.These results suggested that this nanomedicine platform has a great potential for leukemia chemotherapy.Finally,the chapter 4 summarized the two polymersome nanomedicines,and discussed the future perspective.