卓仁禧院士-用于基因和抗癌藥物控制釋放高分子材料研究 (PPTminimizer)1

用于基因和抗癌藥物控制釋放高分子材料研究卓仁禧院士生物醫(yī)用高分子材料教育部重點實驗室武漢大學(xué)化學(xué)與分子科學(xué)學(xué)院一.高分子基因治療載體研究病毒載體和非病毒載體的比較效率低安全容易制備，儲存和質(zhì)量控制傳遞的DNA大小從20個堿基對到幾十萬個堿基對非病毒載體安全隱患DNA大小受限制免疫原性高效病毒載體缺點優(yōu)點載體

非病毒載體

陽離子脂質(zhì)體

高分子:陽離子高分子

水溶性非離子高分子

高分子基質(zhì)

常用的聚陽離子基因載體Poly[-(4-amino-butyl)-L-glycolicacid]SWKim,UtahUnivPoly-L-lysinePolyethylenimines(PEI)BehrJP,FranceDendrimerSzokaUCSF&BakerJUnivMichPolyphosphoesterandPolyphosphoamideLeongKW,JohnsHopkingUnivLangerR,MIT從新的起始核合成聚酰胺胺樹型高分子基因載體DendrimerGT5TransfectionofHEK293cellswithpRELuc/dendrimerGTcomplexes合成的樹型高分子的轉(zhuǎn)染效率與目前最好的陽離子載體PEI相當(dāng)，但是比PEI的毒性低得多CytotoxicityofdendrimerGT3~GT5measuredbytheMTTassay.PEIandPLLwereusedascontrols

肝細胞靶向基因載體

1.0E+041.0E+051.0E+061.0E+071.0E+081.0E+090246810N/PRLU/mgproteinGT5GT5-Gal5%TransfectionofHepG2cellswithpRELucTransfectionofNIH3T3cellswithpRELuc陽離子聚磷酸酯基因載體PPA-DPAGal-PPAGal-PEG-PPAliverspleenlungkidneyheart103105104102RLU/mgproteinPPAGal-PPAGal-PEG-PPA

LuciferaseExpressioninmouseafterintraportalveininjectionofcomplexescontaining50μgplasmid二.藥物控釋生物可降解高分子材料研究聚酯(聚乳酸,聚乙醇酸及其共聚物;聚己內(nèi)酯,聚羥基丁酸及其共聚物)聚酸酐聚碳酸酯及其共聚物聚磷酸酯及其共聚物納米藥物控制釋放溫度敏感快速響應(yīng)PNIPA水凝膠Poly(lactide-co-glycolide)PLGAPolylactidePLAPolyglycolidePGA聚碳酸酯及其共聚物BTMCPTMC卓仁禧,王旭立,劉立建.５－芐氧基－三亞甲基碳酸酯及其制備方法。中國專利ZL01114284.7C07D319/04

卓仁禧，王旭立，劉立建。聚（５－取代基－三亞甲基碳酸酯）及其制備方法和用途。ZL01114285.5InvitrocytotoxicityofPBTMCandPHTMC

COS7cells.Incubationtime:24h.Temp.:37oCBTMCTMCPoly(HTMC-co-TMC)Sn(Oct)2150oCDeprotectionDependenceofhydrophilicityoncopolymercontentInvitrodegradabilityofcopolymers,PBSpH7.4，37oC0246810121416182022242628020406080100P(HTMC-co-TMC)10/90PTMCP(HTMC-co-TMC)50/50WeightLoss(%)Time(day)PHTMC100%-OHwithout-OH50%-OH10%-OH5-Fureleaseprofilesofcopolymers,PBSpH7.4，37oCZhangY,ZhuoRX,Synthesisanddrugreleasebehaviorofpoly(trimethylenecarbonate)–poly(ethyleneglycol)–poly(trimethylenecarbonate)nanoparticles,Biomaterials(Inpress)PTETtriblockcopolymer納米藥物控制釋放SynthesisandpropertiesofPTETtriblockcopolymersParticlesizes,drugloadingcontent,loadingefficiency,andyieldofthePTETpolymericnanoparticlesPolymericnanoparticleswerepreparedbythedialysistechnique.Drug:methotrexate(MTX)TEMimageofPTET-7nanoparticlesloadedmethotrexate(MTX)EffectofmolecularweightofPEGinthecopolymersontheMTXreleaseratePBS,pH=7.4,37oC.PEG6000PEG4000PEG2000EffectofcontentofPEGblockinthecopolymersontheMTXreleaseratePBS,pH=7.4,37oC.PEG:6.17wt%PEG:24.12wt%PEG:28.94wt%PEG:54.26wt%溫度敏感快速響應(yīng)PNIPA水凝膠A混合溶劑法B相分離法C使用成孔劑:如PEGD形成互穿網(wǎng)絡(luò)在溫度敏感水凝膠領(lǐng)域發(fā)表SCI論文30多篇。靶向性抗癌藥物5-Fu抗癌藥物PMliver-targetinggroup肝靶向高分子抗癌藥物肝靶向高分子抗癌藥物5-Fu-(99mTc–DTPA)-PAEA-PM注射后不同時間在大鼠體內(nèi)各器官的分布62.5μg/mLBel-7204體外凋亡率:51%135μg/mLBel-7204體外凋亡率:62%Control肝靶向高分子抗癌藥物5-Fu-PAEA-PM對人體肝癌細胞(Bel-7204)的體外凋亡實驗的熒光照片P(TMC-co-EEP)PorcinePancreasLipase(PPL)CandidaRugosaLipase(CL)Al(OiPr)3酶催化開環(huán)聚合反應(yīng)Ring-openingcopolymerizationofTMCandEEPcatalyzedbyenzymesMw/MnMnYield(%)Time(d)Molarratio(TMC:EEP)[E](mg/mmol)Lipase-<500-210:510--<500-210:110-1.69641042.1210:510CL1.83644062.0210:310CL2.23786075.6210:110CL2.18323019.8210:510PPL1.66802060.1210:310PPL1.711025082.8210:110PPL2.63573060.2410:210CL2.97601057.0310:210CL1.99683050.2110:210CL2.75343065.2410:210PPL1.91398072.3310:210PPL2.47597056.2110:210PPL1.81532860.2210:250CL1.87650057.6210:225CL2.27649058.3210:210CL2.43623036.5210:225PPL2.31933068.9210:210PPLPolymerizationcatalyzedbyPPLimmobilizedonsilicamicroparticles(PISM)

EffectoflipaseconcentrationonMnandyield0.00.51.01.52.02.55000100001500020000250003000035000400004500050000Concentration(wt%)Molecularweight3035404550556065707580859095100Yield(%)MnYieldTimedependenceofMnandyieldduringpolymerization1020304050601000012000140001600018000200002200024000Time(h)Mn404550556065707580859095100YieldMnYieldDependenceofMnandyieldontheimmobilizedlipasePPLrecyclingtimeRecyclingTimeLipaseConc.(wt%)MnMw/MnYield(%)I1.0147001.9270II1.0254001.7775III1.0308002.1181IV1.0452002.0178VI1.0617001.9483VII1.0630002.5381VIII1.0640002.2072VIII0.1874002.0669Reactiontemperature:100℃.Reactiontime:24hPolymerizationofDTCcatalyzedbyPPLAimmobilizedonsilicamicroparticles

BimmobilizedonsilicananoparticlesRecyclingtimeofIMPPL