Ring Opening Polymerizations Of NCA And Ester Monomers Catalyzed By Rare Earth Compounds And Polvmer Degradation Behavoir Investigation

With excellent biocompatible ability and distinguished self-assemble ability, polypeptide has been widely used in biomedical area such as drug release and tissue engineering, and shows great potential in these applications. The performance of polypeptide is closely related to its micro-structure. However, the available catalysts can be used to catalyze living/controlled ring opening polymerization (ROP) of NCA (amino acid-N-carboxyanhydride) to prepare polypeptide are quite rare, and these catalysts still have their limitations in their use. Exploring new catalytic systems is urgently needed. In this paper, we applied four rare earth complexes, i.e., rare earth tris(borohydride)(Ln(BH4)3(THF)3), rare earth tris[bis(trimethylsilyl)amide](Ln(NTMS)3), rare earth isopropoxide (Ln(OiPr)3) and rare earth tris(2,6-di-tert-butyl-4-methylphenolate)(Ln(OAr)3) to catalyze the ROP of NCA. Polymerization features and mechanisms are detailedly studied, and telechelic polypeptides are synthesized.Ln(BH4)3(THF)3has been firstly used to catalyze the ROP of NCA. The results show that Ln(BH4)3(THF)3(Ln=Sc, Y, La and Dy) are efficient catalysts for ROP of BLG (γ-benzyl-L-glutamate) NCA. In40℃,[BLG NCA]/[Y(BH4)3]=1160,[BLG NCA]=0.5mol/L, PBLG (poly(γ-benzyl-L-glutamate)) could be obtained in92%yield with the number average molecular weight (Mn) of8.6×104Da and molecular weight distribution (MWD) of1.32after24h in DMF. Molecular weights (MWs) and MWDs are varied with the rare earth metals and reaction temperature. The kinetic study exhibits a liner relationship indicating a controlled polymerization behavior of this polymerization system. Block and random copolypeptides with narrow MWD (MWD<1.2) can also been synthesized by Ln(BH4)3(THF)3. Polymerization mechanism study shows that Ln(BH4)3(THF)3catalyzes the ROP of NCA through two modes at room temperature. One is nucleophilic attack at the5-CO of NCA by Ln(BH4)3(THF)3to initiate the polymerization, and after propagation and termination, α-hydroxyl-ω-aminotelechelic polypeptide is formed. The other is that Ln(BH4)3(THF)3deprotonates the3-NH group of NCA, leading to a N-rare earthlated NCA which is served as an initiation center and finally affords a α-carboxylic-ω-aminotelechelic polypeptide. By decreasing the reaction temperature, the second reaction mode can be effectively depressed and polypeptide with hydroxyl group can be exclusively synthesized.Ln(NTMS)3has been firstly used to catalyze the ROP of NCA. The results show that Ln(NTMS)3(Ln=Sc, Y, La, Dy and Lu) are efficient catalysts for ROP of BLG NCA. In40℃,[BLG NCA]/[Y((NTMS)3]=1040,[BLG NCA]=0.5mol/L, PBLG with the Mn of6.5×104Da and MWD of1.24could be obtained in96%yield after24h in DMF. MWs and MWDs are varied with the rare earth metals and reaction temperature. The MWs can be efficiently tuned by the feeding ratios. Block and random copolypeptides with narrow MWD (MWD<1.2) can also been synthesized by Ln(NTMS)3. Polymerization mechanism study shows that in the initiation step, Ln(NTMS)3not only deprotonates the3-NH but also deprotonates the4-CH group of NCA, forming N-rare earthlated NCA and C-rare earthlated NCA respectively along with hexamethyldisilazane (HMDS). The in situ HDMS is responsible for further chain growth and finally produces the α-amide-ω-aminotelechelic polypeptide, while N-rare earthlated NCA and C-rare earthlated NCA are isomerized into more stable rare earth α-isocyanato carboxylate and rare earth ketenyl carbamate respectively. In this system, we firstly report deprotonation reaction at4-CH of NCA, proving the acidity of4-CH in NCA. This result not only provides a direct proof for racemization phenomenon of NCA in strong base environment but also sheds light on strong base-catalyzed N-substituted NCA polymerization.Ln(OR)3(R=iPr or Ar) have been firstly used to catalyze the ROP of NCA. The results showed that Ln(OR)3(Ln=Y, La and Dy) were efficient catalysts for ROP of BLG NCA. In40℃,[BLG NCA]/[Y(OAr)3]=760,[BLG NCA]=0.5mol/L, PBLG with the Mn of8.8×104Da and MWD of1.33could be obtained in94%yield after24h. The two systems are especially useful to prepare high MW polypeptides; however, the MWs can not be tuned by the feeding ratios. The kinetic study showed that both yields and MWs were increased dramatically with the reaction time, but the MW's increasing rate was slower than that of the yield. Polymerization mechanism shows that in the initiation step, Ln(OR)3(R=iPr or Ar) depronates the3-NH of NCA, forming N-rare earthlated NCA. N-rare earthlated NCA serves as the truly initiation center and is responsible for further chain growth and produces α-carboxylic-ω-aminotelechelic polypeptide after termination. In these two systems, polypeptides with the hydantoinic end and hydantoic acid end are also found as by-products.Low crystalline copolyester PCD has been synthesized by random copolymerization of ε-caprolactone (CL) with5～8mol%of2,2-dimethyl-trimethylene carbonate (DTC) in the presence of La(OAr)3as the catalyst. PCD, as well as PCL homopolymer, are fabricated into electrospun mats (EMs) and compression molding films (CMFs) and measured for their crystallinity. The results indicate that in EMs, the crystallinity of PCD has been decreased to40%in comparison with79%for PCL while in CMFs, the corresponding crystallinity is decreased to28%compared to45%for PCL.It is found for the first time that porcine pancreatic lipase (PP lipase) can effectively catalyze the degradation of PCD while it shows no detectable effect on PCL. For PCD EM, the weight loss reached80%within10days while it is70%for PCD CMF within35days. The degradation rates of EMs are faster than CMFs, and PCD's degradation rate is much faster than PCL. Based on the experimental results, the above degradation behaviors have been explained. Degradation mechanism study shows in PCD degradation catalyzed by PP lipase, surface erosion is the main degradation mode. Salicylic acid is used as a model drug to test the drug release behavior of PCD. It is found PCD EM showed a controlled drug release behavior in comparison with PCL EM which exhibited a burst-release behavior. This difference is closely related with the crystallinity of the two polymer samples.Poly[(ε-caprolactone-r-2,2-dimethyltrimethylene carbonate)-b-PEG-b-(ε-caprolactone-r-2,2-dimethyltrimethylene carbonate)](PECD) and poly[MPEG-b-(ε-caprolactone-r-2,2-dimethyltrimethylene carbonate)](MPECD) have been synthesized by using PEG and MPEG as the initiators and La(OAr)3as the catalysts. With similar MW and EO amount, MPECD is more brittle and has a smaller contact angle. It is found that PP lipase can effectively catalyze the degradations of PCD, PCD/PECD and PCD/MPECD EMs. For PCD EM, the weight loss reaches92%within7days while it is around60%for PCD/PECD or PCD/MPECD EMs within23days. A PEG segment enrichment process on the EM surface is detected, which prevents the contact of PP lipase with PCD segments in the PEG-involved EMs and further decreases the corresponding degradation rates. Surface erosion mechanism is proved in this degradation.