Synthesis,Pharmacokinetics And Pharmacodynamics Of Star-shaped Polyester-based Elastomers As A Controlled Release System For Protein Drug

Peptide and protein drugs have been greatly development in curing tumor,cardiovascular and cerebrovascular diseases,diabetes mellitus,immunological diseases,and infection.However,the disadvantage of tradition delivery such as poor stability,short half-life and easy degradation has greatly hindered the application in clinic.It's significant to develop effective carriers which have slow-release and long-action ability for protein drugs.In this paper,a series of elastomers were copolymerized by UV cross-link.The intensive study of physicochemical property and the morphology of these elastomers were carried.The degradation of elastomers and drug(BSA as a model drug)release in vitro was performed and their toxicology was assessed.After that,insulin and interleukin-2 as mold drug were choosen to embed these elatomers and their pharmacokinetics and pharmacodynamics were studied.The main research contents and results were shown as follows:Firstly,CLPEGCLs and SCPs as polymer monomers were performed by ring opening reaction at high temperature.Meanwhile,the preparation process was optimized.A series of CLPEGCLs(Mn 4904?12132,PDI<1.25)and SCPs(Mn 3432?3960,PDI<1.40)with different molecular weight and low PDI were synthesized.Then different polymer monomers reacted with methacrylic anhydride to get CLPEGCLMAs and MASCPs.The optimum was reached and the transformation rate from this study was all above 85%under the optimal condition.Finally,elastomers were synthesized by UV cross-linking.The optimum was as follows:DMPA(photoinitiator)15 mg/ml,wave length365 nm,5 min.The physicochemical property and the morphology were characterized by gravimetry,DSC and SEM method which could be conducive to deeply understand the regularity of degradation and control release in vitro.(1)Gravimetry analysis results showed that PV became larger as the content of CLPEGCLMA increased;the change of DS had a positive correlation with PEG molecular weight and CLPEGCLMA contents;the swelling equilibrium time was extension as the CL/PEG ratio increased.(2)T_g increased as PEG molecular weight(CLPEGCLMA 30%),CLPEGCLMA contents and CL/LA ratio decreased;inversely,the change of T_m and?H_f had a positive correlation with PEG molecular weight(CLPEGCLMA 30%).(3)SEM results showed that different elastomers present similar surface sharps features,while the“roughness”of the internal structure was affected by the different composition of elastomers.The degradation study in vitro showed that MASCP-CLPEGCLMA elastomers went though a“slow-fast”process.Cross-linking density,the degree of swelling and degradation environment(p H)was considered the main factors influencing the degradation rate.Diffusion and the network degradation are two major factors affecting drug release.In this study,diffusion driven by osmotic pressure was the key factor in BSA release.(1)Only change the composition of elastomer,the release rate decreased as the CL content increased and the CLPEGCLMA content decreased.(2)As the CL/LA ratio in MASCP increased,the release rate became higher(in the first 60 days).Later,the release process went into a fast period which was in according with the degradation rules.(3)As the amount of trehalose and drug-loading increasing,the BSA release rate became faster.MASCP-CLPEGCLMA as a novel implant for protein drug,material safety had a significant impact in its clinical application.MTT and inflammation factor experiment showed that elastomer and its degradation products were little harm to the cell.Insulin and interleukin-2 is currently frequently-used protein drugs for diabetes and cancer treating,In this study,3432:5.2:20:30%,3432:5.2:30:30%,3432:10:20:30%and 3432:10:20:10%were chosen as drug delivery for insulin and interleukin-2,and their pharmacokinetics and pharmacodynamics was studied.The results showed as follows:(1)elastomer prepareing process had a little influence for insulin and interleukin-2 biological activity.(2)For the release rate,3432:10:20:30%>3432:10:20:10%>3432:5.2:20:30%>3432:5.2:30:30%.(3)Under the same releaseing condition,the cumulative release of interleukin-2 was significantly less than insulin due to a greater molecular weight and more complex spatial structure.(4)The best release model for insulin and interleukin-2 releasing was Weibull equation and Higuchi equation respectively.(5)The change of rats'blood glucose level and weight was measured everyday after the drug loading elastomer implantation.The results showed 3432:10:20:30%had the most effective in prior period but the blood glucose level was not stable.3432:5.2:20:30%,3432:5.2:30:30%and 3432:10:20:10%also reduced the blood glucose level and sustained the blood glucose stability in the whole process.Meanwhile it was effective to reduce the side effect,emaciation etc.,which was caused by diabetes.(6)Interleukin-2pharmacodynamics study was verified by RAW264.7 phagocytosis using flow cytometry(FCM)and fluorescence imaging technique.The results showed that cell phagocytosis enhanced as the interleukin-2 release content increased which was in according with the interleukin-2 release rule in vitro.In conclusion,MASCP-CLPEGCLMA elastomers as low-toxic and non-toxic biomaterial was successful embedded with BSA,insulin and interleukin-2,and realized the drugs'slow and long-acting release.The drug release rate could be adjusted by monomer composition,the amount of trehalose and drug loading.It could be a potential effective carrier for protein drugs delivery.