Design, Synthesis And Characterization Of New Poly (Ortho Esters)

Poly(ortho esters)(POE) as an acid-sensitive biodegradable polymer materials wassynthesized for the first time by Heller and colleagues in the1960s, which have attractedattention of many researchers as its unique performance. However, the existing syntheticpoly(ortho esters) by addition polymerization method with a spiro diketene acetal,3,9-diethylidene-2,4,8,10-tetraoxaspiro[5,5]undecane (DETOSU). The monomer (DETOSU)is sensitive to light and moisture, hard to prepare, store and use, which largely restricted thedevelopment of poly(ortho esters). Development of a new synthesis method of polyorthoesteris one of research focus.Based on previous experience and literature reading, the conception of this paper asfollows: a new diamine monomer containing a built-in, stabilized ortho ester group wassynthesized by diglycerol with two steps of transesterification. Two new highly hydrophobiccopolymer poly(ortho ester amides)(POEAd-1and POEAd-2) were obtained bypolycondensation of the monomer with suberic acid bis(N-hydroxysuccinimide ester) anddodecanedioic acid bis(N-hydroxysuccinimide ester). Evaluation of the biocompatibility ofthe copolymer by cytotoxicity test in vitro and acute toxicity experiment in vivo. Evaluationof the performance of polymer drug deliever by mouse model of liver cancer. Hemolysis testand MTT cytotoxicity test indicate that POEAd-1and POEAd-2has good biocompatibility asa potential biomedical material, can be widely used in the field of controlled drug deliever.Based on cytotoxicity evaluation of the biocompatibility evaluationin vitro, studied the acutetoxicity, and evaluated capability of drug deliever by mouse hepatoma model, in vivo. Maincontents and results are as follows:1. Synthesis and characterization of polymer: first, a new diamine monomer containing abuilt-in, stabilized ortho ester group was synthesized by diglycerol with two steps oftransesterification. Second, Two new highly hydrophobic copolymer poly(ortho ester amides)(POEAd-1and POEAd-2) were obtained by polycondensation of the monomer c with subericacid bis(N-hydroxysuccinimide ester) and dodecanedioic acid bis(N-hydroxysuccinimideester). Then, The number average molecular weight of POEAd-1and POEAd-2weredetermined by gel permeation chromatography (GPC),and calculated to be1.24×10~4Da and1.81×10~4Da with polydispersity index(PDI) of1.59and1.93, respectively. The initialdegradation temperature up to198.5°C and202.5°C, respectively by thermogravimetricanalysis, which confirmed POEAd-1, and POEAd-2having high thermal stability.2. Cytotoxicity evaluation: no cytotoxicity was found for the polymer directlyco-culturedwith NIH3T3as a concentration of5mg/mL. Slight cytotoxicity was found forthe polymer degradation co-cultured with NIH3T3as a concentration of5mg/mL. Thenormalmorphology of fibroblasts cultured directly in contact with POEA films was not altered.The hemolytic activity of polymer and polymer degradation were less than5%even at thehighest polymer concentration of5mg/mL. Therefore POEAd has no cytotoxicity and hasgood prospects in biomedical application.3. Actue toxicity test: the actue toxicity was studied in vivo by clinical behavior, biochemical analysis and histochemistry analysis, by in vivo acute toxicology, the resultsshowed that the polymer was safe and non-toxic. This polymer is according with therequirement of biomedical materials, can be used for biomedical applications4. In vivo antitumor efficacy evaluation: the effects on tumor growth inhibition in micewere investigated. it was demonstrated that5-FU or POEAd/5-FU group significantlyinhibited the tumor growth in mice xenografted H22tumors compared with other groups.POEAd/5-FU group display better effect than5-FU group in vivo.In respect to safetyevaluation, the toxicity was studied in vivo by biochemical analysis and histochemistryanalysis, there was no noticeable signal of histopathological abnormalities or lesions wasobserved in all of mice. From these results, it was implied that the POEAd delivery systemwas efficient and safe.Therefore POEAd is expected to become an excellent biomedicalmaterial.