Novel thermogelling poly(ε-caprolactone-co-lactide)-poly(ethylene glycol)-poly(ε-caprolactone-co-lac

Available online at www.sciencedirect.comCHINESEScienceDirectCHEMICALL .ETTERSEL SEVIERChinese Chemical Letters 18 (207) 747-749www.clsevier.com/locate/ccletNovel thermoelling poly(e-caprolactone co-lactide)- -poly(ethyleneglycol)- poly(ε caprolacone-co-latide) aqueous solutionsZhi Qiang Jiang ab, Xian Mo Deng a, Jian Yuan Hao aD.**Chengdu Istinte of Organic Chemisty, Chinse Academy of Sciences, PO. Box 415, Chegdu 6001, China"Graduae School of Chinese Academy of Sciences, Bejing 10039, ChinaAbstractThe aqueous solutions of plye_caprolactoneon catade-ooylethylene gyl)lyaproaconco-oactde undergoingsol-gel ransition as the temperature icreases from 20to 50 °C were scsull prepared The termoglling tiblock copolymerswere syubesied by subile tuning of the chemical composition and the hyopilititytrophobit balance. The sol-geltranstion was studied focuing on structure property rlatioship, The amphiphilic copolymer formed micelles in aqueoussolutions. It is believed to have potential aplications in drug delivery and tssuse engineering.C 2007 Jian Yuan Hao. Published by EIlsevier B.V. on behalf of Chinese Chemical Society All rights reserved.Keywords: Biomaterials; Hydrogels; Miells; Phase behaviorBiodegradable tereogleling hyrogels as ijecable drug delivery systems [1- -3] and tssuse egneering saffoldls[4]have ben studied exensively over the past few years due to the advantages incuding ease of apcatin, lcalzeddelivery for a sitesecif.c actin, prolonged delivry periods and improved patient compliance. In this work, we reportnovel thermal gels composed of poly(ε- caprolactone co-actide)- -poly(ethylene glycol) poly(E-caprolactone-co-lactide) [P(CL-LA)-PEG- P(CL-LA)], the aqucous solutios of which underwent sol-gel transition as temperatureincreased from ro temperature to body temperature. It is expected to be a promising biomedical material for drugdelivery and tssue engineering applications.The P(CL-LA)-PEG P(CLLA) tiblock copolymers were synthesied by ringopening polymerization of 8caprolactone and lactide monomers in the presence of PEG using sanous octoate [Sn(Oct)2] as the catalyst. TheH NMR spectra of P(CLLA)-PEG- P(CL-LA) copolymer was shown in Fig. 1. The characteristic signals ataround 4.9 5.2, 3.6 and 1.4 ppm are assigned to the methine protons of the lactide units and the methyleneprotons of PEG and e-caprolactone units, respectively. The signals around 4.1 and 2.3 ppm are assigned to a,o-methylene protons of caproyl units subdivided into two triplets. From these peaks, the parameters that mightinfuence the phase tanition behavior of the copolymer solutions, such as the EG/LA + CL) ratio, LA/CL ratio,molecular weight (M) and block length of the copolymers were calculated and listed in Table 1 for the ease ofcomparison.The efet of P(CL-LA) block length on the sol to gel transition curves of PI, PII and PII while LACL ratios inP(CL-LA) block were kept constant were presented in Fig 2. The phase transition behavior was measured by a testtube ivering method [5]. With increasing P(CL-LA) block lengh, the lower crtical gelation temperature (CCT)中国煤化工* Corresponding author at: Chengdu Institute of Organic Chemitry, Chinese AJMYHC N M H GChengdu 60041, China.E-mail adress: j.hao@cioc.ac cn (.Y. Hao).1001-8417/5- see front matter o 200 Jian Yuan Hao. Published by Elseier B.V. on behalf of Chinese Chemical Society. All rights reserved.doi: 10.1016/.clet.2007.04.037748ZQ. Jiang er al/Chinese Chemical Ltters 18 (2007) 747-749HotyoPEG(CH) a_从iFig. 1. 'H NMR spectra of the chemical structure of P(CL -LA)-PEG -P(CL-LA) triblock copolymer.Table 1Chemical compositions and molecular weights of the synthesized triblock copolymersNo.Block lenghEG/LA + CL (mol/mo)LA/CL (mo/mol)Mn (NMR)PI(CLA)123/1.4-(EG)35 (CLLA)123/1.41.260.1111630-1540-1630PII(CLA)4s/1.6-(EG)3s- (CL/LA)451.60.1101880-1540-1880(CL/LA1)6.61.8-(EG)3s-(CLA)16.6/180.950.1132170- 1540-2170decreased and the temperature for gel to collapse shifted to higher temperatures, which leaded to broadened gel phasetemperature. Longer P(CL LA) chain in the triblock copolymers induced stronger hydrophobic interaction andprobably formed more bridging connections between micelles leading to a lower CGT.P(CL-LA)-PEG- _P(CL-LA) triblock copolymers are amphiphilic in nature and readily form micelles in waterbecause water is a poor solvent for the hydrophobic P(CL-LA) block while it is a good solvent for the hydrophilic PEGblocks. Micelles were formed due to the hydrophobic effect, which contributes to the self-association of polyesterchains. The formation of micelles was confirmed dye solubilization. The hydrophobic dye, 1,6-diphenyl-1,3,5-hexatriene, (DPH), are preferentially partitioned into the hydrophobic core of micelles showing a increasedabsorbance because it has a higher absorptivity at 356 nm in the hydrophobic environment compared with that inaqueous environment. The absorbance increased with concentration. The abrupt increase in absorbance reflected themicelle formation (Fig. 3).The development of elastic modulus with increasing temperature of 25% aqueous solution of P(CL-LA) -PEG-P(CL-LA) was presented in Fig. 4. The elastic modulus at room temperature was less than 0.1 Pa, which made it easyto formulate and inject through a syringe needle. It increased abruptly at the sol-t0-gel transition temperature (about32 °C). At low temperature unimers and independent micelles were dispersed discretely in water and the solutionbehaved as a fuid. As temperature increased more micelles were formed and micelles aggregated. A physical networkwas established when the micelles cooperatively formed associations with each other and the fuid changed into solid-like gel state.50- PI4C35-， 30-中国煤化工25YHCNMHG520253035Concentration (Wt %)Fig. 2. P(CL-LA) block length efet on the phase diagram of PI, PII and PII aqueous soutions.zQ. Jiang et al./Chinese Chemical Leters 18 (2007) 747-7497490.70.6-0.5-0.4g0.30.20.1-32Log Conc.(wt %)Fig. 3. Critical micelle concentration determination of PI aqucous solutions at 20°C.0-1.^、 0.120 304(50Temperature °CFig. 4. Dynamic mechanical analysis of PI aqueous solution as a function of temperature.AcknowledgmentsThis work was supported by the National Natural Sciences Foundation of China No.50603025) and the SpecialResearch Grant from the Dean of Chinese Academy of Sciences.References[1] G. Zentner, R. Rathi, c. Shih, J.C. Mcrea, M.H. Seo, H. Oh, B.C. Rhee, I. Mestechy, z. Moldoveanu, M. Morgan, s. Weitman, J Contol.Rclease 72 (2001) 203.[2] s. Choi, M. Baudys, S.W. Kim, Pharm. Res. 21 (200) 827.[3] P Lemieux, N. Guerin, G. Paradi, R. Proulx, L. Chistyakova, A. Kabanov, V. Alakhov, Gene Ther. 7 (2000 986.[4] C. Lee, A. Grodzinsky, M. Spector, Biomaterials 22 (200) 3145.[5] P. Alexandrisdis, J.F. Holzwarth, TA. Hatton, Macromolecules 27 (1994) 2414.中国煤化工MYHCNMHG