title: Facile Synthesis of Reductively Degradable Biopolymers Using Cystamine Diisocyanate as a Coupling Agent.
abstract: Reductively degradable biopolymers have emerged as a unique class of smart biomedical materials. Here, a functional coupling agent, cystamine diisocyanate (CDI), was designed to offer a facile access to reductively degradable biopolymers via polycondensation with various diols. CDI was readily obtained with a decent yield of 46% by reacting cystamine dihydrochloride with triphosgene. The polycondensation of oligo(ethylene glycol) diol (Mn = 0.4 or 1.5 kg/mol) or oligo(ε-caprolactone) diol (Mn = 0.53 kg/mol) with CDI in N,N-dimethylformamide at 60 °C using dibutyltin dilaurate as a catalyst afforded reductively degradable poly(ethylene glycol) (SSPEG, Mn = 6.2-76.8 kg/mol) or poly(ε-caprolactone) (SSPCL, Mn = 6.8-16.3 kg/mol), in which molecular weights were well controlled by diol/CDI molar ratios. Moreover, PEG-SSPCL-PEG triblock copolymers could be readily prepared by reacting dihydroxyl-terminated SSPCL with PEG-isocyanate derivative. PEG-SSPCL-PEG with an Mn of 5.0-16.3-5.0 kg/mol formed small-sized micelles with an average diameter of about 85 nm in PB buffer. The in vitro release studies using doxorubicin (DOX) as a model drug showed that, in sharp contrast to reduction-insensitive PEG-PCL(HDI)-PEG controls, drug release from PEG-SSPCL-PEG micelles was fast and nearly complete in 24 h under a reductive condition containing 10 mM glutathione. The confocal microscopy experiments in drug-resistant MCF-7 cells (MCF-7/ADR) displayed efficient cytoplasmic DOX release from PEG-SSPCL-PEG micelles. MTT assays revealed that DOX-loaded PEG-SSPCL-PEG micelles were much more potent against MCF-7/ADR cells than reduction-insensitive PEG-PCL(HDI)-PEG controls (IC50: 6.3 vs 55.4 μg/mL). It should further be noted that blank PEG-SSPCL-PEG micelles were noncytotoxic up to a tested concentration of 1 mg/mL. Hence, cystamine diisocyanate appears to be an innovative coupling agent that facilitates versatile synthesis of biocompatible and reductively degradable biopolymers.
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering, and Materials Science, Soochow University , Suzhou, 215123, People's Republic of China.
authors.forename: Xiuxiu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering, and Materials Science, Soochow University , Suzhou, 215123, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering, and Materials Science, Soochow University , Suzhou, 215123, People's Republic of China.
authors.forename: Ru
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering, and Materials Science, Soochow University , Suzhou, 215123, People's Republic of China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Meng
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering, and Materials Science, Soochow University , Suzhou, 215123, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering, and Materials Science, Soochow University , Suzhou, 215123, People's Republic of China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D063566:Biodegradable Plastics / Q000009:adverse effects / Q000138:chemical synthesis*; D002208:Caproates / Q000737:chemistry; D003485:Cyanates / Q000737:chemistry; D003538:Cystamine / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers / Q000009:adverse effects / Q000138:chemical synthesis*; D006801:Humans; D007783:Lactones / Q000737:chemistry; D061986:MCF-7 Cells; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D063566:Biodegradable Plastics; D002208:Caproates; D003485:Cyanates; D004337:Drug Carriers; D007783:Lactones; D008823:Micelles; D011092:Polyethylene Glycols; C121056:caprolactone; D004317:Doxorubicin; D003538:Cystamine