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Development of Degradable, pH‐Sensitive Star Vectors for Enhancing the Cytoplasmic Delivery of Nucleic Acids
dc.contributor.authorDurmaz, Yasemin Yukselen_US
dc.contributor.authorLin, Yen‐lingen_US
dc.contributor.authorElSayed, Mohamed E. H.en_US
dc.date.accessioned2013-09-04T17:18:38Z
dc.date.available2014-10-06T19:17:42Zen_US
dc.date.issued2013-08-19en_US
dc.identifier.citationDurmaz, Yasemin Yuksel; Lin, Yen‐ling ; ElSayed, Mohamed E. H. (2013). "Development of Degradable, pHâ Sensitive Star Vectors for Enhancing the Cytoplasmic Delivery of Nucleic Acids." Advanced Functional Materials 23(31): 3885-3895. <http://hdl.handle.net/2027.42/99666>en_US
dc.identifier.issn1616-301Xen_US
dc.identifier.issn1616-3028en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/99666
dc.description.abstractThe report describes the synthesis of degradable, pH‐sensitive, membrane‐destabilizing, star‐shaped polymers where copolymers of hydrophobic hexyl methacrylate (HMA) and 2‐(dimethylamino)ethyl methacrylate (DMAEMA) monomers are grafted from the secondary face of a beta‐cyclodextrin (β‐CD) core via acid‐labile hydrazone linkages using atom transfer radical polymerization. The effect of the graft's molecular weight, HMA/DMAEMA molar ratio, and the fraction of DMAEMA converted to cationic N,N,N‐trimethylaminoethyl methacrylate (TMAEMA) monomers on polymer's transfection capacity is systematically investigated. Results show that all star‐shaped polymers condense anti‐GAPDH silencing RNA (siRNA) into nanosized particles at +/‐ ratio ≤ 4:1. Star polymers with shorter (25kDa) P(HMA‐ co ‐DMAEMA‐ co ‐TMAEMA) grafts are more efficient and less cytotoxic than carriers with longer (40kDa) grafts. The results show that increasing the ratio of hydrophobic HMA monomers in graft's composition higher than 50 mole% dramatically reduces polymer's aqueous solubility and abolishes their transfection capacity. Further, retention of DMAEMA monomers in graft's composition provide a buffering capacity that enhanced the endosomal escape and transfection capacity of the polymers. These systematic studies show that β‐CD‐P(HMA‐ co ‐DMAEMA‐ co ‐TMAEMA) 4.8 polymer with a 25 kDa average graft's molecular weight and a 50/25/25 ratio of HMA/DMAEMA/TMAEMA monomers is the most efficient carrier in delivering the siRNA cargo into the cytoplasm of epithelial cancer cells. A series of degradable, pH‐sensitive, membrane‐destabilizing, star‐shaped polymers is synthesized. Star polymers are engineered to “sense” the drop in endosomal pH, which triggers the hydrolysis of acid‐labile hydrazone linkages and release of membrane‐active grafts that rupture the endosomal membrane and release the loaded siRNA cargo into the cytoplasm to produce the desired knockdown of targeted gene expression at both the mRNA and protein levels.en_US
dc.publisherWILEY‐VCH Verlagen_US
dc.subject.otherAcid‐Labile Hydrazone Linkageen_US
dc.subject.otherCytoplasmic Silencing RNA Deliveryen_US
dc.subject.otherStar Polymersen_US
dc.subject.otherPH‐Sensitive Carriersen_US
dc.subject.otherBeta‐Cyclodextrinen_US
dc.titleDevelopment of Degradable, pH‐Sensitive Star Vectors for Enhancing the Cytoplasmic Delivery of Nucleic Acidsen_US
dc.typeArticleen_US
dc.rights.robotsIndexNoFollowen_US
dc.subject.hlbsecondlevelMaterials Science and Engineeringen_US
dc.subject.hlbsecondlevelEngineering (General)en_US
dc.subject.hlbtoplevelEngineeringen_US
dc.description.peerreviewedPeer Revieweden_US
dc.contributor.affiliationumUniversity of Michigan, Department of Biomedical Engineering, 1101 Beal Avenue, Lurie Biomedical Engineering Building, Ann Arbor, MI 48109, USAen_US
dc.contributor.affiliationumUniversity of Michigan, Department of Biomedical Engineering, 1101 Beal Avenue, Lurie Biomedical Engineering Building, Ann Arbor, MI 48109, USA.en_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/99666/1/3885_ftp.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/99666/2/adfm_201203762_sm_suppl.pdf
dc.identifier.doi10.1002/adfm.201203762en_US
dc.identifier.sourceAdvanced Functional Materialsen_US
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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