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Acid-labile pHPMA modification of four-arm oligoaminoamide pDNA polyplexes balances shielding and gene transfer activity in vitro and in vivo
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SYSNO ASEP 0460354 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Acid-labile pHPMA modification of four-arm oligoaminoamide pDNA polyplexes balances shielding and gene transfer activity in vitro and in vivo Tvůrce(i) Beckert, L. (DE)
Kostka, Libor (UMCH-V) RID, ORCID
Kessel, E. (DE)
Krhac Levacic, A. (DE)
Kostková, Hana (UMCH-V) RID
Etrych, Tomáš (UMCH-V) RID, ORCID
Lächelt, U. (DE)
Wagner, E. (DE)Zdroj.dok. European Journal of Pharmaceutics and Biopharmaceutics. - : Elsevier - ISSN 0939-6411
Roč. 105, August (2016), s. 85-96Poč.str. 12 s. Jazyk dok. eng - angličtina Země vyd. NL - Nizozemsko Klíč. slova pH-sensitive shielding ; pHPMA ; AzMMMan Vědní obor RIV CD - Makromolekulární chemie CEP LO1507 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy LQ1604 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy ED1.1.00/02.0109 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UMCH-V - RVO:61389013 UT WOS 000380079100010 EID SCOPUS 84975042083 DOI 10.1016/j.ejpb.2016.05.019 Anotace We report novel pH-reversibly surface-shielded polyplexes with enhanced gene transfer activity upon systemic administration. A four-arm-structured sequence-defined cationic oligomer KK[HK[(H-Sph-K)3HC]2]2 was designed and synthesized on solid-phase, containing additional lysine residues not only for improved pDNA polyplex stability, but also providing attachment points for subsequent polyplex functionalization with amine-reactive shielding polymers. Herein, the surface of polyplexes was shielded with hydrophilic polymers, monovalent PEG or monovalent and multivalent pHPMA, optionally attached to the polyplex via the acid-labile linker AzMMMan. Overall, surface modification with PEG or pHPMA resulted in a decrease in the zeta potential of polyplexes, consistent with the degree of surface shielding. At pH 6.0, only polyplexes modified via the acid-labile linkage showed an increase in zeta potential, consistent with a “deshielding” in acidic environment, expected as beneficial for endosomal escape. Shielding was more efficient for multivalent pHPMA (20 kDa, 30 kDa) as compared to monovalent pHPMA (10 kDa, 20 kDa, 30 kDa) or PEG (5 kDa). In vitro transfection studies revealed higher gene expression by the polyplexes with the acid-labile shield as compared to their irreversibly shielded counterparts. Intravenous administration of AzMMMan-pHPMA modified polyplexes in an in vivo tumor mouse model mediated enhanced gene expression in the subcutaneous tumor and reduced undesirable expression in the liver. Pracoviště Ústav makromolekulární chemie Kontakt Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Rok sběru 2017
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