Acid-labile pHPMA modification of four-arm oligoaminoamide pDNA polyplexes balances shielding and gene transfer activity in vitro and in vivo

0460354 - ÚMCH 2017 RIV NL eng J - Článek v odborném periodiku
Beckert, L. - Kostka, Libor - Kessel, E. - Krhac Levacic, A. - Kostková, Hana - Etrych, Tomáš - Lächelt, U. - Wagner, E.
Acid-labile pHPMA modification of four-arm oligoaminoamide pDNA polyplexes balances shielding and gene transfer activity in vitro and in vivo.
European Journal of Pharmaceutics and Biopharmaceutics. Roč. 105, August (2016), s. 85-96. ISSN 0939-6411. E-ISSN 1873-3441
Grant CEP: GA MŠMT(CZ) LO1507; GA MŠMT(CZ) LQ1604; GA MŠMT(CZ) ED1.1.00/02.0109
Institucionální podpora: RVO:61389013
Klíčová slova: pH-sensitive shielding * pHPMA * AzMMMan
Kód oboru RIV: CD - Makromolekulární chemie
Impakt faktor: 4.159, rok: 2016

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.
Trvalý link: http://hdl.handle.net/11104/0260477