Acid-labile pHPMA modification of four-arm oligoaminoamide pDNA polyplexes balances shielding and gene transfer activity in vitro and in vivo
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389013%3A_____%2F16%3A00460354" target="_blank" >RIV/61389013:_____/16:00460354 - isvavai.cz</a>
Result on the web
<a href="http://dx.doi.org/10.1016/j.ejpb.2016.05.019" target="_blank" >http://dx.doi.org/10.1016/j.ejpb.2016.05.019</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejpb.2016.05.019" target="_blank" >10.1016/j.ejpb.2016.05.019</a>
Alternative languages
Result language
angličtina
Original language name
Acid-labile pHPMA modification of four-arm oligoaminoamide pDNA polyplexes balances shielding and gene transfer activity in vitro and in vivo
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
CD - Macromolecular chemistry
OECD FORD branch
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Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2016
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
European Journal of Pharmaceutics and Biopharmaceutics
ISSN
0939-6411
e-ISSN
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Volume of the periodical
105
Issue of the periodical within the volume
August
Country of publishing house
NL - THE KINGDOM OF THE NETHERLANDS
Number of pages
12
Pages from-to
85-96
UT code for WoS article
000380079100010
EID of the result in the Scopus database
2-s2.0-84975042083