Among non-viral vectors, cationic polymers, such as poly(propylene imine) (PPI), play
a prominent role in nucleic acid delivery. However, limitations of polycationic polymer-based
DNA delivery systems are (i) insufficient target specificity, (ii) unsatisfactory transgene expression,
and (iii) undesired transfer of therapeutic DNA into non-target cells. We developed single-chain
antibody fragment (scFv)-directed hybrid polyplexes for targeted gene therapy of prostate stem cell
antigen (PSCA)-positive tumors. Besides mono-biotinylated PSCA-specific single-chain antibodies
(scFv(AM1-P-BAP)) conjugated to neutravidin, the hybrid polyplexes comprise -cyclodextrinmodified
PPI as well as biotin/maltose-modified PPI as carriers for minicircle DNAs encoding for
Sleeping Beauty transposase and a transposon encoding the gene of interest. The PSCA-specific hybrid
polyplexes efficiently delivered a GFP gene in PSCA-positive tumor cells, whereas control hybrid
polyplexes showed low gene transfer efficiency. In an experimental gene therapy approach, targeted
transposition of a codon-optimized p53 into p53-deficient HCT116p53 /PSCA cells demonstrated
decreased clonogenic survival when compared to mock controls. Noteworthily, p53 transposition
in PTEN-deficient H4PSCA glioma cells caused nearly complete loss of clonogenic survival. These
results demonstrate the feasibility of combining tumor-targeting hybrid polyplexes and Sleeping
Beauty gene transposition, which, due to the modular design, can be extended to other target genes
and tumor entities.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:85928 |
| Date | 09 June 2023 |
| Creators | Jugel, Willi, Tietze, Stefanie, Daeg, Jennifer, Appelhans, Dietmar, Broghammer, Felix, Aigner, Achim, Karimov, Michael, Schackert, Gabriele, Temme, Achim |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1925 |
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