- Title
- Combined MUC1-specific nanobody-tagged PEG-polyethylenimine polyplex targeting and transcriptional targeting of tBid transgene for directed killing of MUC1 over-expressing tumour cells
- Creator
- Sadeqzadeh, Elham; Rahbarizadeh, Fatemeh; Rasaee, Mohammad J.; Parhamifar, Ladan; Moghimi, S. Moein
- Relation
- Journal of Controlled Release Vol. 156, Issue 1, p. 85-91
- Publisher Link
- http://dx.doi.org/10.1016/j.jconrel.2011.06.022
- Publisher
- Elsevier
- Resource Type
- journal article
- Date
- 2011
- Description
- We provide evidence for combining a single domain antibody (nanobody)-based targeting approach with transcriptional targeting as a safe way to deliver lethal transgenes to MUC1 over-expressing cancer cells. From a nanobody immune library, we have isolated an anti-DF3/Mucin1 (MUC1) nanobody with high specificity for the MUC1 antigen, which is an aberrantly glycosylated glycoprotein over-expressed in tumours of epithelial origin. The anti-MUC1 nanobody was covalently linked to the distal end of poly(ethylene glycol)₃₅₀₀ (PEG₃₅₀₀) in PEG₃₅₀₀-25 kDa polyethylenimine (PEI) conjugates and the resultant macromolecular entity successfully condensed plasmids coding a transcriptionally targeted truncated-Bid (tBid) killer gene under the control of the cancer-specific MUC1 promoter. The engineered polyplexes exhibited favourable physicochemical characteristics for transfection and dramatically elevated the level of Bid/tBid expression in both MUC1 over-expressing caspase 3-deficient (MCF7 cells) and caspase 3-positive (T47D and SKBR3) tumour cell lines and, concomitantly, induced considerable cell death. Neither transgene expression nor cell death occurred when the MUC1 promoter was replaced with the CNS-specific synapsin I promoter. Since PEGylated PEI was only responsible for DNA compaction and played no significant role in direct transfection and cell killing, our attempts overcome previously reported PEI-mediated apoptotic and necrotic cell death, which is advantageous for future in vivo transcriptional targeting as this will minimize (or eliminate) non-targeted cell damage.
- Subject
- cancer nanomedicines; MUC1; nanobody; poly(ethylene glycol); polyethylenimine; transcriptional targeting
- Identifier
- http://hdl.handle.net/1959.13/1038865
- Identifier
- uon:13590
- Identifier
- ISSN:0168-3659
- Language
- eng
- Full Text
- Reviewed
- Hits: 3759
- Visitors: 4561
- Downloads: 666
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT03 | Author final version | 760 KB | Adobe Acrobat PDF | View Details Download |