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Cyclic RGD Peptide-Conjugated Polyplex Micelles as a Targetable Gene Delivery System Directed to Cells Possessing αvβ3 and αvβ5 Integrins
Abstract
A cyclic RGD peptide-conjugated block copolymer, cyclo[RGDfK(CX-)]-poly(ethylene glycol)-polylysine (c(RGDfK)-PEG-PLys), was synthesized from acetal-PEG-PLys under mild acidic conditions and spontaneously associated with plasmid DNA (pDNA) to form a polyplex micelle in aqueous solution. The cyclic RGD peptide recognizes alphavbeta3 and alphavbeta5 integrin receptors, which play a pivotal role in angiogenesis, vascular intima thickening, and the proliferation of malignant tumors. The c(RGDfK)-PEG-PLys/pDNA polyplex micelle showed a remarkably increased transfection efficiency (TE) compared to the PEG-PLys/pDNA polyplex micelle for the cultured HeLa cells possessing alphavbeta3 and alphavbeta5 integrins. On the other hand, in the transfection against the 293T cells possessing no alphavbeta3 and a few alphavbeta5 integrins, the TE of the c(RGDfK)-PEG-PLys/pDNA micelle showed no increase compared to the TE of the PEG-PLys/pDNA micelle. Flow cytometric analysis revealed a higher uptake of the c(RGDfK)-PEG-PLys/pDNA micelle than the PEG-PLys/pDNA micelle against HeLa cells, consistent with the transfection results. Furthermore, a confocal laser scanning microscopic observation revealed that the pDNA in the c(RGDfK)-PEG-PLys micelle preferentially accumulated in the perinuclear region of the HeLa cells within 3 h of incubation. No such fast and directed accumulation of pDNA to the perinuclear region was observed for the micelles without c(RGDfK) ligands. These results indicate that the increase in the TE induced by the introduction of the c(RGDfK) peptide ligand was due to an increase in cellular uptake as well as facilitated intracellular trafficking of micelles toward the perinuclear region via alphavbeta3 and alphavbeta5 integrin receptor-mediated endocytosis, suggesting that the cyclic RGD peptide-conjugated polyplex micelle has promising feasibility as a site-specifically targetable gene delivery system.
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Citations
Cited by
Miyata, K., Nishiyama, N., & Kataoka, K. (2012) · Chem. Soc. Rev. · doi:10.1039/c1cs15258k · Cited by 451
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Mi, P., Cabral, H., & Kataoka, K. (2020) · Advanced Materials · doi:10.1002/adma.201902604 · Cited by 350
Self-citationOsada, K., Christie, R. J., & Kataoka, K. (2009) · Journal of The Royal Society Interface · doi:10.1098/rsif.2008.0547.focus · Cited by 218
Self-citationLiu, D., Liu, F., Liu, Z., Wang, L., & Zhang, N. (2011) · Molecular Pharmaceutics · doi:10.1021/mp200402e · Cited by 108
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Metadata
- Authors
- Oba, M., Fukushima, S., Kanayama, N., Aoyagi, K., Nishiyama, N., Koyama, H., & Kataoka, K.
- Venue
- Bioconjugate Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2007-06-27
- Volume
- 18
- Issue
- 5
- Pages
- 1415-1423
- ISSN
- 1043-1802 (ISSN-L)
- 1520-4812
- OpenAlex
- W2054877253
- Cited by
- 197
- References
- 0
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- closed
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