Adenoviral Vectors Coated with PAMAM Dendrimer Conjugates Allow CAR Independent Virus Uptake and Targeting to the EGF Receptor
- 18 January 2013
- journal article
- research article
- Published by American Chemical Society (ACS) in Molecular Pharmaceutics
- Vol. 10 (2), 606-618
- https://doi.org/10.1021/mp300366f
Abstract
Adenovirus type 5 (Ad) is an efficient gene vector with high gene transduction potential, but its efficiency depends on its native cell receptors coxsackie- and adenovirus receptor (CAR) for cell attachment and αvβ3/5 integrins for internalization. To enable transduction of CAR negative cancer cell lines, we have coated the negatively charged Ad by noncovalent charge interaction with cationic PAMAM (polyamidoamine) dendrimers. The specificity for tumor cell infection was increased by targeting the coated Ad to the epidermal growth factor receptor using the peptide ligand GE11, which was coupled to the PAMAM dendrimer via a 2 kDa PEG spacer. Particles were examined by measuring surface charge and size, the degree of coating was determined by transmission electron microscopy. The net positive charge of PAMAM coated Ad enhanced cellular binding and uptake leading to increased transduction efficiency, especially in low to medium CAR expressing cancer cell lines using enhanced green fluorescent protein or luciferase as transgene. While PAMAM coated Ad allowed for efficient internalization, coating with linear polyethylenimine induced excessive particle aggregation, elevated cellular toxicity and lowered transduction efficiency. PAMAM coating of Ad enabled successful transduction of cells in vitro even in the presence of neutralizing antibodies. Taken together, this study clearly proves noncovalent, charge-based coating of Ad vectors with ligand-equipped dendrimers as a viable strategy for efficient transduction of cells otherwise refractory to Ad infection.Keywords
This publication has 49 references indexed in Scilit:
- Update on non-viral delivery methods for cancer therapy: possibilities of a drug delivery system with anticancer activities beyond delivery as a new therapeutic toolExpert Opinion on Drug Delivery, 2010
- HPMA copolymers for masking and retargeting of therapeutic viruses☆Advanced Drug Delivery Reviews, 2010
- Adenovirus Serotype 5 Hexon Mediates Liver Gene TransferCell, 2008
- Modification of Adenovirus Gene Transfer Vectors With Synthetic Polymers: A Scientific Review and Technical GuideMolecular Therapy, 2008
- Biology of Adenovirus and Its Use as a Vector for Gene TherapyHuman Gene Therapy, 2004
- Chloride Accumulation and Swelling in Endosomes Enhances DNA Transfer by Polyamine-DNA PolyplexesJournal of Biological Chemistry, 2003
- Heparan Sulfate Glycosaminoglycans Are Involved in Adenovirus Type 5 and 2-Host Cell InteractionsVirology, 2000
- Complexes of Adenovirus with Polycationic Polymers and Cationic Lipids Increase the Efficiency of Gene Transfer in Vitro and in VivoJournal of Biological Chemistry, 1997
- Isolation of a Common Receptor for Coxsackie B Viruses and Adenoviruses 2 and 5Science, 1997
- Integrins αvβ3 and αvβ5 promote adenovirus internalization but not virus attachmentCell, 1993