The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
Hypersensitivity and Loss of Disease Site Targeting Caused by Antibody Responses to PEGylated Liposomes
Open accessAbstract
The systemic application of nucleic acid drugs requires delivery systems that overcome the poor pharmacokinetics, limited biodistribution, and inefficient uptake of nucleic acids. PEGylated liposomes show considerable promise because of their intrinsic ability to accumulate at disease sites and facilitate transfection of target cells. Unlike many viral vectors, PEGylated liposomes are generally considered to be nonimmunogenic. We have developed a PEGylated liposome for the systemic administration of plasmid DNA that achieves high levels of selective gene expression at distal tumor sites. Here we report that the in vivo efficacy and safety of these systems can be severely compromised following repeat administration. This phenomenon is characterized by a loss of disease site targeting, accelerated clearance from the blood, and acute hypersensitivity. These effects are fully attributable to a surprisingly robust, long-lived antibody response generated against polyethylene glycol (PEG) that results from the strong adjuvant effect of the plasmid payload. Importantly, immunogenicity may be substantially reduced by modifying the alkyl chain of the PEG-lipid conjugate, thereby allowing successful repeat dosing of the modified plasmid formulations without adverse side effects. Immunogenicity is a relevant concern for a number of nonviral delivery systems given the potent immunostimulatory properties of many nucleic acid drugs.
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Cites
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Cited by
PEGylation as a strategy for improving nanoparticle-based drug and gene delivery
Suk, J. S., Xu, Q., Kim, N., Hanes, J., & Ensign, L. M. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.09.012 · Cited by 4,523
The current landscape of nucleic acid therapeutics
Kulkarni, J. A., Witzigmann, D., Thomson, S. B., Chen, S., Leavitt, B. R., Cullis, P. R., & van der Meel, R. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00898-0 · Cited by 1,371
Polyethylene glycol (PEG): A versatile polymer for pharmaceutical applications
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Targeting nanoparticles to cancer
Wang, M., & Thanou, M. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.03.005 · Cited by 931
Metadata
- Authors
- Judge, A., McClintock, K., Phelps, J. R., & MacLachlan, I.
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 13
- Issue
- 2
- Pages
- 328-337
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W1990622580
- Cited by
- 280
- References
- 47
- FWCI
- 2.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Judge, A., McClintock, K., Phelps, J. R., & MacLachlan, I. (2006). Hypersensitivity and Loss of Disease Site Targeting Caused by Antibody Responses to PEGylated Liposomes. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2005.09.014
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
