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Factors affecting blood clearance and in vivo distribution of polyelectrolyte complexes for gene delivery
Abstract
Self-assembling polycation/DNA complexes represent a promising synthetic vector for gene delivery. However, despite considerable versatility and transfectional activity in vitro, such materials are quickly eliminated from the bloodstream following intravenous injection (plasma alpha half-life typically less than 5 min). For targeted systemic delivery a more prolonged plasma circulation of the vector is essential. Here we have examined factors contributing to rapid elimination of poly(L-lysine) (pLL)/DNA complexes from the bloodstream, and implicate the binding of proteins to the polyelectrolyte complexes as a likely cause for their blood clearance. pLL/DNA complexes reisolated from serum associate with several proteins, depending on their net charge, although the major band on SDS-PAGE co-migrates with albumin. Serum albumin binds to pLL/DNA complexes in vitro, forming a ternary pLL/DNA/albumin complex which regains some ethidium bromide fluorescence and fails to move during agarose electrophoresis. Albumin also causes increased turbidity of complexes, and reduces their zeta potential to the same level (-16 mV) as is measured in serum. We propose that rapid plasma elimination of polycation/DNA complexes results from their binding serum albumin and other proteins, perhaps due to aggregation and phagocytic capture or accumulation of the ternary complexes in fine capillary beds.
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“On the other hand, cationic non-viral vectors used to condense negatively charged CRISPR RNPs and plasmids are prone to interact with plasma proteins and the physiological salt in physiological conditions, resulting in the recognition and clearance by the reticuloendothelial system (RES) [141–143].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [142]
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Metadata
- Authors
- Dash, P. R., Read, M. L., Barrett, L. B., Wolfert, M. A., & Seymour, L. W.
- Affiliations
- University of Birmingham (GB)
- Venue
- Gene Therapy
- Published
- 1999-04-01
- Volume
- 6
- Issue
- 4
- Pages
- 643-650
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- OpenAlex
- W2031185644
- Cited by
- 386
- References
- 24
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 1 · 2023: 7 · 2022: 3 · 2021: 5 · 2020: 9 · 2019: 14 · 2018: 11 · 2017: 13 · 2016: 14 · 2015: 11 · 2014: 22 · 2013: 31 · 2012: 22
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- British Heart Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- polyelectrolyte complexes, gene delivery, poly-L-lysine, DNA, blood clearance, serum albumin, protein binding, plasma half-life, zeta potential, complex aggregation, phagocytosis, intravenous injection, systemic drug delivery
- MeSH terms
- Albumins, Animals, DNA, Electrophoresis, Agar Gel, Female, Genetic Vectors, Metabolic Clearance Rate, Mice, Inbred BALB C, Polylysine, Protein Binding, Transfection, Genetic Therapy, Treatment Failure, Mice
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