Show simple item record

dc.contributor.authorWard, Christopher M
dc.contributor.authorRead, Martin L
dc.contributor.authorSeymour, Leonard W
dc.date.accessioned2009-11-06T09:47:51Z
dc.date.available2009-11-06T09:47:51Z
dc.date.issued2001-04-15
dc.identifier.citationSystemic circulation of poly(L-lysine)/DNA vectors is influenced by polycation molecular weight and type of DNA: differential circulation in mice and rats and the implications for human gene therapy. 2001, 97 (8):2221-9 Blooden
dc.identifier.issn0006-4971
dc.identifier.pmid11290582
dc.identifier.urihttp://hdl.handle.net/10541/85499
dc.description.abstractEffective gene therapy for diseases of the circulation requires vectors capable of systemic delivery. The molecular weight of poly(L-lysine) (pLL) has a significant effect on the circulation of pLL/DNA complexes in mice, with pLL(211)/DNA complexes displaying up to 20 times greater levels in the blood after 30 minutes compared with pLL(20)/DNA. It is shown that pLL(20)/DNA complexes fix mouse complement C3 in vitro, independent of immunoglobulin binding; are less soluble in the blood in vivo; bind erythrocytes; are rapidly removed by the liver, where they associate predominantly with Kupffer cells; and result in a rapid increase in hepatic leukocytes expressing high levels of complement receptor 3 (CR3). The circulation properties of these complexes are also dependent on the type of DNA used, with circular plasmid DNA complexes exhibiting increased circulation compared with linear DNA. PLL(211)/DNA complexes bind erythrocytes and associate with Kupffer cells but, in contrast, do not fix mouse complement in vitro and are unaffected by the type of DNA used. In rats, both types of complexes produce hematuria and are rapidly removed from the circulation. Correlation of in vivo and in vitro results suggests that the solubility of complexes in physiological saline and species-matched complement fixation and erythrocyte lysis may correlate with systemic circulation. Analysis using human blood in vitro shows no hemolysis, but both types of complexes fix complement and bind IgG, suggesting that pLL/DNA complexes may be rapidly cleared from the human circulation.
dc.language.isoenen
dc.subjectHaematuriaen
dc.subject.meshAnimals
dc.subject.meshBlood Proteins
dc.subject.meshComplement Activation
dc.subject.meshComplement C3
dc.subject.meshDNA, Circular
dc.subject.meshDNA, Recombinant
dc.subject.meshFemale
dc.subject.meshGene Therapy
dc.subject.meshGenetic Vectors
dc.subject.meshHematuria
dc.subject.meshHumans
dc.subject.meshImmunomagnetic Separation
dc.subject.meshInjections, Intravenous
dc.subject.meshKupffer Cells
dc.subject.meshLeukocytes
dc.subject.meshLiver
dc.subject.meshMice
dc.subject.meshMice, Inbred BALB C
dc.subject.meshMolecular Weight
dc.subject.meshPolylysine
dc.subject.meshRats
dc.subject.meshRats, Wistar
dc.subject.meshReceptors, Complement
dc.subject.meshSolubility
dc.subject.meshSpecies Specificity
dc.subject.meshTissue Distribution
dc.subject.meshTransfection
dc.titleSystemic circulation of poly(L-lysine)/DNA vectors is influenced by polycation molecular weight and type of DNA: differential circulation in mice and rats and the implications for human gene therapy.en
dc.typeArticleen
dc.contributor.departmentCRC Institute for Cancer Studies, University of Birmingham, United Kingdom. wardcm@hotmail.comen
dc.identifier.journalBlooden
html.description.abstractEffective gene therapy for diseases of the circulation requires vectors capable of systemic delivery. The molecular weight of poly(L-lysine) (pLL) has a significant effect on the circulation of pLL/DNA complexes in mice, with pLL(211)/DNA complexes displaying up to 20 times greater levels in the blood after 30 minutes compared with pLL(20)/DNA. It is shown that pLL(20)/DNA complexes fix mouse complement C3 in vitro, independent of immunoglobulin binding; are less soluble in the blood in vivo; bind erythrocytes; are rapidly removed by the liver, where they associate predominantly with Kupffer cells; and result in a rapid increase in hepatic leukocytes expressing high levels of complement receptor 3 (CR3). The circulation properties of these complexes are also dependent on the type of DNA used, with circular plasmid DNA complexes exhibiting increased circulation compared with linear DNA. PLL(211)/DNA complexes bind erythrocytes and associate with Kupffer cells but, in contrast, do not fix mouse complement in vitro and are unaffected by the type of DNA used. In rats, both types of complexes produce hematuria and are rapidly removed from the circulation. Correlation of in vivo and in vitro results suggests that the solubility of complexes in physiological saline and species-matched complement fixation and erythrocyte lysis may correlate with systemic circulation. Analysis using human blood in vitro shows no hemolysis, but both types of complexes fix complement and bind IgG, suggesting that pLL/DNA complexes may be rapidly cleared from the human circulation.


This item appears in the following Collection(s)

Show simple item record