N-(2-Hydroxypropyl)methacrylamide copolymers targeted to the hepatocyte galactose-receptor: pharmacokinetics in DBA2 mice

Seymour, Len; Ulbrich, Karel; Wedge, S. R.; Hume, Isabella C.; Strohalm, J.; Duncan, Ruth

doi:10.1038/bjc.1991.190

Cited by 113 publications

(38 citation statements)

References 29 publications

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“…Several targeting agents, including mixtures, can be incorporated to modulate selectivity of delivery, and sequences can be introduced into the polymers to tailor the complexes as pro-forms for activation by specific target-associated enzymes. 23 In addition, hydrolytically unstable polymer linkages may yield the possibility of long-term release of DNA within the nuclear compartment. Finally, polyvalent surface modification with hydrophilic polymers, as well as enabling attachment of targeting agents, also permits protection of the complexes from inappropriate protein binding, one of the major factors implicated in rapid elimination from the circulation.…”

Section: Discussionmentioning

confidence: 99%

A versatile system for receptor-mediated gene delivery permits increased entry of DNA into target cells, enhanced delivery to the nucleus and elevated rates of transgene expression

et al. 2000

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We have developed a method for stabilisation of polyelectrolyte gene delivery vectors by crosslinking their surfaces with biodegradable multivalent copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA). The resulting nanoparticulate vectors resist attack by serum proteins and can be modified for cell-specific delivery by incorporation of targeting ligands onto the polymer coating. Here we show that vascular endothelial growth factor (VEGF), transferrin and basic fibroblast growth factor (bFGF) can each be linked to polyHPMA-coated poly(L-lysine)/DNA complexes. All ligandtargeted complexes demonstrated increased uptake into receptor-positive cells (measured using plasmids containing 32 P-dCTP), that could be antagonised with excess free ligand. Targeted complexes also showed increased trans-

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Section: Discussionmentioning

confidence: 99%

A versatile system for receptor-mediated gene delivery permits increased entry of DNA into target cells, enhanced delivery to the nucleus and elevated rates of transgene expression

et al. 2000

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“…Organs were either homogenised or dissolved in sodium hydroxide (10 N), before geometry-corrected analysis of their contained radioactivity in a Packard scintillation counter. A bloodstream volume of 8.64 ml/100 g body weight was assumed, 23 and the component of muscle and skin was assumed to be 45% and 16% of the total body weight, respectively. 24 Determination of complement activation in vitro pLL/DNA complexes were formed at N:P ratios of 2.0 and 0.8 and were incubated in full human serum for either 20 or 60 min at 37°C.…”

Section: Determination Of Plasma Clearance and Body Distributionmentioning

confidence: 99%

Factors affecting blood clearance and in vivo distribution of polyelectrolyte complexes for gene delivery

et al. 1999

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Self-assembling polycation/DNA complexes represent a net charge, although the major band on SDS-PAGE copromising synthetic vector for gene delivery. However, migrates with albumin. Serum albumin binds to pLL/DNA despite considerable versatility and transfectional activity complexes in vitro, forming a ternary pLL/DNA/albumin in vitro, such materials are quickly eliminated from the complex which regains some ethidium bromide fluorbloodstream following intravenous injection (plasma ␣ halfescence and fails to move during agarose electrophoresis. life typically less than 5 min). For targeted systemic delivAlbumin also causes increased turbidity of complexes, and ery a more prolonged plasma circulation of the vector is reduces their zeta potential to the same level (−16 mV) essential. Here we have examined factors contributing to as is measured in serum. We propose that rapid plasma rapid elimination of poly(L-lysine) (pLL)/DNA complexes elimination of polycation/DNA complexes results from their from the bloodstream, and implicate the binding of proteins binding serum albumin and other proteins, perhaps due to to the polyelectrolyte complexes as a likely cause for their aggregation and phagocytic capture or accumulation of the blood clearance. pLL/DNA complexes reisolated from ternary complexes in fine capillary beds. serum associate with several proteins, depending on their

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“…A bloodstream volume of 8.64 ml/100 g body weight was assumed. 19 To separate red blood cells, the blood samples were centrifuged at 5000 r.p.m. for 1 min.…”

Section: Microinjection Into Xenopus Oocytesmentioning

confidence: 99%

Triggered intracellular activation of disulfide crosslinked polyelectrolyte gene delivery complexes with extended systemic circulation in vivo

2001

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We have developed polyelectrolyte gene delivery vectors that display good extracellular stability and are activated intracellularly to permit transgene expression. The strategy comprises covalent crosslinking of primary amines in poly-L-lysine/DNA complexes with a crosslinking agent that can later be cleaved by reduction. Crosslinked complexes maintained the same size and surface charge but showed increased stability against polyelectrolyte exchange with poly-L-aspartic acid. Surface modification with polyethyleneglycol improved solubility and masked their positive surface charge. Crosslinked complexes showed 10-fold increased plasma circulation following intravenous administration to Balb/c mice. In the absence of chloroquine, the levels of transgene expression in B16F10 murine melanoma cells were similar for crosslinked and non-crosslinked complexes, however, chloroquine selectively potentiated trans-

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N-(2-Hydroxypropyl)methacrylamide copolymers targeted to the hepatocyte galactose-receptor: pharmacokinetics in DBA2 mice

Abstract: Summary N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers containing doxorubicin (DOX)

Cited by 113 publications

References 29 publications

A versatile system for receptor-mediated gene delivery permits increased entry of DNA into target cells, enhanced delivery to the nucleus and elevated rates of transgene expression

A versatile system for receptor-mediated gene delivery permits increased entry of DNA into target cells, enhanced delivery to the nucleus and elevated rates of transgene expression

Factors affecting blood clearance and in vivo distribution of polyelectrolyte complexes for gene delivery

Triggered intracellular activation of disulfide crosslinked polyelectrolyte gene delivery complexes with extended systemic circulation in vivo

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