Dendrimers in gene delivery

Dufès, Christine; Uchegbu, Ijeoma F.; Schätzlein, Andreas

doi:10.1016/j.addr.2005.09.017

Cited by 906 publications

(676 citation statements)

References 139 publications

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“…The resulting siRNA polyconjugate is negatively charged, soluble, and nonaggregating under physiological conditions. The size of the siRNA polyconjugate is 10 Ϯ 2 nm as measured by particle sizing, making it substantially smaller than the SNALP or iNOP siRNA complexes (21,34).…”

Section: Resultsmentioning

confidence: 99%

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

Rozema

Lewis

Wakefield

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

609

624

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Achieving efficient in vivo delivery of siRNA to the appropriate target cell would be a major advance in the use of RNAi in gene function studies and as a therapeutic modality. Hepatocytes, the key parenchymal cells of the liver, are a particularly attractive target cell type for siRNA delivery given their central role in several infectious and metabolic disorders. We have developed a vehicle for the delivery of siRNA to hepatocytes both in vitro and in vivo, which we have named siRNA Dynamic PolyConjugates. Key features of the Dynamic PolyConjugate technology include a membrane-active polymer, the ability to reversibly mask the activity of this polymer until it reaches the acidic environment of endosomes, and the ability to target this modified polymer and its siRNA cargo specifically to hepatocytes in vivo after simple, low-pressure i.v. injection. Using this delivery technology, we demonstrate effective knockdown of two endogenous genes in mouse liver: apolipoprotein B (apoB) and peroxisome proliferator-activated receptor alpha (ppara). Knockdown of apoB resulted in clear phenotypic changes that included a significant reduction in serum cholesterol and increased fat accumulation in the liver, consistent with the known functions of apoB. Knockdown of ppara also resulted in a phenotype consistent with its known function, although with less penetrance than observed in apoB knockdown mice. Analyses of serum liver enzyme and cytokine levels in treated mice indicated that the siRNA Dynamic PolyConjugate was nontoxic and well tolerated.pH labile bonds ͉ nonviral siRNA delivery ͉ siRNA-polymer conjugates ͉ endosomolytic polymers

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Section: Resultsmentioning

confidence: 99%

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

Rozema

Lewis

Wakefield

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

609

624

View full text Add to dashboard Cite

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“…For targeting purposes, Kukowska-Latallo et al (26) performed studies on folate-conjugated MTX dendrimers administered intravenously, showing 10 times more effective growth delay of KB tumors in mice (26). Also, cationic polypropylenimine dendrimers systemically administered for gene delivery purposes exhibited moderate tumor growth delay, however no mechanism for such effects was shown (27). Despite the fact that previous reports have demonstrated that antiangiogenic activity may be an intrinsic property of some dendrimer molecules, to our knowledge no study has illustrated antiangiogenesis from systemic dendrimer administrations that can be utilized against tumorinduced neovascularization.…”

Section: Discussionmentioning

confidence: 99%

Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth

Al‐Jamal

Al-Jamal

Akerman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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This study describes the previously unreported intrinsic capacity of poly-L-lysine (PLL) sixth generation (G(6)) dendrimer molecules to exhibit systemic antiangiogenic activity that could lead to solid tumor growth arrest. The PLL-dendrimer-inhibited tubule formation of SVEC4-10 murine endothelial cells and neovascularization in the chick embryo chick chorioallantoic membrane (CAM) assay. Intravenous administration of the PLL-dendrimer molecules into C57BL/6 mice inhibited vascularisation in Matrigel plugs implanted subcutaneously. Antiangiogenic activity was further evidenced using intravital microscopy of tumors grown within dorsal skinfold window chambers. Reduced vascularization of P22 rat sarcoma implanted in the dorsal window chamber of SCID mice was observed following tail vein administration (i.v.) of the PLL dendrimers. Also, the in vivo toxicological profile of the PLL-dendrimer molecules was shown to be safe at the dose regime studied. The antiangiogenic activity of the PLL dendrimer was further shown to be associated with significant suppression of B16F10 solid tumor volume and delayed tumor growth. Enhanced apoptosis/necrosis within tumors of PLL-dendrimer-treated animals only and reduction in the number of CD31 positive cells were observed in comparison to protamine treatment. This study suggests that PLL-dendrimer molecules can exhibit a systemic antiangiogenic activity that may be used for therapy of solid tumors, and in combination with their capacity to carry other therapeutic or diagnostic agents may potentially offer capabilities for the design of theranostic systems

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“…A sua estrutura única permite que possuam uma série de características interessantes como tamanho bem definido, baixa polidispersão, e a capacidade de serem facilmente funcionalizados em sua síntese. [33][34][35] A associação de dendrímeros com material gené-tico dá-se por interações eletrostáticas, principalmente com grupos amino terminais carregados positivamente. Esse é justamente um dos principais limitantes, pois essas interações podem ser facilmente deslocadas devido à força iônica dos fluidos oculares.…”

Section: Vetores Não Virais Com Base Nanotecnológica Para a Via Ocularunclassified