Delivery Systems and Local Administration Routes for Therapeutic siRNA

Vicentini, Fabiana T. M. C.; Borgheti-Cardoso, Lívia Neves; Depieri, Lívia Vieira; Mano, Danielle de Macedo; Abelha, Thais Fedatto; Petrilli, Raquel; Bentley, Maria Vitória Lopes Badra

doi:10.1007/s11095-013-0971-1

Cited by 93 publications

(73 citation statements)

References 136 publications

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“…22 Thus, nonviral siRNA delivery systems based on polymers, lipids, and proteins have been developed. [23][24][25] Low-density lipoprotein (LDL) isolated from human plasma contains a hydrophobic core surrounded by a phospholipid monolayer with apolipoprotein B-100, which can be recognized by the LDL receptor (LDLr) that is abundantly expressed in tumor membranes via active lysine residues.…”

Section: Introductionmentioning

confidence: 99%

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

Zhu¹,

Yang²,

Qu³

et al. 2017

IJN

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Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new “binary polymer” low-density lipoprotein– N -succinyl chitosan–cystamine–urocanic acid (LDL–NSC–SS–UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA–PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA–PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

Zhu¹,

Yang²,

Qu³

et al. 2017

IJN

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“…21 Recently, local gene delivery systems have yielded promising results, some of which are currently undergoing testing in clinical trials. 22 Vascular endothelial growth factor (VEGF) is an important angiogenic factor. One of its key functions is stimulating vasculogenesis and angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury

Tian¹,

Cao²,

Zou³

et al. 2015

IJN

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Upregulation of vascular endothelial growth factor (VEGF) expression can inhibit intimal thickening after vascular injury. However, the lack of efficient gene delivery systems leads to insufficient VEGF expression, which prevents its application in gene therapy. In the present study, to improve the delivery of the plasmid vector with the VEGF gene (pVEGF165) to the injured vessel wall, we explored the potentially important difference between endothelial cell-targeted and nontargeted polymeric carriers. The α v β 3 integrin is overexpressed on activated endothelial cells but not on normal quiescent vessels. In this study, CDG2-cRGD, synthesized by conjugating an α v β 3 integrin-binding cyclic arginylglycylaspartic acid (cRGD) peptide with the Generation 2 polycation polyamidoamine (PAMAMG2)-g-cyclodextrin (termed as CDG2), was developed as a targetable carrier. It was observed that the specific integrin–ligand interactions greatly enhanced cellular internalization of CDG2-cRGD in human umbilical vein endothelial cells (HUVECs), which are notoriously difficult to transfect. Consequently, HUVECs were found to show remarkably high levels of VEGF165 expression induced by the CDG2-cRGD polyplex. Interestingly, VEGF165 overexpression in vivo was more complex than that in vitro, and in vivo assays demonstrated that the stimulus response to balloon injury in arteries could obviously upregulate VEGF165 expression in the saline-treated group, although it was not enough to prevent intimal thickening. In gene-transfected groups, intravascular delivery of pVEGF165 with the CDG2-cRGD polyplex into rabbits after vascular injury resulted in a significant inhibition of intimal thickening at 4 weeks, whereas the low therapeutic efficacy in the nontargeted CDG2-treated group was only comparable to that in the saline-treated group. It is becoming clear that the conflicting results of VEGF165 gene therapy in two gene-transfected groups are reflective of the pivotal role of the cRGD-conjugated carriers in achieving the beneficial therapeutic effects of vascular gene therapy.

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“…Na fase de execução, o siRNA e o miRNA são incorporados em complexos proteicos denominados RISC (RNA Induced Silencing Complex). Uma helicase presente neste complexo abre a dupla-fita do siRNA, a fita antisense é usada como guia para reconhecer o RNAm alvo, que é clivado pelo complexo, degradando-o (DE PAULA; BENTLEY; MAHATO, 2007;ELBASHIR;LENDECKEL;TUSCHL, 2001;VICENTINI et al, 2013b;WHITEHEAD;ANDERSON, 2009 MAHATO, 2007;MASIERO et al, 2007;WHITEHEAD;ANDERSON, 2009), isto porque em princípio qualquer alvo pode ser inibido, o siRNA é especifico, facilmente sintetizado e será sempre uma molécula com as mesmas características físico-químicas (BUMCROT et al, 2006;DAKA;PEER, 2012;XU;WANG, 2015). RNAi tem mostrado potencial para tratar diversas doenças incluindo desordens da pele (JACOBSON et al, 2010;VICENTINI et al, 2013a), aterosclerose (LI et al, 2010), câncer (ABBASI et al, 2011;ARIMA et al, 2012;HSU et al, 2013;TARATULA et al, 2011) e infecções virais (ALVAREZ et al, 2009;BITKO et al, 2005;DEVINCENZO et al, 2008DEVINCENZO et al, , 2010LI et al, 2005;ZAMORA et al, 2011).…”

Section: Interferência Por Rna (Rnai)unclassified

Sistemas líquido cristalinos de geleificação in situ de administração intratumoral para liberação localizada de siRNA na terapia do câncer de pele

Cardoso¹

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Delivery Systems and Local Administration Routes for Therapeutic siRNA

Cited by 93 publications

References 136 publications

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury

Sistemas líquido cristalinos de geleificação in situ de administração intratumoral para liberação localizada de siRNA na terapia do câncer de pele

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