Engineering Clustered Ligand Binding Into Nonviral Vectors: αvβ3 Targeting as an Example

Ng, Quinn K. T.; Sutton, Marie K; Soonsawad, Pan; Li, Xing; Cheng, Harry H.; Segura, Tatiana

doi:10.1038/mt.2009.11

Cited by 37 publications

(43 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, a complete abolishment of transfection was not observed, suggesting that the carrier binds also through other nonspecific interactions with the cells. 42 CLSM observations further confirmed that attachment of the cRGD ligand greatly enhanced cellular internalization of the pDNA polyplex, compared with CDG2, in HUVECs that overexpress α v β 3 integrin (Figure 6), apparently through receptor-mediated endocytosis. Moreover, among the various cRGD-coupling carriers, CDG2-cRGD-5 was the most efficient carrier for delivering pDNA into HUVECs, which is in good agreement with the transfection activity of the optimal formulation.…”

Section: Discussionsupporting

confidence: 55%

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

Tian¹,

Cao²,

Zou³

et al. 2015

IJN

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 55%

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

Tian¹,

Cao²,

Zou³

et al. 2015

IJN

View full text Add to dashboard Cite

show abstract

“…The structure of viruses such as adenovirous type 2 and the surface density of their ligands have been studied to surmise the importance of multivalent ligands on binding efficiency 11 . Studies showed that penton-base proteins presented on adenovirus type 2 cover the surface of these viruses with regular spacing 11 . The surface density presented by this virus may substantially improve binding avidity to the cell receptors.…”

Section: Introductionmentioning

confidence: 99%

“…The surface density presented by this virus may substantially improve binding avidity to the cell receptors. The simulation of the natural structure of viruses based on their ligand density has been utilized to engineer targeted clustered ligands 11–12 . Studies showed that, the optimum distribution of ligands on the surface of viruses is a key factor for binding and cellular uptake.…”

Section: Introductionmentioning

confidence: 99%

Controlling Ligand Surface Density Optimizes Nanoparticle Binding to ICAM-1

Fakhari

Baoum

Siahaan

et al. 2011

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

During infection, pathogens utilize surface receptors to gain entry into intracellular compartments. Multiple receptor-ligand interactions that lead to pathogen internalization have been identified and the importance of multivalent ligand binding as a means to facilitate internalization has emerged. The effect of ligand density, however; is less well known. In this study, ligand density was examined using poly(dl-lactic-co-glycolic acid) nanoparticles (PLGA NPs). A cyclic peptide, cLABL, was used as a targeting moiety as it is a known ligand for intercellular cell adhesion molecule-1 (ICAM-1). To modulate the number of reactive sites on the surface of PLGA NPs, modified Pluronic® with carboxyl groups and Pluronic® with hydroxyl groups were combined at different ratios and the particle properties were examined. Utilizing a surfactant mixture directly affected the particle charge and the number of reactive sites for cLABL conjugation. The surface density of cLABL peptide increased as the relative amount of reactive Pluronic® was increased. Studies using carcinomic human alveolar basal epithelial cells (A549) showed that cLABL density may be optimized to improve cellular uptake. These results compliment other studies suggesting surface density of the targeting moiety on the NP surface should be considered to enhance the effect of ligands employed for cell targeting.

show abstract

“…Conjugation of folic acid with the aminomethacrylate-phosphoryl-choline based copolymer, allowed transfection of cells overexpressing the receptor for folic acid in some human tumors cells (Lam et al, 2009). A PEI-derived polyplex conjugated with an Arg-Gly-Asp peptide, which binds to the α v β 3 integrin receptor, resulted in efficient transfection of HeLa cells with low and high densities of α v β 3 integrin (Ng et al, 2009). As observed in viral vectors and lipoplexes, antibodies can be also conjugated with polyplexes to target genetic material to specific cell types.…”

Section: Polyplexesmentioning

confidence: 99%