The role of caveolin-1 and syndecan-4 in the internalization of PEGylated PAMAM dendrimer polyplexes into myoblast and hepatic cells

Shen, Wenwen; Dongen, Mallory A. van; Han, Yingchun; Yu, Maomao; Li, Yanzhi; Liu, George; Holl, Mark M. Banaszak; Qi, Rong

doi:10.1016/j.ejpb.2014.07.010

Cited by 19 publications

(14 citation statements)

References 34 publications

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“…It was a critical step before released plasmid could further translocate into the nucleus for transcription and translation. Those observations are consistent with facilitated gene transfection delivered by PEGylated-PAMAM dendrimer reported by other researchers [60, 61]. …”

Section: Resultssupporting

confidence: 93%

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis

Lancina

Wang

et al. 2017

Biomaterials

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Current atherosclerosis treatment strategies primarily focus on limiting further cholesteryl esters (CE) accumulation by reducing endogenous synthesis of cholesterol in the liver. No therapy is currently available to enhance the removal of CE, a crucial step to reduce the burden of the existing disease. Given a central role of hepatic cholesteryl ester hydrolase (CEH) in intrahepatic hydrolysis of CE and subsequent removal of the resulting free cholesterol, in this work, we applied galactose-functionalized polyamidoamine (PAMAM) dendrimer G5 (Gal-G5) for hepatocyte-specific delivery of CEH expression vector. The data presented herein show increased specific uptake of Gal-G5 by the hepatocytes in vitro and in vivo. Furthermore, the upregulated CEH expression in the hepatocytes significantly enhanced intracellular hydrolysis of HDL-CE and subsequent conversion/secretion of hydrolyzed free cholesterol (FC) as bile acids. Increased CEH expression in the liver significantly increased the flux of HDL-CE to biliary as well as fecal FC and bile acids. Meanwhile, Gal-G5 did not induce hepatic or renal toxicity. It was not immunotoxic. Because of these encouraging pre-clinical testing results, using this safe and highly efficient hepatocyte-specific gene delivery platform to enhance the hepatic processes involved in cholesterol elimination is a promising strategy for alleviation of atherosclerosis.

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Section: Resultssupporting

confidence: 93%

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis

Lancina

Wang

et al. 2017

Biomaterials

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“…For example, PEGylation can be used to increase water solubility, permeability, stability; dendrimer size can be properly retained to have favorable retention and biodistribution characteristics; therapeutic agents can be internalized into the void space between the branches or covalently attached to surface groups; and addition of targeting moieties/ligands can bring about binding to the dendrimer surface to selectively deliver the drug to diseased cells. Dendrimers usually cross cellular barriers by endocytosis; 60 , 61 thus, they are entrapped in endososomes and only a small amount of the active drug can reach the intracellular target. However, most dendrimers exhibit toxic and hemolytic activity due to their positively charged surface.…”

Section: Discussionmentioning

confidence: 99%

A study on the hemocompatibility of dendronized chitosan derivatives in red blood cells

Zhou¹,

Li²,

Lu³

et al. 2015

DDDT

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Dendrimers are hyperbranched macromolecules with well-defined topological structures and multivalent functionalization sites, but they may cause cytotoxicity due to the presence of cationic charge. Recently, we have introduced alkyne-terminated poly(amidoamine) (PAMAM) dendrons of different generations (G=2,3) into chitosan to obtain dendronized chitosan derivatives [Cs-g-PAMAM (G=2,3)], which exhibited a better water solubility and enhanced plasmid DNA transfection efficiency. In this study, we attempted to examine the impact of Cs-g-PAMAM (G=2,3) at different concentrations (25 μg/mL, 50 μg/mL, and 100 μg/mL) on the morphology, surface structure, and viability of rat red blood cells (RBCs). The results showed that treatment of RBCs with Cs-g-PAMAM (G=2,3) at 50 μg/mL and 100 μg/mL induced a slightly higher hemolysis than Cs, and Cs-g-PAMAM (G=3) caused a slightly higher hemolysis than Cs-g-PAMAM (G=2), but all values were <5.0%. Optical microscopic and atomic force microscopic examinations indicated that Cs-g-PAMAM (G=2,3) caused slight RBC aggregation and lysis. Treatment of RBCs with 100 μg/mL Cs-g-PAMAM (G=3) induced echinocytic transformation, and RBCs displayed characteristic irregular contour due to the folding of the periphery. Drephanocyte-like RBCs were observed when treated with 100 μg/mL Cs-g-PAMAM (G=3). Erythrocytes underwent similar shape transition upon treatment with Cs-g-PAMAM (G=2) or Cs. The roughness values (Rms) of RBCs incubated with Cs-g-PAMAM (G=2,3) were significantly larger than those for RBCs incubated with physiological saline (P<0.01), but the Rms showed no difference for Cs and Cs-g-PAMAM (G=2,3) (P>0.05). Furthermore, Cs-g-PAMAM (G=2,3) exhibited a lower cytotoxicity in human kidney 293T cells. These results indicate that Cs-g-PAMAM (G=2,3) are hemocompatible but may disturb membrane and lipid structures at higher concentrations. Further safety and biocompatibility evaluations are warranted for Cs-g-PAMAM. Our findings prove helpful for a better understanding of the advantages of combining PAMAM dendrimers and chitosan to design and develop new, safe, and effective drug delivery vehicles.

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“…The excess of positive charges on a dendriplex surface promotes penetration through cell membranes, generally by adsorption endocytosis. Generally, endocytosis can be effected by various mechanisms: phagocytosis, adsorption endocytosis, pinocytosis, or clathrin- and caveolin-mediated endocytosis [ 67 , 68 , 69 ]. The mechanism of cell uptake of dendriplexes depends significantly on their size and can involve one or more of the mechanisms mentioned [ 70 ].…”

Section: The Mechanism Of Action Of Dendriplexes In a Cellmentioning

confidence: 99%

Dendrimers Show Promise for siRNA and microRNA Therapeutics

et al. 2018

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The lack of an appropriate intracellular delivery system for therapeutic nucleic acids (TNAs) is a major problem in molecular biology, biotechnology, and medicine. A relatively new class of highly symmetrical hyperbranched polymers, called dendrimers, shows promise for transporting small TNAs into both cells and target tissues. Dendrimers have intrinsic advantages for this purpose: their physico-chemical and biological properties can be controlled during synthesis, and they are able to transport large numbers of TNA molecules that can specifically suppress the expression of single or multiple targeted genes. Numerous chemical modifications of dendrimers extend the biocompatibility of synthetic materials and allow targeted vectors to be designed for particular therapeutic purposes. This review summarizes the latest experimental data and trends in the medical application of various types of dendrimers and dendrimer-based nanoconstructions as delivery systems for short small interfering RNAs (siRNAs) and microRNAs at the cell and organism levels. It provides an overview of the structural features of dendrimers, indicating their advantages over other types of TNA transporters.

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The role of caveolin-1 and syndecan-4 in the internalization of PEGylated PAMAM dendrimer polyplexes into myoblast and hepatic cells

Cited by 19 publications

References 34 publications

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis

A study on the hemocompatibility of dendronized chitosan derivatives in red blood cells

Dendrimers Show Promise for siRNA and microRNA Therapeutics

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