Alpha‐Tocopheryl Succinate‐Conjugated G5 PAMAM Dendrimer Enables Effective Inhibition of Ulcerative Colitis

Wang, Yunan; Shen, Wenwen; Shi, Xiangyang; Fu, Fanfan; Fan, Yu; Shen, Wanli; Cao, Yini; Zhang, Qiang; Qi, Rong

doi:10.1002/adhm.201700276

Cited by 27 publications

(20 citation statements)

References 59 publications

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“…The alteration of colons and spleens of the mice treated with DSS is reported to be an important indicator of IBD severity. As shown in Figure b, the average colon length in the normal group was significantly longer than that of the DSS treated groups, consistent with the reported data that the DSS‐induced colitis would lead to colon shortening . Compared with the DSS control, DSS+CA/s‐LNT2/DNA3 obviously increased the colon length ( p < 0.05), while both DSS+CA/s‐LNT2 and DSS+CA/DNA3 groups did not show any statistical differences.…”

Section: Resultsmentioning

confidence: 99%

Orally Delivered Antisense Oligodeoxyribonucleotides of TNF‐α via Polysaccharide‐Based Nanocomposites Targeting Intestinal Inflammation

Duan

Sun

et al. 2019

Adv Healthcare Materials

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has been regarded as an alternative strategy to treat IBD by downregulating TNF-α levels produced by the activated macrophages. [17][18][19][20] However, the success of RNAi has to mainly rely on the gene carriers to protect the target genes. Many researchers have been working on the discovery of drug and gene carriers with high efficiency and biocompatibility. [21][22][23][24][25] Electrostatic condensation of macromolecular genes into nanoparticles by cationic carriers has been acknowledged to be a common strategy for the nonviral delivery. [26][27][28] As reported, polycations acting as gene carriers possess such limitation as lack of superior biocompatibility, insufficient release of delivered genes, easy absorption, and quick elimination in the bloodstream. [29][30][31][32] Therefore, developing new delivery strategies is necessitated to substantially overcome these shortcomings for promoting application of RNAi technology.Polysaccharides such as schizophyllan, curdlan, yeast glucan, lentinan, and auricularian have been introduced as soft matrices to accommodate inorganic nanoparticles, fluorescent dyes, drugs, and oligonucleotides for versatile therapeutic functions due to their unique structural characteristics. [33] Of these, lentinan (LNT for short) has been demonstrated to exist as a triple helix (denoted t-LNT) in water and as a single flexible chain (denoted s-LNT) under such conditions as in dimethyl sulfoxide (DMSO), [34,35] in aqueous sodium hydroxide (NaOH) solution with the NaOH concentration higher than 0.08 m, [36] and in water at the temperature of higher than 135 °C. [37] When the DMSO content decreases gradually through adding water or dialysis against water, the s-LNT chains reassemble into the triple helix (denoted r-LNT) owing to the hydrophobic and hydrogen bonding interactions. [38] Moreover, when single polydeoxyadenylic acid (poly(dA)) chains are added during the reassembling process of s-LNT, two s-LNT chains are able to selectively combine a poly(dA) chain via hydrogen bonding to form a novel triple helical hybrid (denoted s-LNT/ poly(dA)) with high thermal stability under the physiological condition, [39] effectively protecting poly(dA) from degradation. Based on these findings, we have established a promising gene delivering vehicle based on the s-LNT/poly(dA) nanocomposite, in which an immune gene of CpG DNA was linked with a poly(dA) tail through a disulfide bond to stimulate IL-12p40 Tumor necrosis factor alpha (TNF-α) is usually regarded as a potential target for inflammatory bowel disease therapy. Herein, a promising strategy for effective delivery of phosphorothioated antisense oligodeoxyribonucleotide of TNF-α (PS-ATNF-α), targeting the intestinal inflammation based on the interaction of the single chain of triple helical β-glucan (s-LNT) with polydeoxyadenylic acid [poly(dA)], and the colon-specific degradation of chitosanalginate (CA) hydrogel, is reported. The target gene of PS-ATNF-α, with a poly(dA) tail through a disulfide bond (-SS-), interacts with s-LNT to form a r...

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Section: Resultsmentioning

confidence: 99%

Orally Delivered Antisense Oligodeoxyribonucleotides of TNF‐α via Polysaccharide‐Based Nanocomposites Targeting Intestinal Inflammation

Duan

Sun

et al. 2019

Adv Healthcare Materials

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“…Moreover, the expression of antioxidative factors in a gene level was also assessed by real time-polymerase chain reaction (RT-PCR) according to literature protocols. [12] As shown in Figure 3d-f, the mRNA expression of heme oxygenase 1 (HO-1), superoxide dismutase 2 (SOD-2), and NADPH oxidase 2 (NOX-2) genes is greater in the LPS-activated RAW264.7 cells than in the normal RAW264.7 cells. After treatment with L1, L2, or free α-TOS, the mRNA expression of the above three genes decreases and the relative expression of HO-1 and NOX-2 in different groups is in an order of L2 > free α-TOS > L1 in the LPS-activated RAW264.7 cells.…”

Section: Combined Antioxidative and Anti-inflammatory Therapy Of Macrmentioning

confidence: 94%

“…As is known, the highly efficient ROS elimination capacity of α-TOS plays a major role in antioxidant therapy of dysfunctional macrophages. [12] We next examined the ROS level of activated RAW264.7 cells treated with both L1 and L2 via fluorescence microscopic imaging ( Figure S11, Supporting Information) and flow cytometry assay (Figure 3c) of cells treated with a ROS probe, 2',7'-dichlorofluorescein diacetate (DCFH-DA) emitting green fluorescence signals. Apparently, as opposed to the regular macrophage cells having no ROS production, the positive control of LPS-treated cells displays significant ROS production.…”

Section: Combined Antioxidative and Anti-inflammatory Therapy Of Macrmentioning

confidence: 99%

Targeted Combination of Antioxidative and Anti‐Inflammatory Therapy of Rheumatoid Arthritis using Multifunctional Dendrimer‐Entrapped Gold Nanoparticles as a Platform

Chen

et al. 2020

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Abundant reactive oxygen species and tumor necrosis factor-α (TNF-α) cytokine supply of M1-type macrophages boost rheumatoid arthritis (RA) pathological process. For efficient RA therapy, here a multifunctional nanoplatform is presented based on generation 5 (G5) poly(amidoamine) dendrimer-entrapped gold nanoparticles (Au DENPs) to achieve co-delivery of antioxidant alpha-tocopheryl succinate (α-TOS) and anti-inflammatory anti-TNF-α siRNA to macrophage cells. G5 dendrimers with amine termini are sequentially functionalized with 1,3-propane sultone (1,3-PS), α-TOS through a polyethylene glycol (PEG) spacer, and PEGylated folic acid (FA), and subsequently entrapped with Au NPs. The generated functional Au DENPs exhibit desired cytocompatibility, zwitterion-rendered antifouling property, and FAmediated targeting specificity, enabling serum-enhanced siRNA delivery to M1-type macrophage cells. Meanwhile, the attached α-TOS affords enhanced oxidation resistance of macrophage cells. In vivo investigation shows that the treatment of a collagen-induced arthritis mouse model using α-TOSmodified Au DENPs/TNF-α siRNA polyplexes can achieve excellent combination therapy effect in inflammatory cytokines downregulation of RA lesion and bone erosions. The therapeutic efficacy is also supported by 3D microcomputed tomography analysis and TNF-α cytokine reduction of RA lesion joints in the mRNA, protein, and histology levels. The created multifunctional nanoplatform may be employed in antioxidative and anti-inflammatory combination therapy of RA.

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“…However, the changes of gastrointestinal pH, transit time, enzyme and microbiome are unclear in the development of IBD, which results in aimless drug release, unsatisfactory therapeutic efficacy and enhanced ADR 8 . In recent years, novel nanocarriers, like liposome 9 , nanoparticle 10 , hydrogel 11 , dentrimer 12 , have received substantial attention and investigation due to their excellent physicochemical properties. The tissue permeability is increased in the inflamed colon, due to destroyed intestinal tight junction, the loss of cellular integrity and the infiltration of immune cells caused by inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies

Liu

Gao

Hong-guo

et al. 2021

Acta Pharmaceutica Sinica B

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Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.

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Alpha‐Tocopheryl Succinate‐Conjugated G5 PAMAM Dendrimer Enables Effective Inhibition of Ulcerative Colitis

Cited by 27 publications

References 59 publications

Orally Delivered Antisense Oligodeoxyribonucleotides of TNF‐α via Polysaccharide‐Based Nanocomposites Targeting Intestinal Inflammation

Orally Delivered Antisense Oligodeoxyribonucleotides of TNF‐α via Polysaccharide‐Based Nanocomposites Targeting Intestinal Inflammation

Targeted Combination of Antioxidative and Anti‐Inflammatory Therapy of Rheumatoid Arthritis using Multifunctional Dendrimer‐Entrapped Gold Nanoparticles as a Platform

Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies

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