Browse
Submit Data
Databases
API
Help

Dataset Information

31 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Norepinephrine transporter-derived homing peptides enable rapid endocytosis of drug delivery nanovehicles into neuroblastoma cells.

ABSTRACT: BACKGROUND:Currently, the diagnosis and treatment of neuroblastomas-the most frequent solid tumors in children-exploit the norepinephrine transporter (hNET) via radiolabeled norepinephrine analogs. We aim to develop a nanomedicine-based strategy towards precision therapy by targeting hNET cell-surface protein with hNET-derived homing peptides. RESULTS:The peptides (seq. GASNGINAYL and SLWERLAYGI) were shown to bind high-resolution homology models of hNET in silico. In particular, one unique binding site has marked the sequence and structural similarities of both peptides, while most of the contribution to the interaction was attributed to the electrostatic energy of Asn and Arg (

SUBMITTER: Haddad Y

PROVIDER: S-EPMC7359476 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Norepinephrine transporter-derived homing peptides enable rapid endocytosis of drug delivery nanovehicles into neuroblastoma cells.

Haddad Yazan Y Charousova Marketa M Zivotska Hana H Splichal Zbynek Z Merlos Rodrigo Miguel Angel MA Michalkova Hana H Krizkova Sona S Tesarova Barbora B Richtera Lukas L Vitek Petr P Stokowa-Soltys Kamila K Hynek David D Milosavljevic Vedran V Rex Simona S Heger Zbynek Z

Journal of nanobiotechnology 20200713 1

<h4>Background</h4>Currently, the diagnosis and treatment of neuroblastomas-the most frequent solid tumors in children-exploit the norepinephrine transporter (hNET) via radiolabeled norepinephrine analogs. We aim to develop a nanomedicine-based strategy towards precision therapy by targeting hNET cell-surface protein with hNET-derived homing peptides.<h4>Results</h4>The peptides (seq. GASNGINAYL and SLWERLAYGI) were shown to bind high-resolution homology models of hNET in silico. In particular, ...[more]

PMID: 32660596

Similar Datasets

Imaging the norepinephrine transporter in neuroblastoma: a comparison of [18F]-MFBG and 123I-MIBG.

Project description:The norepinephrine transporter (NET) is a critical regulator of catecholamine uptake in normal physiology and is expressed in neuroendocrine tumors like neuroblastoma. Although the norepinephrine analog, meta-iodobenzylguanidine (MIBG), is an established substrate for NET, (123)I/(131)I-MIBG has several clinical limitations for diagnostic imaging. In the current studies, we evaluated meta-[(18)F]-fluorobenzylguanidine ([(18)F]-MFBG) and compared it with (123)I-MIBG for imaging NET-expressing neuroblastomas.NET expression levels in neuroblastoma cell lines were determined by Western blot and (123)I-MIBG uptake assays. Five neuroblastoma cell lines and two xenografts (SK-N-BE(2)C and LAN1) expressing different levels of NET were used for comparative in vitro and in vivo uptake studies.The uptake of [(18)F]-MFBG in cells was specific and proportional to the expression level of NET. Although [(18)F]-MFBG had a 3-fold lower affinity for NET and an approximately 2-fold lower cell uptake in vitro compared with that of (123)I-MIBG, the in vivo imaging and tissue radioactivity concentration measurements demonstrated higher [(18)F]-MFBG xenograft uptake and tumor-to-normal organ ratios at 1 and 4 hours after injection. A comparison of 4 hours [(18)F]-MFBG PET (positron emission tomography) imaging with 24 hours (123)I-MIBG SPECT (single-photon emission computed tomography) imaging showed an approximately 3-fold higher tumor uptake of [(18)F]-MFBG, but slightly lower tumor-to-background ratios in mice.[(18)F]-MFBG is a promising radiopharmaceutical for specifically imaging NET-expressing neuroblastomas, with fast pharmacokinetics and whole-body clearance. [(18)F]-MFBG PET imaging shows higher sensitivity, better detection of small lesions with low NET expression, allows same day scintigraphy with a shorter image acquisition time, and has the potential for lower patient radiation exposure compared with (131)I/(123)I-MIBG.

| S-EPMC4072734 | biostudies-literature

Inorganic Kernel-Reconstituted Lipoprotein Biomimetic Nanovehicles Enable Efficient Targeting "Trojan Horse" Delivery of STAT3-Decoy Oligonucleotide for Overcoming TRAIL Resistance.

Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in a variety of tumor cells, but not most normal cells. Nevertheless, its therapeutic potential is limited due to the frequent occurrence of resistance in tumor cells, especially hepatocellular carcinoma cell lines. Therefore, we investigated the reversal effect of STAT3-decoy oligonucleotides (ODNs) on TRAIL resistance. Methods. Considering that the drawback of poor cellular permeability and rapid degradation in vivo limited ODNs' further clinical applications, we developed a biomimetic calcium phosphate-reconstituted low density lipoprotein nanovehicle (CaP@LDL) that would serve as a "Trojan horse" to carry STAT3-decoy ODNs into tumor cells and then regulate TRAIL-induced apoptosis. Results. In comparison with native ODNs, the reconstituted CaP@LDL packaged ODNs showed significantly increased serum stability, cellular transfection, in vitro synergistic cytotoxicity and apoptosis in hepatoma cells, while there was no cytotoxicity to normal cells. The improved TRAIL sensitization is attributed to blocking of STAT3 signaling and consequent expression of the downstream target antiapoptotic gene. Following systemic administration, CaP@LDL displayed LDL-mimicking pharmacokinetic behavior such as attenuated blood clearance as well as enhanced accumulation in tumor and hepatorenal sites. With the synergistic combination of decoyODN/CaP@LDL, TRAIL dramatically inhibited hepatic tumor growth in a xenograft model and induced significant tumor apoptosis in vivo. Conclusion. These results suggested that CaP@LDL-mediated STAT3-decoy ODN delivery might be a promising new strategy for reversing TRAIL resistance in hepatocellular carcinoma therapy.

| S-EPMC5695144 | biostudies-literature

Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems.

Project description:PurposeHistone deacetylase (HDAC) inhibition causes transcriptional activation or repression of several genes that in turn can influence the biodistribution of other chemotherapeutic agents. Here, we hypothesize that the combination of vorinostat, a HDAC inhibitor, with (131)I-meta-iodobenzylguanidine (MIBG) would lead to preferential accumulation of the latter in neuroblastoma (NB) tumors via increased expression of the human norepinephrine transporter (NET).Experimental designIn vitro and in vivo experiments examined the effect of vorinostat on the expression of NET, an uptake transporter for (131)I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691-luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on (123)I-MIBG biodistribution.ResultsPreincubation of NB cell lines, Kelly, and SH-SY-5Y, with vorinostat caused dose-dependent increases in NET mRNA and protein levels. Accompanying this was a corresponding dose-dependent increase in MIBG uptake in NB cell lines. Four- and 2.5-fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pretreated with vorinostat in comparison to untreated cells. Similarly, NB xenografts, created by intravenous tail vein injection of NB1691-luc, and harvested from nude mice livers treated with vorinostat (150 mg/kg i.p.) showed substantial increases in NET protein expression. Maximal effect of vorinostat pretreatment in NB xenografts on (123)I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat-treated [0.062 ± 0.011 μCi/(mg tissue-dose injected)] vs. -untreated mice [0.022 ± 0.003 μCi/(mg tissue-dose injected); P < 0.05].ConclusionsThe results of our study provide preclinical evidence that vorinostat treatment can enhance NB therapy with (131)I-MIBG.

| S-EPMC3247296 | biostudies-literature

Silk-based nanocomplexes with tumor-homing peptides for tumor-specific gene delivery.

Project description:Nanoscale complexes of recombinant silk molecules containing THPs with DNA are designed as less cytotoxic and highly target-specific gene carriers. Genetically engineered silk proteins containing poly(L-lysine) domains to interact with pDNA and the THP to bind to specific tumorigenic cells for target-specific pDNA delivery are prepared, followed by in vitro transfection into MDA-MB-435 melanoma cells, highly metastatic human breast tumor MDA-MB-231?cells, and non-tumorigenic MCF-10A breast epithelial cells. The silk/poly(L-lysine) block copolymer containing Lyp1 (ML-Lyp1) shows significant differences from silk/poly(L-lysine) block copolymer containing F3 (ML-F3) in cytotoxicity to MCF10A cells. ML-F3 is the most promising candidate for target delivery into tumorigenic cells.

| S-EPMC3724333 | biostudies-literature

Norepinephrine transporter-deficient neural crest cells

Project description:Background: The goal of this study was to determine the transcriptional consequences of norepinephrine transporter (NET) gene deletion in noradrenergic neuron differentiation. The norepinephrine transporter (NET) is the target of powerful mind-altering substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET function in adult noradrenergic neurons of the peripheral and central nervous systems is that of a scavenger that internalizes norepinephrine from the synaptic cleft. By contrast, norepinephrine (NE) transport has a different role in embryogenesis. It promotes differentiation of neural crest cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors, such as the tricyclic antidepressant desipramine and the drug of abuse, cocaine, inhibit noradrenergic differentiation. While NET structure und regulation of NET function is well described, little is known about downstream targets of NE transport. Results: We have determined by long serial analysis of gene expression (LongSAGE) the gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) neural crest derivatives. Comparison analyses with the wild type library (GSM 105765) have identified a number of important differentially expressed genes, including genes relevant to noradrenergic neuron differentiation and to the phenotype of NETKO mice. Furthermore we have identified novel differentially expressed genes. Conclusions: Loss of NET function during embryonic development deregulates signaling pathways that are critically involved in neural crest formation and noradrenergic neuron differentiation.

2008-06-23 | GSE11788 | GEO

Norepinephrine transporter-deficient neural crest cells

2008-06-23 | E-GEOD-11788 | biostudies-arrayexpress

Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group.

Project description:Purpose. (123)I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N = 82) and immunohistochemistry (IHC; N = 61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performed. Results. Median NET mRNA expression level for the 19 MIBG avid patients was 12.9% (range 1.6-73.7%) versus 5.9% (range 0.6-110.0%) for the 8 nonavid patients (P = 0.31). Median percent NET protein expression was 50% (range 0-100%) in MIBG avid patients compared to 10% (range 0-80%) in nonavid patients (P = 0.027). MYCN amplified tumors had lower NET protein expression compared to nonamplified tumors (10% versus 50%; P = 0.0002). Conclusions. NET protein expression in neuroblastoma correlates with MIBG avidity. MYCN amplified tumors have lower NET protein expression.

| S-EPMC3463166 | biostudies-literature

Tumor-homing peptides as tools for targeted delivery of payloads to the placenta.

Project description:The availability of therapeutics to treat pregnancy complications is severely lacking mainly because of the risk of causing harm to the fetus. As enhancement of placental growth and function can alleviate maternal symptoms and improve fetal growth in animal models, we have developed a method for targeted delivery of payloads to the placenta. We show that the tumor-homing peptide sequences CGKRK and iRGD bind selectively to the placental surface of humans and mice and do not interfere with normal development. Peptide-coated nanoparticles intravenously injected into pregnant mice accumulated within the mouse placenta, whereas control nanoparticles exhibited reduced binding and/or fetal transfer. We used targeted liposomes to efficiently deliver cargoes of carboxyfluorescein and insulin-like growth factor 2 to the mouse placenta; the latter significantly increased mean placental weight when administered to healthy animals and significantly improved fetal weight distribution in a well-characterized model of fetal growth restriction. These data provide proof of principle for targeted delivery of drugs to the placenta and provide a novel platform for the development of placenta-specific therapeutics.

| S-EPMC4928982 | biostudies-literature

Phosphobisaromatic motifs enable rapid enzymatic self-assembly and hydrogelation of short peptides.

Project description:Enzyme-instructed self-assembly (EISA) and hydrogelation is a versatile approach for generating soft materials. Most of the substrates for alkaline phosphatase catalysed EISA utilize phosphotyrosine (pTyr) as the enzymatic trigger for EISA and hydrogelation. Here we show the first example of phosphonaphthyl (pNP) and phosphobiphenyl (pBP) motifs acting as faster enzymatic triggers than phosphotyrosine for EISA and hydrogelation. This work illustrates novel enzyme triggers for rapid enzymatic self-assembly and hydrogelation.

| S-EPMC8600407 | biostudies-literature

BG-P400TAT, A Dual Targeting of Norepinephrine Transporter Function and Thyrointegrin αvβ3 receptors to Treat Neuroblastoma cancer

Project description:To explore molecular mechanisms of anti-cancer activities of BG-P400-TAT, genome-wide expression profiling experiments were carried out . Human neuroblastoma SKNAS cells were treated with 30µM of the BG-P400-TAT for 48 hours, harvested, and immediately processed for RNA isolation from three biological replicates of control and drug-treated cells. BG-P400-TAT targets among intracellular multiprotein complexes NF-kB complex, Survivin complex, Bcl-2 complex, and VEGF-A complex and integrated with signal transduction pathways of EGF, FGF1, AR, estradiol, TNF, and IL-1

2021-09-03 | GSE183170 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data