In Vivo Gene Transfer to Dopamine Neurons of Rat Substantia Nigra via the High-Affinity Neurotensin Receptor

Álvarez-Maya, Ikuri; Navarro-Quiroga, Iván; Meraz-Ríos, Marco Antonio; Aceves, Jorge; Martínez‐Fong, Daniel

doi:10.1007/bf03401952

Cited by 37 publications

(43 citation statements)

References 37 publications

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“…The NT-polyplex is an attractive alternative because it is specific, effective, biodegradable and nontoxic. 1,3,5,8,12 The new advantage of the NT-polyplex shown in this study is the ability to effectively transfect tumoral cells after its administration through the blood stream. This feature will be of great use to target metastasis sites very small or unreachable by surgery.…”

Section: Discussionmentioning

confidence: 93%

“…These results support that the systemic transfection of the NT-polyplex depends on NTSR1, as shown previously using blockage assays with either NT (1 mM) or SR 48692, a synthetic NT competitive antagonist. 1,3,5,8 The specificity was also demonstrated by the negative results of internalization and expression assays after the systemic transfection with an untargeted polyplex (without the ligand NT) or the KP-pDNA complex. The second conclusion is that the specific transfection of a suicide gene into neuroblastoma tumor cells expressing NTSR1 causes a therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

“…8 The first use of the NT-polyplex in gene therapy was the transfection of the GDNF gene in nigral dopaminergic neurons in an animal model of Parkinson's disease, because these neurons express 4,10 and internalize NTSR1. 5,8,11 The efficacy of the NT-polyplex is supported by the morphological and functional recovery from dopaminergic neurodegeneration in experimental hemiparkinsonism. 12 The neuroblastoma, an embryonic tumor derived from the neural crest, is the second most common solid tumor in childhood, 13 with invasion of locoregional nodes and distant metastasis in approximately 75% of cases in children older than 1 year.…”

Section: Introductionmentioning

confidence: 99%

“…3 The tridecapeptide NT is the natural ligand of NTSR1 4 that on its activation causes NT-polyplex endocytosis. 2,5 The FP (22 amino acids) is the pH-sensitive HA2-fusion domain from the influenza virus hemagglutinin known to cause membrane fusion and leakage of a lipid bilayer in endosomes. 6 This peptide is used to prevent pDNA degradation in the acidic endosomes.…”

Section: Introductionmentioning

confidence: 99%

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NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

et al. 2009

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and 4 Molecular and Steroid hormones, Neurotensin and Tumor Progression INSERM UPMC Cdr Saint-Antoine Eq 7, Paris, France Neurotensin (NT)-polyplex is a nonviral system for the targeted gene delivery to cells that express and internalize the high-affinity NT receptor (NTSR1). In hemiparkinsonian rats, we previously demonstrated the morphological and functional recovery from dopaminergic neurodegeneration using the NT-polyplex as a vehicle to transfect a neurotrophic gene. The main objective of this work was to demonstrate the feasibility of NT-polyplex to transfect reporter or therapeutic genes into neuroblastoma tumors through the blood stream or by intratumoral injection. N1E-115 cells known to express NTSR1 were allografted into athymic mice to generate the neuroblastoma tumor model. Both routes of administration allowed the NT-polyplex to reach and transfect tumoral cells. A low transgene expression was also detected in intestinal tract cells only after the injection into the blood stream. The transfection of the thymidine kinase (HSVTK) suicide gene followed by ganciclovir (GCV) treatment decreased the size and weight of neuroblastoma tumors by 30-50% and increased apoptosis compared to controls. This study shows the potential of the NTpolyplex as specific gene-transfer system for NTSR1 cancer cells.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

et al. 2009

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“…The neurotensin (NTS)-polyplex consists of synthetic nanoparticles that can transfer plasmid DNA (pDNA) encoding any gene of interest into cells that express and internalize the NTSR1, including dopaminergic neurons [25]–[28] and cancer cells [24], [29]. The NTS-polyplex nanoparticles result from the compaction of a pDNA via the electrostatic binding of the Vp1 SV40 karyophilic peptide (KP) and the NTS-carrier, which is a conjugate of poly-L-lysine (PLL), NTS, and the hemagglutinin-derived HA2 fusogenic peptide (FP) [25], [30].…”

Section: Introductionmentioning

confidence: 99%

Suicide HSVtk Gene Delivery by Neurotensin-Polyplex Nanoparticles via the Bloodstream and GCV Treatment Specifically Inhibit the Growth of Human MDA-MB-231 Triple Negative Breast Cancer Tumors Xenografted in Athymic Mice

et al. 2014

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The human breast adenocarcinoma cell line MDA-MB-231 has the triple-negative breast cancer (TNBC) phenotype, which is an aggressive subtype with no specific treatment. MDA-MB-231 cells express neurotensin receptor type 1 (NTSR1), which makes these cells an attractive target of therapeutic genes that are delivered by the neurotensin (NTS)-polyplex nanocarrier via the bloodstream. We addressed the relevance of this strategy for TNBC treatment using NTS-polyplex nanoparticles harboring the herpes simplex virus thymidine kinase (HSVtk) suicide gene and its complementary prodrug ganciclovir (GCV). The reporter gene encoding green fluorescent protein (GFP) was used as a control. NTS-polyplex successfully transfected both genes in cultured MDA-MB-231 cells. The transfection was demonstrated pharmacologically to be dependent on activation of NTSR1. The expression of HSVtk gene decreased cell viability by 49% (P<0.0001) and induced apoptosis in cultured MDA-MB-231 cells after complementary GCV treatment. In the MDA-MB-231 xenograft model, NTS-polyplex nanoparticles carrying either the HSVtk gene or GFP gene were injected into the tumors or via the bloodstream. Both routes of administration allowed the NTS-polyplex nanoparticles to reach and transfect tumorous cells. HSVtk expression and GCV led to apoptosis, as shown by the presence of cleaved caspase-3 and Apostain immunoreactivity, and significantly inhibited the tumor growth (55–60%) (P<0.001). At the end of the experiment, the weight of tumors transfected with the HSVtk gene was 55% less than that of control tumors (P<0.05). The intravenous transfection did not induce apoptosis in peripheral organs. Our results offer a promising gene therapy for TNBC using the NTS-polyplex nanocarrier.

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Plasmid DNA–Mediated Gene Therapy

Banerjee

Huang

2003

Burger's Medicinal Chemistry and Drug Discovery

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Non‐viral gene delivery has earned a special position in gene therapy because of its less immunogenic and less toxic effect than the viral counter part. One of the methods is direct injection of naked DNA to the organs of interest. Plasmid DNA (pDNA) that carry recombinant genes of interest are used for introducing genes to cells and organs. Various physical methods, e.g., gene gun and electroporation, increase the efficiency of the naked DNA incorporation. Lipid‐based vectors have the advantage of protecting the DNA against degradation by endogenous DNAase in vivo and can be targeted to specific cellular site in some special cases. A variety of lipid‐based systems have been designed, mostly containing cationic lipids of different structures. Second‐generation vectors containing polymers are more stable and more targetable than the first‐generation vectors. Although significant progress has been made, non‐viral vectors are still limited by their efficiency and some cytotoxicity inherited in the bacterial pDNA. Understanding mechanisms and means to overcome the cellular barriers for the DNA delivery will undoubtly promote further development of pDNA mediated gene delivery.

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In Vivo Gene Transfer to Dopamine Neurons of Rat Substantia Nigra via the High-Affinity Neurotensin Receptor

Cited by 37 publications

References 37 publications

NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

Suicide HSVtk Gene Delivery by Neurotensin-Polyplex Nanoparticles via the Bloodstream and GCV Treatment Specifically Inhibit the Growth of Human MDA-MB-231 Triple Negative Breast Cancer Tumors Xenografted in Athymic Mice

Plasmid DNA–Mediated Gene Therapy

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