Triggered intracellular activation of disulfide crosslinked polyelectrolyte gene delivery complexes with extended systemic circulation in vivo

Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. However, the site-specific delivery of common gene vectors such as adeno-associated viruses (AAVs) is typically performed via invasive injections, limiting their scope of research and clinical applications. Alternatively, focused ultrasound blood-brain-barrier opening (FUS-BBBO), performed noninvasively, enables the site-specific entry of AAVs into the brain from systemic circulation. However, when used in conjunction with natural AAV serotypes, this approach has limited transduction efficiency, requires ultrasound parameters close to tissue damage limits, and results in undesirable transduction of peripheral organs. Here, we use high throughput in vivo selection to engineer new AAV vectors specifically designed for local neuronal transduction at the site of FUS-BBBO. The resulting vectors substantially enhance ultrasound-targeted gene delivery and neuronal tropism while reducing peripheral transduction, providing a more than ten-fold improvement in targeting specificity. In addition to enhancing the only known approach to noninvasively target gene delivery to specific brain regions, these results establish the ability of AAV vectors to be evolved for specific physical delivery mechanisms.

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1004: In-Vivo Transfection of the Rat Corpus Cavernosum Using a Non-Viral, Linear Polyethylenimine Gene Delivery System: A Novel Application

The Journal of Urology ◽

10.1016/s0022-5347(18)33229-4 ◽

2006 ◽

Vol 175 (4S) ◽

pp. 323-324 ◽

Cited By ~ 1

Author(s):

Joseph Dall'era ◽

Sweaty Koul ◽

Jesse Mills ◽

Jeremy Myers ◽

Randall B. Meacham ◽

...

Keyword(s):

Gene Delivery ◽

Delivery System ◽

Corpus Cavernosum ◽

Gene Delivery System ◽

System A ◽

In Vivo Transfection ◽

Linear Polyethylenimine

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Exosome as a Natural Gene Delivery Vector for Cancer Treatment

Current Cancer Drug Targets ◽

10.2174/1568009620666200924154149 ◽

2020 ◽

Vol 20 (11) ◽

pp. 821-830

Author(s):

Prasad Pofali ◽

Adrita Mondal ◽

Vaishali Londhe

Keyword(s):

Gene Therapy ◽

Gene Delivery ◽

Nucleic Acids ◽

Cancer Treatment ◽

Intestinal Barrier ◽

Gene Carrier ◽

Gene Delivery Vector ◽

Delivery Vector

Background: Current gene therapy vectors such as viral, non-viral, and bacterial vectors, which are used for cancer treatment, but there are certain safety concerns and stability issues of these conventional vectors. Exosomes are the vesicles of size 40-100 nm secreted from multivesicular bodies into the extracellular environment by most of the cell types in-vivo and in-vitro. As a natural nanocarrier, exosomes are immunologically inert, biocompatible, and can cross biological barriers like the blood-brain barrier, intestinal barrier, and placental barrier. Objective: This review focusses on the role of exosome as a carrier to efficiently deliver a gene for cancer treatment and diagnosis. The methods for loading of nucleic acids onto the exosomes, advantages of exosomes as a smart intercellular shuttle for gene delivery and therapeutic applications as a gene delivery vector for siRNA, miRNA and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and also the limitations of exosomes as a gene carrier are all reviewed in this article. Methods: Mostly, electroporation and chemical transfection are used to prepare gene loaded exosomes. Results: Exosome-mediated delivery is highly promising and advantageous in comparison to the current delivery methods for systemic gene therapy. Targeted exosomes, loaded with therapeutic nucleic acids, can efficiently promote the reduction of tumor proliferation without any adverse effects. Conclusion: In the near future, exosomes can become an efficient gene carrier for delivery and a biomarker for the diagnosis and treatment of cancer.

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Increased Circulatory Extrarenal 1α,25-Dihydroxyvitamin D3 in Bilaterally Nephrectomized Rats

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200530222426 ◽

2020 ◽

Vol 20 (9) ◽

pp. 1523-1530

Author(s):

Murat Dabak ◽

Durrin O. Dabak ◽

Tuncay Kuloglu ◽

Ersoy Baydar ◽

Hakan Bulut ◽

...

Keyword(s):

Immune Cells ◽

Low Dose ◽

Systemic Circulation ◽

Bilateral Nephrectomy ◽

Dihydroxyvitamin D3 ◽

Hydroxyvitamin D ◽

Inflammatory Conditions ◽

Calcium Phosphorus ◽

25 Hydroxyvitamin D

Background: Extrarenal 1α,25-dihydroxyvitamin D3 (1,25-D) locally produced by immune cells plays crucial roles in the regulation of the immune system. However, in vivo status of extrarenal 1,25-D and 25-hydroxyvitamin D (25-D) in acute inflammatory conditions are unknown. Objective: The aim of this study was to determine the extrarenal 1,25-D level in circulation in bilaterally nephrectomized rats, induced by low-dose lipopolysaccharide (LPS). Methods: Renal 1,25-D synthesis was terminated through bilateral nephrectomy in rats. The rats received intraperitoneal LPS (50 μg/kg BW) three times and the experiment was ended 24 hours after nephrectomy. Serum 1,25-D, 25-D, calcium, phosphorus, intact parathyroid hormone, and calcitonin levels were measured and immunohistochemistry was applied to detect the sources of extrarenal 1,25- D synthesis. Results: Circulatory 1,25-D concentration remarkably increased in both LPS-treated and non-treated bilaterally nephrectomized rats. Elevated circulatory 1,25-D did not have hypercalcemic endocrinal effects. The increased 1,25-D level also resulted in a concurrent rapid and dramatic depletion of circulatory 25-D. Conclusions: Extrarenal 1,25-D could enter into the systemic circulation and, therefore, might have systemic effects besides its autocrine and paracrine functions.

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In Vivo Digestion of Egg Products Enriched with DHA: Effect of the Food Matrix on DHA Bioavailability

Foods ◽

10.3390/foods10010006 ◽

2020 ◽

Vol 10 (1) ◽

pp. 6

Author(s):

Carlos Pineda-Vadillo ◽

Françoise Nau ◽

Catherine Guérin-Dubiard ◽

Claire Bourlieu ◽

Francesco Capozzi ◽

...

Keyword(s):

Docosahexaenoic Acid ◽

Venous Catheter ◽

Systemic Circulation ◽

Food Matrix ◽

Postprandial Period ◽

Egg Products ◽

Efficient Vector

The aim of the present study was to determine to what extent the food matrix could affect the release of docosahexaenoic acid (DHA) during digestion and its incorporation into systemic circulation. In this aim, three DHA-enriched egg products having the same composition but different structure were developed: omelet, hard-boiled egg, and mousse. Then, nine pigs fitted with T-shape cannulas at duodenal level and a jugular venous catheter were fed with the DHA-enriched egg products, and duodenal effluents and plasma were collected throughout the postprandial period. Results highlighted an undeniable effect of the food matrix on digestion parameters and DHA bioavailability. The transit of DHA and protein through the duodenum was faster after the ingestion of the mousse than after the ingestion of the omelet and hard-boiled egg. While most of the DHA and protein ingested under the form of mousse had already passed through the duodenum 4.5 h after its ingestion, significantly higher quantities were still present in the case of the omelet and hard-boiled egg. In terms of bioavailability, the omelet was the most efficient vector for delivering DHA into systemic circulation. It supplied 56% and 120% more DHA than the hard-boiled egg and the mousse, respectively.

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