scholarly journals Polyethyleneimine-Based Lipopolyplexes as Carriers in Anticancer Gene Therapies

Materials ◽  
2021 ◽  
Vol 15 (1) ◽  
pp. 179
Author(s):  
Julia Jerzykiewicz ◽  
Aleksander Czogalla
Keyword(s):  
Nucleic Acid ◽  
Cancer Treatment ◽  
Future Development ◽  
Viral Vectors ◽  
Lipid Vesicles ◽  
Therapeutic Strategies ◽  
In Vivo Studies ◽  
Great Promise ◽  
Gene Therapies

Recent years have witnessed rapidly growing interest in application of gene therapies for cancer treatment. However, this strategy requires nucleic acid carriers that are both effective and safe. In this context, non-viral vectors have advantages over their viral counterparts. In particular, lipopolyplexes—nanocomplexes consisting of nucleic acids condensed with polyvalent molecules and enclosed in lipid vesicles—currently offer great promise. In this article, we briefly review the major aspects of developing such non-viral vectors based on polyethyleneimine and outline their properties in light of anticancer therapeutic strategies. Finally, examples of current in vivo studies involving such lipopolyplexes and possibilities for their future development are presented.

scholarly journals Nanoparticle Delivered Anti-miR-141-3p for Stroke Therapy

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1011
Author(s):  
Karishma Dhuri ◽  
Rutesh N. Vyas ◽  
Leslie Blumenfeld ◽  
Rajkumar Verma ◽  
Raman Bahal
Keyword(s):  
Ischemic Stroke ◽  
Nucleic Acid ◽  
Double Emulsion ◽  
Artery Occlusion ◽  
Brain Parenchyma ◽  
Confocal Imaging ◽  
In Vivo Studies ◽  
Stroke Therapy ◽  
Systemic Delivery

Ischemic stroke and factors modifying ischemic stroke responses, such as social isolation, contribute to long-term disability worldwide. Several studies demonstrated that the aberrant levels of microRNAs contribute to ischemic stroke injury. In prior studies, we established that miR-141-3p increases after ischemic stroke and post-stroke isolation. Herein, we explored two different anti-miR oligonucleotides; peptide nucleic acid (PNAs) and phosphorothioates (PS) for ischemic stroke therapy. We used US FDA approved biocompatible poly (lactic-co-glycolic acid) (PLGA)-based nanoparticle formulations for delivery. The PNA and PS anti-miRs were encapsulated in PLGA nanoparticles by double emulsion solvent evaporation technique. All the formulated nanoparticles showed uniform morphology, size, distribution, and surface charge density. Nanoparticles also exhibited a controlled nucleic acid release profile for 48 h. Further, we performed in vivo studies in the mouse model of ischemic stroke. Ischemic stroke was induced by transient (60 min) occlusion of middle cerebral artery occlusion followed by a reperfusion for 48 or 72 h. We assessed the blood-brain barrier permeability of PLGA NPs containing fluorophore (TAMRA) anti-miR probe after systemic delivery. Confocal imaging shows uptake of fluorophore tagged anti-miR in the brain parenchyma. Next, we evaluated the therapeutic efficacy after systemic delivery of nanoparticles containing PNA and PS anti-miR-141-3p in mice after stroke. Post-treatment differentially reduced both miR-141-3p levels in brain tissue and infarct injury. We noted PNA-based anti-miR showed superior efficacy compared to PS-based anti-miR. Herein, we successfully established that nanoparticles encapsulating PNA or PS-based anti-miRs-141-3p probes could be used as a potential treatment for ischemic stroke.

Highly efficient cell-mediated gene transfer using non-viral vectors and FuGene™6: in vitro and in vivo studies

2000 ◽  
Vol 57 (8) ◽  
pp. 1326-1333 ◽  
Author(s):  
I. Hellgren* ◽  
V. Drvota ◽  
R. Pieper ◽  
S. Enoksson ◽  
P. Blomberg ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Viral Vectors ◽  
In Vivo Studies ◽  
Highly Efficient

scholarly journals A Gemini Cationic Lipid with Histidine Residues as a Novel Lipid-Based Gene Nanocarrier: A Biophysical and Biochemical Study

Nanomaterials ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. 1061 ◽  
Author(s):  
María Martínez-Negro ◽  
Laura Blanco-Fernández ◽  
Paolo Tentori ◽  
Lourdes Pérez ◽  
Aurora Pinazo ◽  
...  
Keyword(s):  
Biochemical Study ◽  
Cationic Lipid ◽  
Green Fluorescence Protein ◽  
In Vivo Studies ◽  
Interleukin 12 ◽  
Specific Gene ◽  
Gene Therapies ◽  
Biological Studies

This work reports the synthesis of a novel gemini cationic lipid that incorporates two histidine-type head groups (C3(C16His)2). Mixed with a helper lipid 1,2-dioleoyl-sn-glycero-3-phosphatidyl ethanol amine (DOPE), it was used to transfect three different types of plasmid DNA: one encoding the green fluorescence protein (pEGFP-C3), one encoding a luciferase (pCMV-Luc), and a therapeutic anti-tumoral agent encoding interleukin-12 (pCMV-IL12). Complementary biophysical experiments (zeta potential, gel electrophoresis, small-angle X-ray scattering (SAXS), and fluorescence anisotropy) and biological studies (FACS, luminometry, and cytotoxicity) of these C3(C16His)2/DOPE-pDNA lipoplexes provided vast insight into their outcomes as gene carriers. They were found to efficiently compact and protect pDNA against DNase I degradation by forming nanoaggregates of 120–290 nm in size, which were further characterized as very fluidic lamellar structures based in a sandwich-type phase, with alternating layers of mixed lipids and an aqueous monolayer where the pDNA and counterions are located. The optimum formulations of these nanoaggregates were able to transfect the pDNAs into COS-7 and HeLa cells with high cell viability, comparable or superior to that of the standard Lipo2000*. The vast amount of information collected from the in vitro studies points to this histidine-based lipid nanocarrier as a potentially interesting candidate for future in vivo studies investigating specific gene therapies.

Gene therapy comes of age

Science ◽  
2018 ◽  
Vol 359 (6372) ◽  
pp. eaan4672 ◽  
Author(s):  
Cynthia E. Dunbar ◽  
Katherine A. High ◽  
J. Keith Joung ◽  
Donald B. Kohn ◽  
Keiya Ozawa ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
The United States ◽  
Genetically Engineered ◽  
Drug Status ◽  
Hematopoietic Stem ◽  
Gene Therapies ◽  
Engineered T Cells ◽  
Near Future

After almost 30 years of promise tempered by setbacks, gene therapies are rapidly becoming a critical component of the therapeutic armamentarium for a variety of inherited and acquired human diseases. Gene therapies for inherited immune disorders, hemophilia, eye and neurodegenerative disorders, and lymphoid cancers recently progressed to approved drug status in the United States and Europe, or are anticipated to receive approval in the near future. In this Review, we discuss milestones in the development of gene therapies, focusing on direct in vivo administration of viral vectors and adoptive transfer of genetically engineered T cells or hematopoietic stem cells. We also discuss emerging genome editing technologies that should further advance the scope and efficacy of gene therapy approaches.

scholarly journals Clonal reconstruction from co-occurrence of vector integration sites allows accurate quantification of expanding clones in vivo

2021 ◽  
Author(s):  
Sebastian Wagner ◽  
Christoph Baldow ◽  
Andrea Calabria ◽  
Laura Rudilosso ◽  
Pierangela Gallina ◽  
...  
Keyword(s):  
Viral Vectors ◽  
R Package ◽  
Repeated Measurements ◽  
Preclinical Model ◽  
Gene Therapies ◽  
Vector Integration ◽  
Reconstruction Methods ◽  
Integration Sites ◽  
Safety Considerations

High transduction rates of viral vectors in gene therapies (GT) and experimental hematopoiesis ensure a high frequency of gene delivery, although multiple integration events can occur in the same cell. Therefore, tracing of integration sites (IS) leads to mis-quantification of the true clonal spectrum and limits safety considerations in GT. Hence, we use correlations between repeated measurements of IS abundances to estimate their mutual similarity and identify clusters of co-occurring IS, for which we assume a clonal origin. We evaluate the performance, robustness and specificity of our methodology using clonal simulations. The reconstruction methods, implemented and provided as an R-package, are further applied to experimental clonal mixes and to a preclinical model of hematopoietic GT. Our results demonstrate that clonal reconstruction from IS data allows to overcome systematic biases in the clonal quantification as an essential prerequisite for the assessment of safety and long-term efficacy of GT involving integrative vectors.

scholarly journals Targeted Chemotherapy Delivery via Gold Nanoparticles: A Scoping Review of In Vivo Studies

Crystals ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1169
Author(s):  
Ștefan Morărașu ◽  
Ștefan Iacob ◽  
Ionuț Tudorancea ◽  
Sorinel Luncă ◽  
Mihail-Gabriel Dimofte
Keyword(s):  
Gold Nanoparticles ◽  
Cancer Treatment ◽  
Chemical Properties ◽  
In Vivo Studies ◽  
Synthesis Methods ◽  
Experimental Cancer ◽  
Therapy Option ◽  
Physical And Chemical ◽  
System Toxicity

In the field of oncology, a lot of improvements in nanotechnology creates support for better diagnosis and therapeutic opportunities, and due to their physical and chemical properties, gold nanoparticles are highly applicable. We performed a literature review on the studies engaging the usage of gold nanoparticles on murine models with a focus on the type of the carrier, the chemotherapy drug, the target tumoral tissue and outcomes. We identified fifteen studies that fulfilled our search criteria, in which we analyzed the synthesis methods, the most used chemotherapy conjugates of gold nanoparticles in experimental cancer treatment, as well as the improved impact on tumor size and system toxicity. Due to their intrinsic traits, we conclude that chemotherapy conjugates of gold nanoparticles are promising in experimental cancer treatment and may prove to be a safer and improved therapy option than current alternatives.

The Fibrinolytic Potential of the Normal Primate following the Generation of Thrombin In Vivo

1990 ◽  
Vol 63 (03) ◽  
pp. 476-481 ◽  
Author(s):  
Alan R Giles ◽  
Michael E Nesheim ◽  
Steven W Herring ◽  
Hugh Hoogendoorn ◽  
David C Stump ◽  
...  
Keyword(s):  
Time Course ◽  
Factor Xa ◽  
Lipid Vesicles ◽  
Experimental Period ◽  
In Vivo Studies ◽  
Full Time ◽  
Primate Model ◽  
Fibrinolytic Potential

SummaryParameters of the fibrinolytic system were studied in a primate model where the generation of thrombin was promoted in vivo. The procoagulant stimulus used was a combination of human factor Xa in combination with phosphatidylcholine/phos-phatidylserine lipid vesicles (PCPS) as the source of coagulant active phospholipid. The dosage of each component was formulated to provide a gradation of thrombin generating potential assessed prior to in vivo study in an in vitro clotting assay. These ranged from 25.25 - 36.60 pMole/kg (factor Xa) and 18.85 - 56.30 nMole/kg (PCPS). In each case, the ratio of the dose of factor Xa/PCPS was maintained at 0.65 (pMole factor Xa/ nMole PCPS). Individual dosage combinations producing recalcification clotting times in vitro of 15, 20, 25 and 30 s were used in detailed in vivo studies. Previous studies in dogs had confirmed the thrombin generating potential of factor Xa/PCPS infusions and demonstrated an associated activation ot protein C and increased fibrinolytic activity. This has now been extensively characterized in the chimpanzee as follows: 10 min after the infusion of the highest dose (36.6 pMole factor Xa/56.3 nMole PCPS kg bodyweight), the level of circulating t-PA had risen to 900 ng/ml (antigen), 885 IU/ml (functional). Dosage was observed with the lowest dose of 12.25 pMole factor Xa and 18.85 nMole PCPS being associated with relatively minor increases in circulating t-PA activity. There were no changes in u-PA at any dosage during the full time course of the experimental period (90 min). Plasminogen activation was also apparent with alpha-2 antiplasmin levels falling to 30 - 40% of pre-infusion levels at the highest dosages. There was also a significant consumption of fibrinogen and evidence of active fibrinolysis manifested by major increases in the levels of FDP, D-dimer and B-beta 1-42. The data strongly suggested that this was predominantly fibrinolysis rather than fibrinogenolysis and that the fibrinolytic response observed resulted from a major release of t-PA from available stores consequent to thrombin generation and presumably subsequent fibrin generation. These data illustrate the enormous fibrinolytic potential of the intact normal primate and may provide a model for study of the mechanism(s) by which the regulation of t-PA availability can be up- or down-regulated in health and disease.

New gold-198 nanoparticle synthesis to be used in cancer treatment

2021 ◽  
Vol 9 (1A) ◽  
Author(s):  
Carla Daruich de Souza ◽  
Carla Daruich de Souza ◽  
Carlos Alberto Zeituni ◽  
Wilmmer Alexander Arcos Rosero ◽  
Beatriz Ribeiro Nogueira ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Cancer Treatment ◽  
Nuclear Reactor ◽  
Nanoparticle Synthesis ◽  
Average Energy ◽  
In Vivo Studies ◽  
Chloroauric Acid ◽  
Repeated Heating

Gold nanoparticles (NPs) have been intriguing scientists for over 100 years. Recently, they have been studied for new applications such as cancer treatment. Although the synthesis of gold nanoparticles is extensively reported, in the majority of cases the methodology is confused and/or not clear. We describe a new synthesis methodology for radioactive gold‐198 NPs. Gold-198 was activated in IPEN IEA-01 nuclear reactor. After that, chloroauric acid (HAuCl4) was formed by dissolving the radioactive gold with aqua regia and performing repeated heating cycles. 0.1 mM HAuCl4 containing 100 μL of 1 M NaOH was prepared in a flask equipped with a reflux condenser. The solution was brought to boil and stirred with a PTFE‐coated magnetic stir‐bar. Then 5 mL of sodium citrate was rapidly added. The reaction turns from light yellow to clear, black, dark purple until the solution attained a wine‐red color (2–3 min). Dynamic light scattering (DLS) confirmed 8 nm particles. The presence of gold‐198 (197.968 g/mol; half‐life: 2.69517; decay mode: β‐; average energy: 1.3723 MeV) was confirmed by an ORTEC HPGe detector. DLS was performed after complete decay confirming the 8 nm diameter maintenance. We were able to achieve radioactive gold‐198 NPs and are performing further studies such as: coating reactions, in‐vitro and in‐vivo studies.

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