Systemic telomerase gene therapy delivered via targeted lipidic nanoparticles

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13025-13025 ◽  
Author(s):  
A. Goldkorn ◽  
B. Hann ◽  
M. Hayes ◽  
D. C. Drummond ◽  
D. B. Kirpotin ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Time Course ◽  
Cancer Metastasis ◽  
Tumor Formation ◽  
In Vivo Studies ◽  
Control Group ◽  
Telomerase Rna ◽  
Single Chain ◽  
Dna Nanoparticles

13025 Background: Most human cancers possess elevated telomerase activity that promotes proliferation. We developed 2 telomerase-targeting gene constructs: telomerase RNA containing a mutated template sequence (MT-hTer), and short interfering RNA (siRNA) targeting endogenous wild type telomerase RNA. When co-expressed in cancer cell lines and xenografts, MT-hTer/siRNA synergizes to cause rapid cell death (Li, S et al. Cancer Research 2004). Here, we tested the in vivo efficacy of MT-hTer/siRNA delivered systemically via antibody-targeted lipidic nanoparticles in a breast cancer metastasis model. Methods: Nude mice received intracardiac injection of luc+MCF7-C18 breast carcinoma cells ectopically overexpressing HER2 and luciferase. After 3 days, the mice were treated with a single 100 μg i.v. injection of either MT-hTer/siRNA-GFP or control (GFP-only) plasmid formulated into lipid-DNA nanoparticles conjugated to an internalizing anti-HER2 single chain antibody (Genosphere, TM) (Hayes, M et al. Gene Therapy 2005). A third group received saline (PBS) as a vehicle control. Cancer progression was monitored non-invasively via biophotonic imaging (Xenogen) of tumor luciferase signal. Results: By week 2 the PBS control group showed luciferase signal elevation that increased exponentially during the study. Similarly, the GFP-only control group developed significant luciferase signal elevation by week 3, with continued rise at all subsequent time points. In contrast, the MT-hTer/siRNA-GFP group experienced a decreased luciferase signal by week 2, which remained consistently low throughout the experimental time course. There were no observed treatment-related toxicities. Conclusions: In pilot in vivo studies, telomerase therapy dramatically inhibited tumor formation in mice after systemic delivery with cancer-targeting lipid-DNA nanoparticles. Expanded preclinical studies are underway. [Table: see text]

scholarly journals Optimizing Manufacturing and Osseointegration of Ti6Al4V Implants through Precision Casting and Calcium and Phosphorus Ion Implantation? In Vivo Results of a Large-Scale Animal Trial

Materials ◽  
2020 ◽  
Vol 13 (7) ◽  
pp. 1670 ◽  
Author(s):  
Wölfle-Roos JV ◽  
Katmer Amet B ◽  
Fiedler J ◽  
Michels H ◽  
Kappelt G ◽  
...  
Keyword(s):  
Ion Implantation ◽  
Large Scale ◽  
In Vivo Studies ◽  
Control Group ◽  
Implant Surface ◽  
Precision Casting ◽  
Pull Out ◽  
Significant Difference ◽  
Calcium And Phosphorus

Background: Uncemented implants are still associated with several major challenges, especially with regard to their manufacturing and their osseointegration. In this study, a novel manufacturing technique—an optimized form of precision casting—and a novel surface modification to promote osseointegration—calcium and phosphorus ion implantation into the implant surface—were tested in vivo. Methods: Cylindrical Ti6Al4V implants were inserted bilaterally into the tibia of 110 rats. We compared two generations of cast Ti6Al4V implants (CAST 1st GEN, n = 22, and CAST 2nd GEN, n = 22) as well as cast 2nd GEN Ti6Al4V implants with calcium (CAST + CA, n = 22) and phosphorus (CAST + P, n = 22) ion implantation to standard machined Ti6Al4V implants (control, n = 22). After 4 and 12 weeks, maximal pull-out force and bone-to-implant contact rate (BIC) were measured and compared between all five groups. Results: There was no significant difference between all five groups after 4 weeks or 12 weeks with regard to pull-out force (p > 0.05, Kruskal Wallis test). Histomorphometric analysis showed no significant difference of BIC after 4 weeks (p > 0.05, Kruskal–Wallis test), whereas there was a trend towards a higher BIC in the CAST + P group (54.8% ± 15.2%), especially compared to the control group (38.6% ± 12.8%) after 12 weeks (p = 0.053, Kruskal–Wallis test). Conclusion: In this study, we found no indication of inferiority of Ti6Al4V implants cast with the optimized centrifugal precision casting technique of the second generation compared to standard Ti6Al4V implants. As the employed manufacturing process holds considerable economic potential, mainly due to a significantly decreased material demand per implant by casting near net-shape instead of milling away most of the starting ingot, its application in manufacturing uncemented implants seems promising. However, no significant advantages of calcium or phosphorus ion implantation could be observed in this study. Due to the promising results of ion implantation in previous in vitro and in vivo studies, further in vivo studies with different ion implantation conditions should be considered.

scholarly journals Pharmacokinetic–pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies

2021 ◽  
Author(s):  
Sebastian Bauer ◽  
George D. Demetri ◽  
Ensar Halilovic ◽  
Reinhard Dummer ◽  
Christophe Meille ◽  
...  
Keyword(s):  
Partial Response ◽  
Disease Control ◽  
Time Course ◽  
Oral Treatment ◽  
Preliminary Evidence ◽  
Disease Control Rate ◽  
In Vivo Studies ◽  
Hematologic Toxicity ◽  
Next Generation

Abstract Background CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525). Methods Fifty-one patients received oral treatment with CGM097 10–400 mg 3qw (n = 31) or 300–700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics. Results No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined. Conclusions Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors. Translational relevance Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

Antitumoural hydroxyapatite nanoparticles-mediated hepatoma-targeted trans-arterial embolization gene therapy: in vitro and in vivo studies

2012 ◽  
Vol 32 (6) ◽  
pp. 998-1007 ◽  
Author(s):  
Gaopeng Li ◽  
Lu Ye ◽  
Jingsheng Pan ◽  
Miaoyun Long ◽  
Zizhuo Zhao ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Arterial Embolization ◽  
In Vivo Studies ◽  
Hydroxyapatite Nanoparticles

Evaluation of Annona muricata (Graviola) leaves activity against experimental trichinellosis: in vitro and in vivo studies

2021 ◽  
Vol 95 ◽  
Author(s):  
E.S. El-Wakil ◽  
H.F. Abdelmaksoud ◽  
T.S. AbouShousha ◽  
M.M.I. Ghallab
Keyword(s):  
Culture Media ◽  
Trichinella Spiralis ◽  
Drug Effects ◽  
In Vivo Studies ◽  
Control Group ◽  
Annona Muricata ◽  
Group I ◽  
Small Intestinal

Abstract Our work aimed to evaluate the possible effect of Annona muricata (Graviola) leaf extract on Trichinella spiralis in in vitro and in vivo studies. Trichinella spiralis worms were isolated from infected mice and transferred to three culture media – group I (with no drugs), group II (contained Graviola) and group III (contained albendazole) – then they were examined using the electron microscope. In the in vivo study, mice were divided into five groups: GI (infected untreated), GII (prophylactically treated with Graviola for seven days before infection), GIII (infected and treated with Graviola), GIV (infected and treated with albendazole) and GV (infected and treated with a combination of Graviola plus albendazole in half doses). Drug effects were assessed by adults and larvae load beside the histopathological small intestinal and muscular changes. A significant reduction of adult and larval counts occurred in treated groups in comparison to the control group. Histopathologically, marked improvement in the small intestinal and muscular changes was observed in treated groups. Also, massive destruction of the cultured adults’ cuticle was detected in both drugs. This study revealed that Graviola leaves have potential activity against trichinellosis, especially in combination with albendazole, and could serve as an adjuvant to anti-trichinellosis drug therapy.

HERBAL CREAMS OF REISHI EXTRACT AND TEA TREE OIL FOR HIRSUTISM–AN IN VIVO STUDY

2020 ◽  
pp. 106-110
Author(s):  
SANGEETA CHOUDHURY ◽  
BLR MADHAVI
Keyword(s):  
Topical Application ◽  
Hair Growth ◽  
Ethanolic Extract ◽  
Hair Follicles ◽  
In Vivo Studies ◽  
Control Group ◽  
Tea Tree Oil ◽  
Tea Tree

Objective: The aim of this work to formulate, evaluate and compare the effectiveness of herbal creams containing extract of reishi and tea tree oil for treating hirsutism. Methods: Herbal ingredients were authenticated. Cream base was initially formulated. Three formulations of herbal cream were prepared. Reishi ethanolic extract, tea tree oil, and combination of tea tree oil and reishi extract were added to the cream base and formulated cream were named as RHC, THC and RTC respectively. In vitro evaluations on herbal creams were done for the physicochemical characteristics. In vivo studies were carried out on female Swiss Albino mice for the activity against hair growth by topical application of cream to shaved skin. The histological and morphometric evaluation was carried out. Skin irritancy study was conducted. Results: The herbal creams showed desirable physicochemical properties like pH, viscosity and spreadability. Statistical analysis for the length of hair was performed by using one way ANOVA followed by DUNNET’S post hoc test where THC and RTC were found to be significant whereas RHC showed no significant reduction of hair growth compared to control. RTC showed a significant effect at p<0.05 and hair growth reduction was significant for THC at p<0.001 compared to the control group. RTC and THC showed mild to moderate reduction in the size of the hair follicles with a reduction of sebaceous gland size in the histological analysis. Conclusion: Topical application of herbal creams to mice showed that hair growth was fastest in group RHC and was slowest in group THC and intermediate with RTC. It can be concluded that these herbal actives can be used as an effective treatment against hirsutism. Within the study period, tea tree oil was found to be more effective than reishi extract and the combination product. Further formulation studies and in vivo studies need to be carried out on reishi to assess its effectiveness against hirsutism.

scholarly journals Taurine Attenuates Carcinogenicity in Ulcerative Colitis-Colorectal Cancer Mouse Model

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Guifeng Wang ◽  
Ning Ma ◽  
Feng He ◽  
Shosuke Kawanishi ◽  
Hatasu Kobayashi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Drinking Water ◽  
Mouse Model ◽  
Histopathological Examination ◽  
Tumor Formation ◽  
Water Model ◽  
Control Group ◽  
Ki 67

Taurine (2-aminoethane-sulfonic acid) is a type of amino acids and has numerous physiological and therapeutic functions, including anti-inflammation. However, there are few studies on the anticancer action of taurine. Our previous studies have demonstrated that taurine exhibits an apoptosis-inducing effect on human nasopharyngeal carcinoma cells in vitro. In this study, we have investigated whether taurine has an anticancer effect, using azoxymethane (AOM)/sulfate sodium (DSS)- induced mouse model for colon carcinogenesis. All mice, except those in control group, received a single intraperitoneal injection of AOM and DSS in the drinking water for 7 days twice, with 1-week interval. After the first DSS treatment, mice were given distilled water (model group) or taurine in the drinking water (taurine group) ad libitum. No tumor was observed in the control group. Taurine significantly suppressed AOM+DSS-induced tumor formation. Histopathological examination revealed AOM/DSS treatment induced colon cancer in all mice (8/8, 100%), and taurine significantly inhibited the progression of colon cancer (4/9, 44.4%). Taurine significantly attenuated cell proliferation in cancer tissues detected by Ki-67 staining. Taurine significantly increased the levels of an apoptosis marker cleaved caspase-9 and tumor suppressor protein PTEN. This is the first study that demonstrated that taurine significantly reduced carcinogenicity in vivo using AOM/DSS-induced colon cancer mouse model.

Trajectory-Based Tissue Engineering for Cartilage Repair: Correlation Between Maturation Rate and Integration Capacity

2013 ◽  
Author(s):  
Matthew B. Fisher ◽  
Nicole Söegaard ◽  
David R. Steinberg ◽  
Robert L. Mauck
Keyword(s):  
Tissue Engineering ◽  
Time Course ◽  
Biomechanical Properties ◽  
Time Dependent ◽  
In Vivo Studies ◽  
Surgical Approaches ◽  
General Hypothesis ◽  
Vitro Assay

Given the limitations of current surgical approaches to treat articular cartilage injuries, tissue engineering (TE) approaches have been aggressively pursued over the past two decades. Although biochemical and biomechanical properties on the order of the native tissue have been achieved (1–5), several in-vitro and in-vivo studies indicate that increased tissue maturity may limit the ability of engineered constructs to remodel and integrate with surrounding cartilage, although results are highly variable (2, 6–8). Thus, “static” measures of construct maturity (e.g. compressive modulus) upon implantation may not be the best indicators of in-vivo success, which likely requires implanted TE constructs to mature, remodel, and integrate with the host over time to achieve optimal results. We recently introduced the concept of “trajectory-based” tissue engineering (TB-TE), which is based on the general hypothesis that time-dependent increases in construct maturation in-vitro prior to implantation (i.e. positive rates) may provide a better predictor of in-vivo success (9). As a first step in evaluating this concept, in the current study we hypothesized that time-dependent increases in equilibrium modulus (a metric of growth) would be correlated to ability of constructs to integrate to cartilage using an in-vitro assay. To test this hypothesis, the current objective was to determine and model the time course of maturation of TE constructs during in-vitro culture and to assess the ability of these constructs to integrate to cartilage at various points during their maturation.

scholarly journals α-Glucosidase Inhibitory, Anti-Oxidant, and Anti-Hyperglycemic Effects of Euphorbia nivulia–Ham. in STZ-Induced Diabetic Rats

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582093942
Author(s):  
Muhammad Younus ◽  
Muhammad Mohtasheem ul Hasan ◽  
Khalil Ahmad ◽  
Ali Sharif ◽  
Hafiz Muhammad Asif ◽  
...  
Keyword(s):  
High Performance ◽  
Wistar Rat ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
In Vivo Studies ◽  
Control Group ◽  
Control Drug ◽  
Antidiabetic Effects

In this study, we aimed to investigate the antidiabetic effects of Euphorbia nivulia (En), native to Cholistan Desert area of Bahawalpur, Pakistan. First, we performed high-performance liquid chromatography analysis and found that this plant contains ferulic acid, gallic acid, quercetin, benzoic acid, polyphenols, and flavonoids. Then, we performed in vitro and in vivo studies to assess its effects on diabetic Wistar rat model. The experiments were performed and compared with control drug glibenclamide. The 70% hydroalcoholic extract of En exhibited 97.8% in vitro α-glucosidase inhibitory effect at a dose of 1.0 mg/mL. We orally administered the extract of En and control drug to the streptozotocin (STZ)-induced diabetic rats and analyzed its antidiabetic effects. We found that the extract of En with a dose of 500 mg/kg/body weight exhibited significant effect to reduce blood glucose in STZ-induced rats as compared with the control group ( P < .001). Our histological data also showed that the extract significantly improved the histopathology of pancreas. Collectively, both in vitro and in vivo studies revealed that En possesses α-glucosidase inhibitory, antioxidant, and anti-hyperglycemic effect in STZ-induced diabetic rats.

scholarly journals Dickkopf-1 contributes to hepatocellular carcinoma tumorigenesis by activating the Wnt/β-catenin signaling pathway

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Rui Zhang ◽  
Hao-Ming Lin ◽  
Ruth Broering ◽  
Xiang-de Shi ◽  
Xian-huan Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Tumor Formation ◽  
In Vivo Studies ◽  
Qrt Pcr ◽  
Subsequent Investigation ◽  
Dkk1 Expression ◽  
Tumor Number

AbstractDysregulation of dickkopf-related protein 1 (DKK1) expression has been reported in a variety of human cancers. We previously reported that DKK1 was upregulated in hepatocellular carcinoma (HCC). However, the role of DKK1 in HCC remains unclear. This study aimed to investigate the clinical significance and biological functions of DKK1 in HCC. The expression of DKK1 was examined in cirrhotic and HCC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). DKK1 was silenced or overexpressed in HCC cell lines, and in vitro and in vivo studies were performed. Immunohistochemistry revealed that DKK1 was weakly expressed in cirrhotic tissues (8/22, 36.4%) but upregulated in HCC tissues (48/53, 90.6%, cohort 1). Significant upregulation of DKK1 was observed in 57.6% (19/33, cohort 2) of HCC tissues by qRT-PCR, and the expression of DKK1 was associated with tumor size (P = 0.024) and tumor number (P = 0.019). Genetic depletion of DKK1 impaired the proliferation, colony-forming ability, invasion, and tumor formation of HCC cells (HepG2 and HUH-7). Conversely, forced expression of DKK1 increased the proliferation, colony-forming ability, and invasion of HepG2 and HUH-7 cells in vitro and enhanced tumor formation in vivo. Subsequent investigation revealed that the DKK1-mediated proliferation and tumorigenicity of HepG2 and HUH-7 cells is dependent on the Wnt/β-catenin signaling pathway. These findings indicate that DKK1 plays an oncogenic role in HCC by activating the Wnt/β-catenin signaling pathway.

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