scholarly journals Targeted Nanoparticle Delivery of Doxorubicin Into Placental Tissues to Treat Ectopic Pregnancies

Endocrinology ◽  
2013 ◽  
Vol 154 (2) ◽  
pp. 911-919 ◽  
Author(s):  
Tu’uhevaha J. Kaitu’u-Lino ◽  
Scott Pattison ◽  
Louie Ye ◽  
Laura Tuohey ◽  
Pavel Sluka ◽  
...  
Keyword(s):  
Ectopic Pregnancy ◽  
Ex Vivo ◽  
Growth Factor Receptor ◽  
Nanoparticle Delivery ◽  
Dependent Inhibition ◽  
Life Threatening ◽  
Choriocarcinoma Cells ◽  
Ectopic Pregnancies

Abnormal trophoblast growth can cause life-threatening disorders such as ectopic pregnancy, choriocarcinoma, and placenta accreta. EnGeneIC Delivery Vehicles (EDVs) are nanocells that can promote tissue-specific delivery of drugs and may be useful to medically treat such disorders. The objective of this study was to determine whether EDVs loaded with the chemotherapeutic doxorubicin and targeting the epidermal growth factor receptor (EGFR, very highly expressed on the placental surface) can regress placental cells in vitro, ex vivo, and in vivo. In female SCID mice, EGFR-targeted EDVs induced greater inhibition of JEG-3 (choriocarcinoma cells) tumor xenografts, compared with EDVs targeting an irrelevant antigen (nontargeted EDVs) or naked doxorubicin. EGFR-targeted EDVs were more readily taken up by human placental explants ex vivo and induced increased apoptosis (M30 antibody) compared with nontargeted EDVs. In vitro, EGFR-targeted EDVs administered to JEG-3 cells resulted in a dose-dependent inhibition of cell viability, proliferation, and increased apoptosis, a finding confirmed by continuous monitoring by xCELLigence. In conclusion, EGFR-targeted EDVs loaded with doxorubicin significantly inhibited trophoblastic tumor cell growth in vivo and in vitro and induced significant cell death ex vivo, potentially mediated by increasing apoptosis and decreasing proliferation. EDVs may be a novel nanoparticle treatment for ectopic pregnancy and other disorders of trophoblast growth.

Caution with bilateral salpingectomy and consideration of tubal stump ectopic in IVF

2020 ◽  
Vol 13 (11) ◽  
pp. e235893
Author(s):  
Swee Lin Yip ◽  
Shahul Hameed Mohamed Siraj ◽  
Jerry Kok Yen Chan
Keyword(s):  
Ectopic Pregnancy ◽  
Cystic Mass ◽  
In Vitro Fertilisation ◽  
Beta Human Chorionic Gonadotropin ◽  
Life Threatening ◽  
History Of ◽  
Bilateral Salpingectomy ◽  
Ectopic Pregnancies ◽  
The Right

We report a 35-year-old female patient with a history of bilateral salpingectomy from ectopic pregnancies presenting with a positive serum beta-human chorionic gonadotropin (bhCG) result following in vitro fertilisation (IVF) treatment. Apart from per vaginal spotting, she remained asymptomatic. Initial ultrasound showed an empty uterus with a cystic mass on the right side of the uterus. Serum beta-hCG was trended. A follow-up pelvic ultrasound 1 week later showed a live pregnancy in the right adnexa. A diagnostic laparoscopy was performed, which revealed an unruptured right stump ectopic pregnancy that was successfully removed. As a stump ectopic pregnancy can be a potentially life-threatening occurrence, we emphasise caution with salpingectomy and the consideration of tubal stump ectopic pregnancies following IVF treatment.

153. COMBINATION METHOTREXATE AND EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITION AS A NOVEL MEDICATION-BASED CURE OF ECTOPIC PREGNANCIES

2010 ◽  
Vol 22 (9) ◽  
pp. 71 ◽  
Author(s):  
U. Nilsson ◽  
T. G. Johns ◽  
T. Wilmann ◽  
Y. Gao ◽  
C. Whitehead ◽  
...  
Keyword(s):  
Cell Death ◽  
Epidermal Growth Factor Receptor ◽  
Combination Treatment ◽  
Growth Factor Receptor ◽  
Placental Tissue ◽  
Tumour Volume ◽  
Epidermal Growth ◽  
Ectopic Pregnancies

Ectopic pregnancies are serious gynaecological emergencies that can cause fatal haemorrhage. Most are treated surgically. Given the placenta is heavily reliant on Epidermal Growth Factor Receptor (EGFR) signaling, we set out to develop a medication-based treatment of ectopics using combination gefitinib (EGFR inhibitor) and methotrexate (folate antagonist). Both drugs are well tolerated and available in tablet form. We used in vitro and in vivo approaches to test the ability of gefitinib and methotrexate to regress placental tissue, and to explore molecular mechanisms. In vitro assays included immunohistochemistry (EGFR staining) western blot (EGFR phosphorylation), cell viability assays (Cell-Titre Blue, LDH cytotoxicity assay, xCELLigence system), apoptosis assays (PCR, FACS of M30 antibody) and The Bioplex Platform (phosphorylation of the EGFR pathway). JEG-3 xenografts were used to assess regression of placental tissue in vivo, where serum hCG was also measured (ELISA). EGFR was highly expressed in placentae from ectopic pregnancies. Combination treatment was supra-additive in inducing cell death of placental tissue in vitro, with >70% cell death by 48 hours (Syncytialised BeWos, JEG-3 and 1st trimester trophoblast). This supra-additive effect was demonstrated in both end point assays (cell viability) and regular monitoring using The xCELLigence system. Gefitinib potently blocks EGFR phosphorylation in placental tissues in vitro (Western blot). Both drugs may be converging to inhibit Akt phosphorylation (Bioplex analysis). Combination treatment increases apoptosis (FACS of M30 antibody). In vivo, Gefitinib or MTX as single agents induced significant decrease in xenograft tumour volume in a dose dependent manner (n ≤ 5 mice per treatment). However, combining these drugs was supra-additive in decreasing xenograph tumour volume and weight. Serum hCG in mice was lowest with combination treatment. Combination gefitinib and methotrexate potently regresses placental tissue. It may be a novel therapeutic approach to cure ectopic pregnancies, potentially replacing surgery with tablets.

Lu 23051, A New Potent Inhibitor Of Platelet Aggregation

1981 ◽  
Author(s):  
H D Lehmann ◽  
J Gries ◽  
D Lenke
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Coronary Vessels ◽  
Inhibitory Effect ◽  
Spontaneously Hypertensive ◽  
Dependent Inhibition ◽  
Induced Aggregation

6- [p-(2-(Chiorpropionylamino)phenyl] -4.5-dihydro-5-methyl-3(2H)-pyridazinone, LU 23051, is primarily characterized by its strong inhibition of platelet aggregation under in vitro and in vivo conditions. In vitro there is a concentration-dependent inhibition of ADP and collagen induced aggregation in platelet rich plasma of man, rat and dog. The inhibitory concentration EC 33 % is 0.0010-0.030 mg/1 (man: ADP-0.030, col 1.-0.013 mg/l) depending on species and type of aggregation. When administered orally in ex vivo experiments on rats and dogs the substance is found to have a dose-dependent antiaggregatory effect in the range from 0.1-3.16 mg/kg. The ED 33 % is 0.27-0.63 mg/kg.-In addition after oral administration the substance has a good inhibitory effect in models being based on intravascular platelet aggregation. Thus, a dose of 1 mg/kg inhibits laser-induced aggregation in mesenteric venules of rats. Mortality after i.v. injection of collagen in mice is reduced by 50 % after a dose of 0.02 mg/kg. A dose of 0.039 mg/kg prolongs the bleeding time of rats by 50 %. The aggregation-inhibiting action is of long duration (0.1 mg/kg p.o.∼24 h). The substance does not interfere with clotting.Besides its effect on platelet aggregation LU 23051 acts as vasodilatator as well. Dilatation of coronary vessels by 100 % is seen in isolated guinea-pig hearts at a concentration of 0.1 mg/l. In spontaneously hypertensive rats the substance has an anti hypertensive effect. The ED 20 % is 0.36 mg/kg p.o.The combination of antiaggregatory and vasodilatatory effects opens up interesting aspects with respect to the pharmacotherapeutic use of the new substance

scholarly journals A Novel off-the-Shelf Trastuzumab-Armed NK Cell Therapy (ACE1702) Using Antibody-Cell-Conjugation Technology

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2724
Author(s):  
Hao-Kang Li ◽  
Ching-Wen Hsiao ◽  
Sen-Han Yang ◽  
Hsiu-Ping Yang ◽  
Tai-Sheng Wu ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Cancer Cells ◽  
Nk Cell ◽  
Growth Factor Receptor ◽  
Tumorigenic Potential ◽  
Life Threatening ◽  
In Vivo Cytotoxicity ◽  
Nk Cell Therapy

Natural killer (NK) cells harbor efficient cytotoxicity against tumor cells without causing life-threatening cytokine release syndrome (CRS) or graft-versus-host disease (GvHD). When compared to chimeric antigen receptor (CAR) technology, Antibody-Cell Conjugation (ACC) technology has been developed to provide an efficient platform to arm immune cells with cancer-targeting antibodies to recognize and attack cancer cells. Recently, we established an endogenous CD16-expressing oNK cell line (oNK) with a favorable expression pattern of NK activation/inhibitory receptors. In this study, we applied ACC platform to conjugate oNK with trastuzumab and an anti-human epidermal growth factor receptor 2 (HER2) antibody. Trastuzumab-conjugated oNK, ACE-oNK-HER2, executed in vitro and in vivo cytotoxicity against HER2-expressing cancer cells and showed enhanced T cell-recruiting capability and secretion of IFNγ. The irradiated and cryopreserved ACE-oNK-HER2, designated as ACE1702, retained superior HER2-specific in vitro and in vivo potency with no tumorigenic potential. In conclusion, this study provides the evidence to support the potential clinical application of ACE1702 as a novel off-the-shelf NK cell therapy against HER2-expressing solid tumors.

Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2170-2180 ◽  
Author(s):  
Simone Boehrer ◽  
Lionel Adès ◽  
Thorsten Braun ◽  
Lorenzo Galluzzi ◽  
Jennifer Grosjean ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Growth Factor Receptor ◽  
Preclinical Study ◽  
Apoptosis Induction ◽  
Cycle Arrest ◽  
Epidermal Growth ◽  
Target Effect ◽  
Mitochondrial Membrane Permeabilization

Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR), induces differentiation, cell-cycle arrest, and apoptosis of EGFR-negative myeloblasts of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as in EGFR-negative cell lines representing these diseases (P39, KG-1, and HL 60). This off-target effect can be explained by inhibitory effects on JAK2. Apoptosis induction coupled to mitochondrial membrane permeabilization occurred independently from phenotypic differentiation. In apoptosis-sensitive AML cells, erlotinib caused a rapid (within less than 1 hour) nucleocytoplasmic translocation of nucleophosmin-1 (NPM-1) and p14ARF. Apoptosis-insensitive myeloblasts failed to manifest this translocation yet became sensitive to apoptosis induction by erlotinib when NPM-1 was depleted by RNA interference. Moreover, erlotinib reduced the growth of xenografted human AML cells in vivo. Erlotinib also killed CD34+ bone marrow blasts from MDS and AML patients while sparing normal CD34+ progenitors. This ex vivo therapeutic effect was once more associated with the nucleocytoplasmic translocation of NPM-1 and p14ARF. One patient afflicted with both MDS and non–small cell lung cancer manifested hematologic improvement in response to erlotinib. In summary, we here provide novel evidence in vitro, ex vivo, and in vivo for the potential therapeutic efficacy of erlotinib in the treatment of high-risk MDS and AML.

scholarly journals CRISPR/Cas9 gene editing of brain cancer stem cells using lipid-based nano-delivery

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv7-iv7
Author(s):  
Nadia Rouatbi ◽  
Yau Mun Lim ◽  
Vivien Grant ◽  
Pedro Miguel Costa ◽  
Steven M Pollard ◽  
...  
Keyword(s):  
Gene Editing ◽  
Near Infrared ◽  
Ex Vivo ◽  
Therapeutic Targets ◽  
Growth Factor Receptor ◽  
High Specificity ◽  
Intratumor Heterogeneity ◽  
In Vivo Delivery

Abstract Despite advances in cancer therapy glioblastoma (GBM) remains one of the deadliest brain tumours. Effective therapy is restricted by the presence of multiple resistance mechanisms. Physical barriers such as the blood-brain barrier limit the brain delivery of therapeutic compounds. In addition, the presence of a subset of GBM-stem-like cells (GSCs), characterized by radio/chemoresistance, and the intratumor heterogeneity impede standard therapies from being effective. New therapeutic approaches are urgently needed. Given its high specificity, CRISPR/Cas9-mediated genome editing provides new prospects for novel therapeutic targets. While promising, in vivo application of CRISPR/Cas9 is currently hampered by poor pharmacokinetics and limited ability to cross biological membranes. The present research is designed to utilise stable nucleic acid lipid nanoparticles (SNALPs) for in vivo delivery of CRISPR/Cas9 to GSC by disrupting the epidermal growth factor receptor variant III (EGFRvIII), a GBM associated mutation, responsible for tumour cell proliferation, angiogenesis and invasion. Near Infrared fluorescence labelling and live optical imaging confirmed SNALPs uptake in GSC tumours implanted intracranially in mice after intravenous injection. Higher uptake of SNALPs in tumourous tissues compared to healthy brain tissues was further confirmed by ex vivo imaging and flow cytometry. EGFRvIII-specific sgRNA has been designed and validated in GSCs using commercial transfection regents. Studies are underway to load CRISPR/Cas9 mRNA/gRNA into SNALPs to test their in vitro gene editing efficacy. Successful in vivo delivery of CRISPR/Cas9 will represent a promising approach for identifying GBM therapeutic targets in vivo which in the long-run can be applied for GBM treatment.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

In Vivo Effect of Suloctidil as an Antiplatelet Agent

1979 ◽  
Vol 41 (03) ◽  
pp. 465-474 ◽  
Author(s):  
Marcia R Stelzer ◽  
Thomas S Burns ◽  
Robert N Saunders
Keyword(s):  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Ratio Method ◽  
Platelet Aggregate ◽  
Permanent Effect ◽  
Platelet Aggregates ◽  
5 Ht Uptake ◽  
High Doses

SummaryThe relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5- HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

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