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Journal of Nuclear Medicine : Official... Nov 2019We characterize the in vivo biodistribution and tumor selectivity of Y-NM600, a theranostic alkylphosphocholine radiometal chelate with broad tumor selectivity, in a...
We characterize the in vivo biodistribution and tumor selectivity of Y-NM600, a theranostic alkylphosphocholine radiometal chelate with broad tumor selectivity, in a variety of preclinical cancer models. Mice bearing flank tumors (representative of lung, pancreatic, prostate, liver, skin, and lymphoid cancers) were injected intravenously with 9.25 MBq of Y-NM600 and imaged longitudinally over 4-5 d using small-animal PET/CT. Percentage injected activity per gram (%IA/g) for each volume of interest was measured at each time point for the organs of interest. Mice were euthanized after the final time point, and the tumor and organs of interest were counted with an automatic γ-counter. Absorbed doses delivered by Y-NM600 per injected activity (Gy/MBq) were estimated. Mice bearing B78 flank tumors were injected with a prescription of Y-NM600 that delivered 2.5 Gy of absorbed tumor dose and was compared with an equivalent absorbed dose delivered via external-beam radiotherapy using tumor volume as a measure of response. Histology and complete blood counts were analyzed in naïve C57BL/6 mice that were injected with 9.25 MBq of Y-NM600 at 5, 10, and 28 d after injection. PET imaging showed consistent tumor accumulation and retention across all tumor models investigated, with little off-target retention of NM600 except in the liver, as is characteristic of hepatobiliary metabolism. The tumor uptake was highest in the pancreatic and lymphoid cancer models, reaching peak concentrations of 9.34 ± 2.66 %IA/g ( = 3) and 9.10 ± 0.13 %IA/g ( = 3), respectively, at approximately 40-48 h after injection. These corresponded to tumor dose estimates of 2.72 ± 0.33 Gy/MBq and 2.67 ± 0.32 Gy/MBq, respectively. In the toxicity study, there were no visible signs of acute toxicity by histology, and perturbation of hematologic parameters was transient when observed, returning to pretherapy levels after 28 d. NM600 is a theranostic agent with a unique ability to selectively target a variety of cancer types, presenting a unique opportunity for PET image-guided targeted radionuclide therapy and combination with immunotherapies.
Topics: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Humans; Mice; Phosphorylcholine; Radiochemistry; Radiometry; Tissue Distribution; Yttrium Radioisotopes
PubMed: 30954941
DOI: 10.2967/jnumed.118.224808 -
The American Journal of Tropical... Feb 2018Miltefosine is the only orally administrable drug for the treatment of leishmaniasis. But in recent years, a decline in its efficacy points toward the emergence of...
Miltefosine is the only orally administrable drug for the treatment of leishmaniasis. But in recent years, a decline in its efficacy points toward the emergence of resistance to this drug. Knowledge of biomarkers for miltefosine resistance may be beneficial for proper selection of treatment regimen. Splenic aspirates were collected and parasites cultured from patients relapsed after initial cure ( = 15) and successfully treated ( = 15) with miltefosine. Differential expression of genes in miltefosine-resistant strains was examined by DNA microarray and validated by real-time reverse transcription polymerase chain reaction and Western blotting. Of 669 upregulated genes, the cysteine protease-like protein of calpain family (GenBank: CBZ34784) was found to be significantly overexpressed in resistant parasite strains and only anti-calpain antibodies showed its presence in the sera of relapse patients through Western blotting. Calpain family cysteine protease-like protein can be useful as a potential biomarker of miltefosine unresponsiveness.
Topics: Antiprotozoal Agents; Biomarkers; Biopsy, Needle; Calpain; Humans; Leishmania donovani; Leishmaniasis, Visceral; Phosphorylcholine; Real-Time Polymerase Chain Reaction; Recurrence; Spleen
PubMed: 29280431
DOI: 10.4269/ajtmh.16-0983 -
Antimicrobial Agents and Chemotherapy Mar 2018We tested 29 isolates of and one isolate of to investigate their susceptibility to miltefosine and antibacterial drugs from the macrolide, oxazolidinone, and...
We tested 29 isolates of and one isolate of to investigate their susceptibility to miltefosine and antibacterial drugs from the macrolide, oxazolidinone, and pleuromutilin classes. We found that miltefosine, azithromycin, clarithromycin, josamycin, linezolid, sutezolid, retapamulin, tiamulin, and valnemulin had inhibitory and cidal activity against the pathogens at concentrations ranging from 0.25 to 64 μg/ml. Our results suggest that these antimicrobials are promising candidates for future studies on pythiosis in animals and humans.
Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bridged Bicyclo Compounds, Heterocyclic; Clarithromycin; Diterpenes; Humans; Josamycin; Linezolid; Macrolides; Oomycetes; Oxazolidinones; Phosphorylcholine; Polycyclic Compounds; Pythiosis; Pythium; Pleuromutilins
PubMed: 29311087
DOI: 10.1128/AAC.01678-17 -
Molecules (Basel, Switzerland) Sep 2019A novel stereoisomer of eushearilide, 23-demethyleushearilide, was synthesized, and the structure-activity relationships of this compound along with known eushearilide...
Total Synthesis and Antimicrobial Evaluation of 23-Demethyleushearilide and Extensive Antimicrobial Evaluation of All Synthetic Stereoisomers of (16,20)-Eushearilide and (16,20)-Eushearilide.
A novel stereoisomer of eushearilide, 23-demethyleushearilide, was synthesized, and the structure-activity relationships of this compound along with known eushearilide stereoisomers were investigated in order to design novel lead compounds for the treatment of fungal infections. It was discovered that all of these congeners, together with the natural product, exhibited a wide range of antimicrobial activity against not only fungi but also against bacteria, including methicillin-resistant (MRSA) and vancomycin-resistant enterococci (VRE).
Topics: Anti-Infective Agents; Macrolides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Phosphorylcholine; Stereoisomerism; Vancomycin Resistance; Vancomycin-Resistant Enterococci
PubMed: 31546686
DOI: 10.3390/molecules24193437 -
Angewandte Chemie (International Ed. in... Jan 2017Detergents are often used to investigate the structure and dynamics of membrane proteins. Whereas the structural integrity seems to be preserved in detergents for many... (Comparative Study)
Comparative Study
Detergents are often used to investigate the structure and dynamics of membrane proteins. Whereas the structural integrity seems to be preserved in detergents for many membrane proteins, their functional activity is frequently compromised, but can be restored in a lipid environment. Herein we show with per-residue resolution that while OmpX forms a stable β-barrel in DPC detergent micelles, DHPC/DMPC bicelles, and DMPC nanodiscs, the pico- to nanosecond and micro- to millisecond motions differ substantially between the detergent and lipid environment. In particular for the β-strands, there is pronounced dynamic variability in the lipid environment, which appears to be suppressed in micelles. This unexpected complex and membrane-mimetic-dependent dynamic behavior indicates that the frequent loss of membrane protein activity in detergents might be related to reduced internal dynamics and that membrane protein activity correlates with lipid flexibility.
Topics: Bacterial Outer Membrane Proteins; Escherichia coli Proteins; Hydrolases; Micelles; Molecular Dynamics Simulation; Nanostructures; Phosphorylcholine
PubMed: 27882643
DOI: 10.1002/anie.201608246 -
Molecules (Basel, Switzerland) Jan 2020A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of . All 15 tested tetraoxanes displayed...
A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of . All 15 tested tetraoxanes displayed activity, with IC values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC value of 2.52 ± 0.65 µm on intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of -infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.
Topics: Animals; Antiprotozoal Agents; Leishmania donovani; Leishmaniasis; Mice; Phosphorylcholine; Tetraoxanes
PubMed: 31979089
DOI: 10.3390/molecules25030465 -
Journal of Visualized Experiments : JoVE Dec 2016Removable dentures made of poly (methyl methacrylate) (PMMA) are prone to bacterial adherence and dental plaque formation, which is called denture plaque. Denture...
Removable dentures made of poly (methyl methacrylate) (PMMA) are prone to bacterial adherence and dental plaque formation, which is called denture plaque. Denture plaque-associated infection is a source of serious dental and medical complications in the elderly. 2-Methacryloyloxyethyl phosphorylcholine (MPC) is a well-known biomedical material that exhibits marked antithrombogenicity and tissue compatibility because of its high resistance to protein adsorption and cell adhesion. Therefore, MPC polymer coatings are suggested to have the potential to inhibit plaque deposition on the surface of PMMA dentures. However, coating MPC polymer on the surface of a PMMA denture is a complex procedure that requires specialized equipment, which is regarded as a major barrier to its clinical application. Here, we introduce a new MPC polymer treatment procedure that uses poly (MPC-co-BMA-co-MPAz) (PMBPAz) to prevent denture plaque deposition on removable dentures. This procedure enables the MPC coating of PMMA denture surfaces in a simple and stable manner that is resistant to various chemical and mechanical stresses due to the MPC layer of PMBPAz that is covalently bound to the PMMA surface by ultraviolet light irradiation. In addition, the procedure does not require any specialized equipment and can be completed by clinicians within 2 min. We applied this procedure in a clinical setting and demonstrated its clinical utility and efficacy in inhibiting plaque deposition on removable dentures.
Topics: Adsorption; Biocompatible Materials; Dental Plaque; Denture, Complete; Humans; Methacrylates; Phosphorylcholine; Surface Properties
PubMed: 28060350
DOI: 10.3791/54965 -
Acta Biomaterialia Jan 2015The implant-host interface is a critical element in guiding tissue or organ regeneration. We previously developed hydrogels comprising interpenetrating networks of...
The implant-host interface is a critical element in guiding tissue or organ regeneration. We previously developed hydrogels comprising interpenetrating networks of recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) as substitutes for the corneal extracellular matrix that promote endogenous regeneration of corneal tissue. To render them functional for clinical application, we have now optimized their composition and thereby enhanced their mechanical properties. We have demonstrated that such optimized RHCIII-MPC hydrogels are suitable for precision femtosecond laser cutting to produce complementing implants and host surgical beds for subsequent tissue welding. This avoids the tissue damage and inflammation associated with manual surgical techniques, thereby leading to more efficient healing. Although we previously demonstrated in clinical testing that RHCIII-based implants stimulated cornea regeneration in patients, the rate of epithelial cell coverage of the implants needs improvement, e.g. modification of the implant surface. We now show that our 500μm thick RHCIII-MPC constructs comprising over 85% water are suitable for microcontact printing with fibronectin. The resulting fibronectin micropatterns promote cell adhesion, unlike the bare RHCIII-MPC hydrogel. Interestingly, a pattern of 30μm wide fibronectin stripes enhanced cell attachment and showed the highest mitotic rates, an effect that potentially can be utilized for faster integration of the implant. We have therefore shown that laboratory-produced mimics of naturally occurring collagen and phospholipids can be fabricated into robust hydrogels that can be laser profiled and patterned to enhance their potential function as artificial substitutes of donor human corneas.
Topics: Cell Adhesion; Cell Line; Cell Proliferation; Collagen; Humans; Hydrogels; Phosphorylcholine; Recombinant Proteins; Regenerative Medicine
PubMed: 25448347
DOI: 10.1016/j.actbio.2014.10.035 -
Lancet (London, England) Dec 1998There is no effective oral treatment for visceral leishmaniasis (kala-azar), a disseminated intracellular protozoal infection that occurs worldwide. Miltefosine, an... (Clinical Trial)
Clinical Trial
BACKGROUND
There is no effective oral treatment for visceral leishmaniasis (kala-azar), a disseminated intracellular protozoal infection that occurs worldwide. Miltefosine, an alkyl phospholipid developed as an oral antineoplastic agent, is active against visceral infection in animal models. We tested safety, tolerance, and efficacy of miltefosine in kala-azar.
METHODS
Oral doses of miltefosine were given to six groups of five Indian men for 28 days: 50 mg every second day (group 1), 100 mg every second day (group 2), 100 mg/day (group 3), 150 mg/day (group 4), 200 mg/day (group 5), and 250 mg/day (group 6). Assessment for apparent cure--taken as an afebrile state with decreased spleen size and a splenic-aspirate parasite-density score of 0--was done on days 14 and 28. Definitive cure at 8 months required a parasite-free bone-marrow aspirate and no clinical evidence of relapse.
FINDINGS
21 of 30 patients were apparently cured on day 14. Transient episodes of vomiting and diarrhoea, were common during weeks 1-2 and were seen in 22 patients. Four other patients in groups 5 and 6 had miltefosine withdrawn after 7-10 days because of vomiting. One patient in group 6 developed renal insufficiency and severe diarrhoea and died on day 21. On day 28, all 29 remaining patients were apparently cured. By 8 months, seven of ten patients in groups 1 and 2 had relapsed; however, 18 of 19 patients treated daily (groups 3-6) appeared to be cured. Among the 21 definitive cures were the four patients treated for 10 days or less and 12 for whom previous therapy with pentavalent antimony had failed.
INTERPRETATION
Treatment with miltefosine at 100-150 mg/day for 4 weeks has promise as an effective oral treatment of visceral leishmaniasis including antimony-resistant infection.
Topics: Administration, Oral; Adolescent; Adult; Antiprotozoal Agents; Drug Administration Schedule; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Phosphorylcholine; Treatment Outcome; Vomiting
PubMed: 9851383
DOI: 10.1016/S0140-6736(98)04367-0 -
Experimental Parasitology Apr 2018Alkylphospholipid analogs were initially developed as anticancer agents and were later found to antiparasitic activity. Miltefosine is the prototype alkylphosphocholine...
Alkylphospholipid analogs were initially developed as anticancer agents and were later found to antiparasitic activity. Miltefosine is the prototype alkylphosphocholine and is the first oral treatment against visceral leishmaniasis. Here we investigated the effects of miltefosine and two ring-substituted alkylphosphocholine derivatives, TCAN26 and TC70, on the viability, morphology, and ultrastructure of the life stages of Caenorhabditis elegans and infective larvae of the parasite Strongyloides venezuelensis. Miltefosine displayed activity against C. elegans adults at low concentrations and was more effective than TCAN26 and TC70. Miltefosine inhibited the hatching of eggs, leading to embryonic lethality, and showed larvicidal activity against C. elegans and S. venezuelensis larvae after 24 h. Mitelfosine also induced alterations in the reproductive system of hermaphrodites, causing vulvar prolapse and general effects in the body wall. Electron microscopy analysis showed that miltefosine induced selective embryonic lethality, leading to cell death. Our results suggest that alkylphospholipid analogs are a potential new alternative for anti-nematode chemotherapy.
Topics: Animals; Antinematodal Agents; Caenorhabditis elegans; Feces; Larva; Male; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Phospholipids; Phosphorylcholine; Rats; Rats, Wistar; Strongyloides
PubMed: 29496523
DOI: 10.1016/j.exppara.2018.02.004