Anatoliy Popov | University of Pennsylvania (original) (raw)
Papers by Anatoliy Popov
Molecular cancer therapeutics, Jan 5, 2015
Abnormal choline metabolism is a hallmark of cancer and is associated with oncogenesis and tumor ... more Abnormal choline metabolism is a hallmark of cancer and is associated with oncogenesis and tumor progression. Increased choline is consistently observed in both pre-clinical tumor models and in human brain tumors by proton magnetic resonance spectroscopy (MRS). Thus, inhibition of choline metabolism using specific choline kinase inhibitors such as MN58b may be a promising new strategy for treatment of brain tumors. We demonstrate the efficacy of MN58b in suppressing phosphocholine production in three brain tumor cell lines. In vivo MRS studies of rats with intra-cranial F98-derived brain tumors showed a significant decrease in tumor total choline concentration after treatment with MN58b. High resolution MRS of tissue extracts confirmed that this decrease was due to a significant reduction in phosphocholine. Concomitantly, a significant increase in poly-unsaturated lipid resonances was also observed in treated tumors, indicating apoptotic cell death. Magnetic resonance imaging (MRI) ...
Journal of Nuclear Medicine, 2015
We report the design, testing, and in vivo application of pH-sensitive contrast agents designed s... more We report the design, testing, and in vivo application of pH-sensitive contrast agents designed specifically for Cerenkov imaging. Radioisotopes used for PET emit photons via Cerenkov radiation. The multispectral emission of Cerenkov radiation allows for selective bandwidth quenching, in which a band of photons is quenched by absorption by a functional dye. Under acidic conditions, 18 F-labeled derivatives emit the full spectrum of Cerenkov light. Under basic conditions, the dyes change color and a wavelength-dependent quenching of Cerenkov emission is observed. Methods: Monoand di-18 F-labeled derivatives of phenolsulfonphthalein (phenol red) and meta-cresolsulfonphthalein (cresol purple) were synthesized by electrophilic fluorination. Cerenkov emission was measured at different wavelengths as a function of pH in vitro. Intramolecular response was measured in fluorinated probes and intermolecular quenching by mixing phenolphthalein with 18 F-FDG. Monofluorocresol purple (MFCP) was tested in mice treated with acetazolamide to cause urinary alkalinization, and Cerenkov images were compared with PET images. Results: Fluorinated pH indicators were produced with radiochemical yields of 4%-11% at greater than 90% purity. Selective Cerenkov quenching was observed intramolecularly with difluorophenol red or monofluorocresol purple and intermolecularly in phenolphthalein 18 F-FDG mixtures. The probes were selectively quenched in the bandwidth closest to the indicator's absorption maximum (λ max ) at pHs above the indicator pK a (the negative logarithm of the acid dissociation constant). Addition of acid or base to the probes resulted in reversible switching from unquenched to quenched emission. In vivo, the bladders of acetazolamide-treated mice exhibited a wavelength-dependent quenching in Cerenkov emission, with the greatest reduction occurring near the λ max . Ratiometric imaging at 2 wavelengths showed significant decreases in Cerenkov emission at basic pH and allowed the estimation of absolute pH in vivo. Conclusion: We have created contrast agents that selectively quench photons emitted during Cerenkov radiation within a given bandwidth. In the presence of a functional dye, such as a pH indicator, this selective quenching allows for a functional determination of pH in vitro and in vivo. This method can be used to obtain functional information from radiolabeled probes using multimodal imaging. This approach allows for the imaging of nonfluorescent chromophores and is generalizable to any functional dye that absorbs at suitable wavelengths.
The primary focus of this work was to develop activatable probes suitable for in vivo detection o... more The primary focus of this work was to develop activatable probes suitable for in vivo detection of phospholipase activity. Phospholipases (PLs) are ubiquitous enzymes that perform a number of critical regulatory functions. They catalyze phospholipid breakdown and are categorized as A 1 , A 2 (PLA 2 ), C (PLC), and D (PLD) based on their site of action. Here, we report the design, synthesis, and characterization of self-quenching reporter probes that release fluorescent moieties upon cleavage with PLA 2 or PLC. A series of phospholipids were synthesized bearing the NIR fluorophore pyropheophorbide a (Pyro) at the sn-2 position. Fluorescence quenching was achieved by attachment of either a positively charged black hole quencher-3 (BHQ-3) to the phospholipid headgroup or another neutral Pyro moiety at the sn-1 position. The specificity to different phospholipases was modulated by insertion of spacers (C 6 , C 12 ) between Pyro and the lipid backbone. The specificity of the quenched fluorescent phospholipids was assayed on a plate reader against a number of phospholipases and compared with two commercial probes bearing the visible fluorophore BODIPY. While PyroC 6 -PyroC 6 -PtdCho revealed significant background fluorescence, and a 10% fluorescence increase under the action of PLA 2 , Pyro-PtdEtn-BHQ demonstrated high selective sensitivity to PLC, particularly to the PC-PLC isoform, and its sensitivity to PLA 2 was negligible due to steric hindrance at the sn-2 position. In contrast, the C 12 -spacered PyroC 12 -PtdEtn-BHQ demonstrated a remarkable selectivity for PLA 2 and the best relative PLA 2 /PLC sensitivity, significantly outperforming previously known probes. These results open an avenue for future in vivo experiments and for new probes to detect PL activity.
Journal of Fluorine Chemistry, 2013
Molecular cancer therapeutics, 2014
Choline kinase alpha (ChoK) expression is increasingly being recognized as an important indicator... more Choline kinase alpha (ChoK) expression is increasingly being recognized as an important indicator of breast cancer prognosis; however, previous efforts to noninvasively measure ChoK status have been complicated by the spectral limitations of in vivo magnetic resonance spectroscopy (MRS) and the complex network of enzymes involved in choline metabolism. The most effective ChoK inhibitors are symmetric and contain quaternary ammonium groups within heterocyclic head groups connected by an aliphatic spacer. Characterization of these bis-pyridinium and bis-quinolinium compounds has led to phase I clinical trials to assess small-molecule inhibitors of ChoK for solid tumor treatment. We report the development of a novel carbocyanine dye, JAS239, whose bis-indolium structure conforms to the parameters established for ChoK specificity and whose spacer length confers fluorescence in the near-infrared (NIR) window. Fluorimetry and confocal microscopy were used to demonstrate that JAS239 rapidly enters breast cancer cells independent of the choline transporters, with accumulation in the cytosolic space where ChoK is active. Radio-tracing and 1 H MRS techniques were used to determine that JAS239 binds and competitively inhibits ChoK intracellularly, preventing choline phosphorylation while inducing cell death in breast cancer cell lines with similar efficacy to known ChoK inhibitors. Fluorescent molecules that report on ChoK status have potential use as companion diagnostics for noninvasive breast tumor staging, because NIR fluorescence allows for detection of real-time probe accumulation in vivo.
Journal of Fluorine Chemistry, 2015
We present the synthesis and characterization of F18-labeled fluorinated derivatives of resazurin... more We present the synthesis and characterization of F18-labeled fluorinated derivatives of resazurin, a probe for cell viability. The compounds were prepared by direct fluorination of resazurin with diluted [F18]-F2 gas under acidic conditions. The fluorination occurs into the ortho-positions to the hydroxyl group producing various mono-, di-, and trifluorinated derivatives. The properties of the fluorinated resazurins are similar to the parent compound with the addition of fluorine leading to decreased pKa values and a bathochromic shift of the absorption maxima. The fluorinated resazurin derivatives can be used as probes for observation of cell viability in various cells, tissues and organs using a combination of positron emission tomography and direct optical imaging of Cerenkov luminescence.
Progress in Lipid Research, 2016
It is well established that lipid metabolism is drastically altered during tumor development and ... more It is well established that lipid metabolism is drastically altered during tumor development and response to therapy. Choline kinase alpha (ChoKα) is a key mediator of these changes, as it represents the first committed step in the Kennedy Pathway of phosphatidylcholine biosynthesis and ChoKα expression is upregulated in many human cancers. ChoKα activity is associated with drug resistant, metastatic, and malignant phenotypes, and represents a robust biomarker and therapeutic target in cancer. Effective ChoKα inhibitors have been developed and have recently entered clinical trials. ChoKα's clinical relevance was, until recently, attributed solely to its production of second messenger intermediates of phospholipid synthesis. The recent discovery of a non-catalytic scaffolding function of ChoKα may link growth receptor signaling to lipid biogenesis and requires a reinterpretation of the design and validation of ChoKα inhibitors. Advances in positron emission tomography, magnetic resonance spectroscopy, and optical imaging methods now allow for a comprehensive understanding of ChoKα expression and activity in vivo. We will review the current understanding of ChoKα metabolism, its role in tumor biology and the development and validation of targeted therapies and companion diagnostics for this important regulatory enzyme. This comes at a critical time as ChoKα-targeting programs receive more clinical interest.
European radiology, Jan 24, 2016
Dual-energy (DE) mammography has recently entered the clinic. Previous theoretical and phantom st... more Dual-energy (DE) mammography has recently entered the clinic. Previous theoretical and phantom studies demonstrated that silver provides greater contrast than iodine for this technique. Our objective was to characterize and evaluate in vivo a prototype silver contrast agent ultimately intended for DE mammography. The prototype silver contrast agent was synthesized using a three-step process: synthesis of a silver core, silica encapsulation and PEG coating. The nanoparticles were then injected into mice to determine their accumulation in various organs, blood half-life and dual-energy contrast. All animal procedures were approved by the institutional animal care and use committee. The final diameter of the nanoparticles was measured to be 102 (±9) nm. The particles were removed from the vascular circulation with a half-life of 15 min, and accumulated in macrophage-rich organs such as the liver, spleen and lymph nodes. Dual-energy subtraction techniques increased the signal difference...
RSC Adv., 2016
The reversible addition-fragmentation chain transfer (RAFT) of N-vinyl caprolactam (NVCL) using t... more The reversible addition-fragmentation chain transfer (RAFT) of N-vinyl caprolactam (NVCL) using two new xanthates with alkyne functionalities is reported. The kinetic data obtained for polymerization of this non-activated monomer using a protected alkyne-terminated RAFT agent (PAT-X1) revealed a linear increase of the polymer molecular weight with the monomer conversion as well as low dispersity (Đ) during the entire course of the polymerization. The system reported here allowed us to enhance the final conversion, diminish Đ and reduce the polymerization temperature compared to the typical values reported in the scarce literature available for the RAFT polymerization of NVCL. The resulting PNVCL was fully characterized using (1)H nuclear magnetic resonance ((1)H NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), Fourier-transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC) techniques. The temperature-responsive features of PNVCL in aqueous solutions were fully investigated under different conditions using turbidimetry. The presented strategy allows the synthesis of well-defined PNVCL with sharp and reversible phase transition temperatures around 37 °C. By manipulating the polymer molecular weight, or the solution properties, it is possible to tune the PNVCL phase transition. As a proof-of concept, the alkyne functionalized PNVCL was used to afford new linear block copolymers, by reacting with an azide-terminated poly(ethylene glycol) (N3-PEG) through the copper catalyzed azide-alkyne [3+2] dipolar cycloaddition (CuAAC) reaction. The results presented establish a robust system to afford the synthesis of PNCVL with fine tuned characteristics that will enable more efficient exploration of the remarkable potential of this polymer in biomedical applications.
![Research paper thumbnail of Corrigendum to “Synthesis of 3,3,3-trifluoroethyl isocyanate, carbamate and ureas. Anticancer activity evaluation of N-(3,3,3-trifluoroethyl)-N’-substituted ureas” [J. Fluorine Chem. 176 (2015) 82–88]](https://attachments.academia-assets.com/45275595/thumbnails/1.jpg)
](Journal of Fluorine Chemistry, 2015
J Polym Sci a Polym Chem, 2005
Bioconjugate Chemistry, 2015
Activatable fluorophores selective to cytosolic phospholipase A2 (cPLA2) were synthesized and eva... more Activatable fluorophores selective to cytosolic phospholipase A2 (cPLA2) were synthesized and evaluated for their ability to image triple negative breast cancer cells. The activatable constructs were synthesized by esterification of a small molecule fluorophore with a fatty acid resulting in ablated fluorescence. Selectivity for cPLA2 was generated through the choice of fluorophore and fatty acid. Esterification with arachidonic acid was sufficient to impart specificity to cPLA2 when compared to esterification with palmitic acid. In vitro analysis of probes incorporated into phosphatidylcholine liposomes demonstrated that a nonselective phospholipase (sPLA2 group IB) was able to hydrolyze both arachidonate and palmitate coupled fluorophores resulting in the generation of fluorescence. Of the four fluorophores tested, DDAO (7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one)) was observed to perform optimally in vitro and was analyzed further in 4175-Luc+ cells, a metastatic triple negative human breast cancer cell line expressing high levels of cPLA2. In contrast to the in vitro analysis, DDAO arachidonate was shown to activate selectively in 4175-Luc+ cells compared to the control DDAO palmitate as measured by fluorescence microscopy and quantitated with fluorescence spectroscopy. The addition of two agents known to activate cPLA2 enhanced DDAO arachidonate fluorescence without inducing any change to DDAO palmitate. Inhibition of cPLA2 resulted in reduced fluorescence of DDAO arachidonate but not DDAO palmitate. Together, we report the synthesis of a cPLA2 selective activatable fluorophore capable of detecting cPLA2 in triple negative breast cancer cells.
TARGET AUDIENCE. Clinicians and basic sciences interested in preclinical cancer imaging and molec... more TARGET AUDIENCE. Clinicians and basic sciences interested in preclinical cancer imaging and molecular imaging. PURPOSE. Heightened Choline Kinase (ChoK) activity has been reported in nearly 40% of human breast cancers, indicating that a large cohort of patients can benefit from therapies designed to exploit aberrant choline metabolism 1 . ChoK is an oncogene whose overexpression provides cancer cells with growth factors and biosynthetic precursors. With the development of ChoK inhibitors, MRS has been implemented to validate treatment efficacy. We have developed Near Infrared Fluorescence (NIRF) imaging agents, such as JAS239, that act as competitive inhibitors of ChoK 2 and allow for the assessment of ChoK expression complementary to the metabolite levels detected by MRS. Here we employ JAS239 as a companion diagnostic for evaluating ChoK-targeted treatments.
A copolymer comprises: a block copolymer comprising at least one A block and at least one B block... more A copolymer comprises: a block copolymer comprising at least one A block and at least one B block, wherein the B block is a halogen contg. polymer or copolymer having at least one initiator, and, wherein the A block is derived from the living radical polymn. of one or more acrylic monomers in the presence of the initiator contg. B block, and either (i) a metal catalyst, and optionally a ligand, or (ii) a metal-free catalyst, and optionally a buffer. Moreover, block copolymers of vinyl halide monomers and acrylic monomers are described by generally polymg. either the vinyl halide monomers or acrylic monomers utilizing an organo halide initiator in the presence of either a metal catalyst or a metal-free catalyst and subsequently polymg. thereon the remaining type of monomer. [on SciFinder(R)]
ChemInform, 1991
ABSTRACT Fluorination of (RO)2P(O)H (R = Et, Pr, Me2CH) with CF3CHFCF2N3 (I) in Et3N gave 70-75% ... more ABSTRACT Fluorination of (RO)2P(O)H (R = Et, Pr, Me2CH) with CF3CHFCF2N3 (I) in Et3N gave 70-75% (RO)2P(O)F. Treating Ph2P(O)H with I in CHCl3 gave 58% Ph2P(O)F.
Molecular cancer therapeutics, Jan 5, 2015
Abnormal choline metabolism is a hallmark of cancer and is associated with oncogenesis and tumor ... more Abnormal choline metabolism is a hallmark of cancer and is associated with oncogenesis and tumor progression. Increased choline is consistently observed in both pre-clinical tumor models and in human brain tumors by proton magnetic resonance spectroscopy (MRS). Thus, inhibition of choline metabolism using specific choline kinase inhibitors such as MN58b may be a promising new strategy for treatment of brain tumors. We demonstrate the efficacy of MN58b in suppressing phosphocholine production in three brain tumor cell lines. In vivo MRS studies of rats with intra-cranial F98-derived brain tumors showed a significant decrease in tumor total choline concentration after treatment with MN58b. High resolution MRS of tissue extracts confirmed that this decrease was due to a significant reduction in phosphocholine. Concomitantly, a significant increase in poly-unsaturated lipid resonances was also observed in treated tumors, indicating apoptotic cell death. Magnetic resonance imaging (MRI) ...
Journal of Nuclear Medicine, 2015
We report the design, testing, and in vivo application of pH-sensitive contrast agents designed s... more We report the design, testing, and in vivo application of pH-sensitive contrast agents designed specifically for Cerenkov imaging. Radioisotopes used for PET emit photons via Cerenkov radiation. The multispectral emission of Cerenkov radiation allows for selective bandwidth quenching, in which a band of photons is quenched by absorption by a functional dye. Under acidic conditions, 18 F-labeled derivatives emit the full spectrum of Cerenkov light. Under basic conditions, the dyes change color and a wavelength-dependent quenching of Cerenkov emission is observed. Methods: Monoand di-18 F-labeled derivatives of phenolsulfonphthalein (phenol red) and meta-cresolsulfonphthalein (cresol purple) were synthesized by electrophilic fluorination. Cerenkov emission was measured at different wavelengths as a function of pH in vitro. Intramolecular response was measured in fluorinated probes and intermolecular quenching by mixing phenolphthalein with 18 F-FDG. Monofluorocresol purple (MFCP) was tested in mice treated with acetazolamide to cause urinary alkalinization, and Cerenkov images were compared with PET images. Results: Fluorinated pH indicators were produced with radiochemical yields of 4%-11% at greater than 90% purity. Selective Cerenkov quenching was observed intramolecularly with difluorophenol red or monofluorocresol purple and intermolecularly in phenolphthalein 18 F-FDG mixtures. The probes were selectively quenched in the bandwidth closest to the indicator's absorption maximum (λ max ) at pHs above the indicator pK a (the negative logarithm of the acid dissociation constant). Addition of acid or base to the probes resulted in reversible switching from unquenched to quenched emission. In vivo, the bladders of acetazolamide-treated mice exhibited a wavelength-dependent quenching in Cerenkov emission, with the greatest reduction occurring near the λ max . Ratiometric imaging at 2 wavelengths showed significant decreases in Cerenkov emission at basic pH and allowed the estimation of absolute pH in vivo. Conclusion: We have created contrast agents that selectively quench photons emitted during Cerenkov radiation within a given bandwidth. In the presence of a functional dye, such as a pH indicator, this selective quenching allows for a functional determination of pH in vitro and in vivo. This method can be used to obtain functional information from radiolabeled probes using multimodal imaging. This approach allows for the imaging of nonfluorescent chromophores and is generalizable to any functional dye that absorbs at suitable wavelengths.
The primary focus of this work was to develop activatable probes suitable for in vivo detection o... more The primary focus of this work was to develop activatable probes suitable for in vivo detection of phospholipase activity. Phospholipases (PLs) are ubiquitous enzymes that perform a number of critical regulatory functions. They catalyze phospholipid breakdown and are categorized as A 1 , A 2 (PLA 2 ), C (PLC), and D (PLD) based on their site of action. Here, we report the design, synthesis, and characterization of self-quenching reporter probes that release fluorescent moieties upon cleavage with PLA 2 or PLC. A series of phospholipids were synthesized bearing the NIR fluorophore pyropheophorbide a (Pyro) at the sn-2 position. Fluorescence quenching was achieved by attachment of either a positively charged black hole quencher-3 (BHQ-3) to the phospholipid headgroup or another neutral Pyro moiety at the sn-1 position. The specificity to different phospholipases was modulated by insertion of spacers (C 6 , C 12 ) between Pyro and the lipid backbone. The specificity of the quenched fluorescent phospholipids was assayed on a plate reader against a number of phospholipases and compared with two commercial probes bearing the visible fluorophore BODIPY. While PyroC 6 -PyroC 6 -PtdCho revealed significant background fluorescence, and a 10% fluorescence increase under the action of PLA 2 , Pyro-PtdEtn-BHQ demonstrated high selective sensitivity to PLC, particularly to the PC-PLC isoform, and its sensitivity to PLA 2 was negligible due to steric hindrance at the sn-2 position. In contrast, the C 12 -spacered PyroC 12 -PtdEtn-BHQ demonstrated a remarkable selectivity for PLA 2 and the best relative PLA 2 /PLC sensitivity, significantly outperforming previously known probes. These results open an avenue for future in vivo experiments and for new probes to detect PL activity.
Journal of Fluorine Chemistry, 2013
Molecular cancer therapeutics, 2014
Choline kinase alpha (ChoK) expression is increasingly being recognized as an important indicator... more Choline kinase alpha (ChoK) expression is increasingly being recognized as an important indicator of breast cancer prognosis; however, previous efforts to noninvasively measure ChoK status have been complicated by the spectral limitations of in vivo magnetic resonance spectroscopy (MRS) and the complex network of enzymes involved in choline metabolism. The most effective ChoK inhibitors are symmetric and contain quaternary ammonium groups within heterocyclic head groups connected by an aliphatic spacer. Characterization of these bis-pyridinium and bis-quinolinium compounds has led to phase I clinical trials to assess small-molecule inhibitors of ChoK for solid tumor treatment. We report the development of a novel carbocyanine dye, JAS239, whose bis-indolium structure conforms to the parameters established for ChoK specificity and whose spacer length confers fluorescence in the near-infrared (NIR) window. Fluorimetry and confocal microscopy were used to demonstrate that JAS239 rapidly enters breast cancer cells independent of the choline transporters, with accumulation in the cytosolic space where ChoK is active. Radio-tracing and 1 H MRS techniques were used to determine that JAS239 binds and competitively inhibits ChoK intracellularly, preventing choline phosphorylation while inducing cell death in breast cancer cell lines with similar efficacy to known ChoK inhibitors. Fluorescent molecules that report on ChoK status have potential use as companion diagnostics for noninvasive breast tumor staging, because NIR fluorescence allows for detection of real-time probe accumulation in vivo.
Journal of Fluorine Chemistry, 2015
We present the synthesis and characterization of F18-labeled fluorinated derivatives of resazurin... more We present the synthesis and characterization of F18-labeled fluorinated derivatives of resazurin, a probe for cell viability. The compounds were prepared by direct fluorination of resazurin with diluted [F18]-F2 gas under acidic conditions. The fluorination occurs into the ortho-positions to the hydroxyl group producing various mono-, di-, and trifluorinated derivatives. The properties of the fluorinated resazurins are similar to the parent compound with the addition of fluorine leading to decreased pKa values and a bathochromic shift of the absorption maxima. The fluorinated resazurin derivatives can be used as probes for observation of cell viability in various cells, tissues and organs using a combination of positron emission tomography and direct optical imaging of Cerenkov luminescence.
Progress in Lipid Research, 2016
It is well established that lipid metabolism is drastically altered during tumor development and ... more It is well established that lipid metabolism is drastically altered during tumor development and response to therapy. Choline kinase alpha (ChoKα) is a key mediator of these changes, as it represents the first committed step in the Kennedy Pathway of phosphatidylcholine biosynthesis and ChoKα expression is upregulated in many human cancers. ChoKα activity is associated with drug resistant, metastatic, and malignant phenotypes, and represents a robust biomarker and therapeutic target in cancer. Effective ChoKα inhibitors have been developed and have recently entered clinical trials. ChoKα's clinical relevance was, until recently, attributed solely to its production of second messenger intermediates of phospholipid synthesis. The recent discovery of a non-catalytic scaffolding function of ChoKα may link growth receptor signaling to lipid biogenesis and requires a reinterpretation of the design and validation of ChoKα inhibitors. Advances in positron emission tomography, magnetic resonance spectroscopy, and optical imaging methods now allow for a comprehensive understanding of ChoKα expression and activity in vivo. We will review the current understanding of ChoKα metabolism, its role in tumor biology and the development and validation of targeted therapies and companion diagnostics for this important regulatory enzyme. This comes at a critical time as ChoKα-targeting programs receive more clinical interest.
European radiology, Jan 24, 2016
Dual-energy (DE) mammography has recently entered the clinic. Previous theoretical and phantom st... more Dual-energy (DE) mammography has recently entered the clinic. Previous theoretical and phantom studies demonstrated that silver provides greater contrast than iodine for this technique. Our objective was to characterize and evaluate in vivo a prototype silver contrast agent ultimately intended for DE mammography. The prototype silver contrast agent was synthesized using a three-step process: synthesis of a silver core, silica encapsulation and PEG coating. The nanoparticles were then injected into mice to determine their accumulation in various organs, blood half-life and dual-energy contrast. All animal procedures were approved by the institutional animal care and use committee. The final diameter of the nanoparticles was measured to be 102 (±9) nm. The particles were removed from the vascular circulation with a half-life of 15 min, and accumulated in macrophage-rich organs such as the liver, spleen and lymph nodes. Dual-energy subtraction techniques increased the signal difference...
RSC Adv., 2016
The reversible addition-fragmentation chain transfer (RAFT) of N-vinyl caprolactam (NVCL) using t... more The reversible addition-fragmentation chain transfer (RAFT) of N-vinyl caprolactam (NVCL) using two new xanthates with alkyne functionalities is reported. The kinetic data obtained for polymerization of this non-activated monomer using a protected alkyne-terminated RAFT agent (PAT-X1) revealed a linear increase of the polymer molecular weight with the monomer conversion as well as low dispersity (Đ) during the entire course of the polymerization. The system reported here allowed us to enhance the final conversion, diminish Đ and reduce the polymerization temperature compared to the typical values reported in the scarce literature available for the RAFT polymerization of NVCL. The resulting PNVCL was fully characterized using (1)H nuclear magnetic resonance ((1)H NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), Fourier-transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC) techniques. The temperature-responsive features of PNVCL in aqueous solutions were fully investigated under different conditions using turbidimetry. The presented strategy allows the synthesis of well-defined PNVCL with sharp and reversible phase transition temperatures around 37 °C. By manipulating the polymer molecular weight, or the solution properties, it is possible to tune the PNVCL phase transition. As a proof-of concept, the alkyne functionalized PNVCL was used to afford new linear block copolymers, by reacting with an azide-terminated poly(ethylene glycol) (N3-PEG) through the copper catalyzed azide-alkyne [3+2] dipolar cycloaddition (CuAAC) reaction. The results presented establish a robust system to afford the synthesis of PNCVL with fine tuned characteristics that will enable more efficient exploration of the remarkable potential of this polymer in biomedical applications.
Journal of Fluorine Chemistry, 2015
J Polym Sci a Polym Chem, 2005
Bioconjugate Chemistry, 2015
Activatable fluorophores selective to cytosolic phospholipase A2 (cPLA2) were synthesized and eva... more Activatable fluorophores selective to cytosolic phospholipase A2 (cPLA2) were synthesized and evaluated for their ability to image triple negative breast cancer cells. The activatable constructs were synthesized by esterification of a small molecule fluorophore with a fatty acid resulting in ablated fluorescence. Selectivity for cPLA2 was generated through the choice of fluorophore and fatty acid. Esterification with arachidonic acid was sufficient to impart specificity to cPLA2 when compared to esterification with palmitic acid. In vitro analysis of probes incorporated into phosphatidylcholine liposomes demonstrated that a nonselective phospholipase (sPLA2 group IB) was able to hydrolyze both arachidonate and palmitate coupled fluorophores resulting in the generation of fluorescence. Of the four fluorophores tested, DDAO (7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one)) was observed to perform optimally in vitro and was analyzed further in 4175-Luc+ cells, a metastatic triple negative human breast cancer cell line expressing high levels of cPLA2. In contrast to the in vitro analysis, DDAO arachidonate was shown to activate selectively in 4175-Luc+ cells compared to the control DDAO palmitate as measured by fluorescence microscopy and quantitated with fluorescence spectroscopy. The addition of two agents known to activate cPLA2 enhanced DDAO arachidonate fluorescence without inducing any change to DDAO palmitate. Inhibition of cPLA2 resulted in reduced fluorescence of DDAO arachidonate but not DDAO palmitate. Together, we report the synthesis of a cPLA2 selective activatable fluorophore capable of detecting cPLA2 in triple negative breast cancer cells.
TARGET AUDIENCE. Clinicians and basic sciences interested in preclinical cancer imaging and molec... more TARGET AUDIENCE. Clinicians and basic sciences interested in preclinical cancer imaging and molecular imaging. PURPOSE. Heightened Choline Kinase (ChoK) activity has been reported in nearly 40% of human breast cancers, indicating that a large cohort of patients can benefit from therapies designed to exploit aberrant choline metabolism 1 . ChoK is an oncogene whose overexpression provides cancer cells with growth factors and biosynthetic precursors. With the development of ChoK inhibitors, MRS has been implemented to validate treatment efficacy. We have developed Near Infrared Fluorescence (NIRF) imaging agents, such as JAS239, that act as competitive inhibitors of ChoK 2 and allow for the assessment of ChoK expression complementary to the metabolite levels detected by MRS. Here we employ JAS239 as a companion diagnostic for evaluating ChoK-targeted treatments.
A copolymer comprises: a block copolymer comprising at least one A block and at least one B block... more A copolymer comprises: a block copolymer comprising at least one A block and at least one B block, wherein the B block is a halogen contg. polymer or copolymer having at least one initiator, and, wherein the A block is derived from the living radical polymn. of one or more acrylic monomers in the presence of the initiator contg. B block, and either (i) a metal catalyst, and optionally a ligand, or (ii) a metal-free catalyst, and optionally a buffer. Moreover, block copolymers of vinyl halide monomers and acrylic monomers are described by generally polymg. either the vinyl halide monomers or acrylic monomers utilizing an organo halide initiator in the presence of either a metal catalyst or a metal-free catalyst and subsequently polymg. thereon the remaining type of monomer. [on SciFinder(R)]
ChemInform, 1991
ABSTRACT Fluorination of (RO)2P(O)H (R = Et, Pr, Me2CH) with CF3CHFCF2N3 (I) in Et3N gave 70-75% ... more ABSTRACT Fluorination of (RO)2P(O)H (R = Et, Pr, Me2CH) with CF3CHFCF2N3 (I) in Et3N gave 70-75% (RO)2P(O)F. Treating Ph2P(O)H with I in CHCl3 gave 58% Ph2P(O)F.