10 research outputs found
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Formulation and Development of Clinically Relevant Drugs
No full textThis dissertation makes contributions to the fields of anticancer drug formulation, synthesis and applications of nanoparticle adjuvants, and structure-activity relationships in drug discovery. Many drugs that are promising clinical candidates are potent in vitro, however their solubility and pharmacokinetic properties are suboptimal. Here we used various nano-formulations, primarily mesoporous silica nanoparticles, to improve the solubility and release properties of these drugs. In vivo results show that these nanoparticles are safe, multifunctional carriers that can be used for clinical imaging using positron emission tomography. In the second part of this work, porous aluminum oxide nanoparticles were synthesized for applications as immunological adjuvants, and polymer-coated mesoporous silica nanoparticles were used to deliver cyclic dinucleotides to stimulate the innate immune response. Lastly, UV-Vis spectroscopic assays were developed and used to understand how electronic properties of iron-binding heterocyclic thiosemicarbazone analogs are related to their inhibition of ribonucleotide reductase, an important target for cancer therapy. The structure-activity relationships that were discovered led to a promising drug scaffold for the treatment of cancers sensitive to nucleotide deprivation
Enhanced CO Oxidation Rates at the Interface of Mesoporous Oxides and Pt Nanoparticles
No full textThe interaction of the metal and support in oxide-supported transition-metal catalysts has been proven to have extremely favorable effects on catalytic performance. Herein, mesoporous Co3O4, NiO, MnO2, Fe2O3, and CeO2 were synthesized and utilized in CO oxidation reactions to compare the catalytic activities before and after loading of 2.5 nm Pt nanoparticles. Turnover frequencies (TOFs) of pure mesoporous oxides were 0.0002–0.015 s–1, while mesoporous silica was catalytically inactive in CO oxidation. When Pt nanoparticles were loaded onto the oxides, the TOFs of the Pt/metal oxide systems (0.1–500 s–1) were orders of magnitude greater than those of the pure oxides or the silica-supported Pt nanoparticles. The catalytic activities of various Pt/oxide systems were further influenced by varying the ratio of CO and O2 in the reactant gas feed, which provided insight into the mechanism of the observed support effect. In situ characterization using near-edge X-ray absorption fine structure (NEXAFS) and ambient-pressure X-ray photoelectron spectroscopy (APXPS) under catalytically relevant reaction conditions demonstrated a strong correlation between the oxidation state of the oxide support and the catalytic activity at the oxide–metal interface. Through catalytic activity measurements and in situ X-ray spectroscopic probes, CoO, Mn3O4, and CeO2 have been identified as the active surface phases of the oxide at the interface with Pt nanoparticles.close523
Nanoparticle Formulation of Moxifloxacin and Intramuscular Route of Delivery Improve Antibiotic Pharmacokinetics and Treatment of Pneumonic Tularemia in a Mouse Model
No full textActivity and electrochemical properties: iron complexes of the anticancer drug triapine and its analogs
No full textRecommended from our members
Activity and electrochemical properties: iron complexes of the anticancer drug triapine and its analogs
No full textTriapine (3-AP), is an iron-binding ligand and anticancer drug that is an inhibitor of human ribonucleotide reductase (RNR). Inhibition of RNR by 3-AP results in the depletion of dNTP precursors of DNA, thereby selectively starving fast-replicating cancer cells of nucleotides for survival. The redox-active form of 3-AP directly responsible for inhibition of RNR is the Fe(II)(3-AP)2 complex. In this work, we synthesize 12 analogs of 3-AP, test their inhibition of RNR in vitro, and study the electronic properties of their iron complexes. The reduction and oxidation events of 3-AP iron complexes that are crucial for the inhibition of RNR are modeled with solution studies. We monitor the pH necessary to induce reduction in iron complexes of 3-AP analogs in a reducing environment, as well as the kinetics of oxidation in an oxidizing environment. The oxidation state of the complex is monitored using UV–Vis spectroscopy. Isoquinoline analogs of 3-AP favor the maintenance of the biologically active reduced complex and possess oxidation kinetics that allow redox cycling, consistent with their effective inhibition of RNR seen in our in vitro experiments. In contrast, methylation on the thiosemicarbazone secondary amine moiety of 3-AP produces analogs that form iron complexes with much higher redox potentials, that do not redox cycle, and are inactive against RNR in vitro.Graphic abstractThe catalytic subunit of human Ribonucleotide Reductase (RNR), contains a tyrosyl radical in the enzyme active site. Fe(II) complexes of 3-AP and its analogs can quench the radical and, subsequently, inactivate RNR. The potency of RNR inhibitors is highly dependent on the redox properties of the iron complexes, which can be tuned by ligand modifications. Complexes are found to be active within a narrow redox window imposed by the cellular environment
Nanoparticle Formulation of Moxifloxacin and Intramuscular Route of Delivery Improve Antibiotic Pharmacokinetics and Treatment of Pneumonic Tularemia in a Mouse Model
No full textFrancisella tularensis causes a serious and often fatal infection, tularemia. We compared the efficacy of moxifloxacin formulated as free drug vs disulfide snap-top mesoporous silica nanoparticles (MSNs) in a mouse model of pneumonic tularemia. We found that MSN-formulated moxifloxacin was more effective than free drug and that the intramuscular and subcutaneous routes were markedly more effective than the intravenous route. Measurement of tissue silica levels and fluorescent flow cytometry assessment of colocalization of MSNs with infected cells revealed that the enhanced efficacy of MSNs and the intramuscular route of delivery was not due to better delivery of MSNs to infected tissues or cells. However, moxifloxacin blood levels demonstrated that the nanoparticle formulation and intramuscular route provided the longest half-life and longest time above the minimal inhibitory concentration. Thus, improved pharmacokinetics are responsible for the greater efficacy of nanoparticle formulation and intramuscular delivery compared with free drug and intravenous delivery
Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models
No full textEvaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models
No full textThe lead compound, an ⍺-N-heterocyclic
carboxaldehyde thiosemicarbazone HCT-13,
was highly potent against a panel of pancreatic, small cell lung carcinoma, and
prostate cancer models, with IC90 values in the low-to-mid nanomolar
range. We show that the cytotoxicity of HCT-13 is copper-dependent, that it acts as a copper ionophore,
induces production of reactive oxygen species (ROS), and promotes mitochondrial
dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress
response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM)
and Rad3-related protein kinase (ATR), were identified as actionable adaptive
resistance mechanisms following HCT-13 treatment. Taken together, HCT-13
is potent against solid tumor models and warrants in vivo evaluation
against aggressive tumor models, either as a single agent or as part of a
combination therapy
An interactive quantitative temporal physiological model of glucose passage and absorption through the gastrointestinal tract and subsequent modulation of insulin and glucagon secretion in humans
No full textEvaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models
No full textThe lead compound, an ⍺-N-heterocyclic
carboxaldehyde thiosemicarbazone HCT-13,
was highly potent against a panel of pancreatic, small cell lung carcinoma, and
prostate cancer models, with IC90 values in the low-to-mid nanomolar
range. We show that the cytotoxicity of HCT-13 is copper-dependent, that it acts as a copper ionophore,
induces production of reactive oxygen species (ROS), and promotes mitochondrial
dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress
response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM)
and Rad3-related protein kinase (ATR), were identified as actionable adaptive
resistance mechanisms following HCT-13 treatment. Taken together, HCT-13
is potent against solid tumor models and warrants in vivo evaluation
against aggressive tumor models, either as a single agent or as part of a
combination therapy
