Pharmacy and Pharmaceutical Sciences Commons^™

Chromatin Structure In Situ: The Contribution Of Dna Ultrastructural Cytochemistry, Massimo Derenzini, Ada L. Olins, Donald E. Olins

Pharmaceutical Sciences Faculty Publications

Ultrastructural studies conducted in situ using conventional transmission electron microscopy have had relatively little impact on defining the structural organization of chromatin. This is due to the fact that in routine transmission electron microscopy, together with the deoxyribonucleoprotein, many different intermingled substances are contrasted, masking the ultrastructure of chromatin. By selective staining of DNA in thin sections, using the Feulgen-like osmium-ammine reaction, these drawbacks have been overcome and worthwhile data have been obtained both on the gross morphology and the ultrastructural-functional organization of chromatin in situ. In the present study these results are reviewed and discussed in light of recent …

Programmable Folding Of Fusion Rna In Vivo And In Vitro Driven By Prna 3wj Motif Of Phi29 Dna Packaging Motor, Dan Shu, Emil F. Khisamutdinov, Le Zhang, Peixuan Guo

Pharmaceutical Sciences Faculty Publications

Misfolding and associated loss of function are common problems in constructing fusion RNA complexes due to changes in energy landscape and the nearest-neighbor principle. Here we report the incorporation and application of the pRNA-3WJ motif of the phi29 DNA packaging motor into fusion RNA with controllable and predictable folding. The motif included three discontinuous ∼18 nucleotide (nt) fragments, displayed a distinct low folding energy (Shu D et al., Nature Nanotechnology, 2011, 6:658–667), and folded spontaneously into a leading core that enabled the correct folding of other functionalities fused to the RNA complex. Three individual fragments dispersed at any …

Binding, Transcytosis And Biodistribution Of Anti-Pecam-1 Iron Oxide Nanoparticles For Brain-Targeted Delivery, Mo Dan, David B. Cochran, Robert A. Yokel, Thomas D. Dziubla

Pharmaceutical Sciences Faculty Publications

OBJECTIVE: Characterize the flux of platelet-endothelial cell adhesion molecule (PECAM-1) antibody-coated superparamagnetic iron oxide nanoparticles (IONPs) across the blood-brain barrier (BBB) and its biodistribution in vitro and in vivo.

METHODS: Anti-PECAM-1 IONPs and IgG IONPs were prepared and characterized in house. The binding affinity of these nanoparticles was investigated using human cortical microvascular endothelial cells (hCMEC/D3). Flux assays were performed using a hCMEC/D3 BBB model. To test their immunospecificity index and biodistribution, nanoparticles were given to Sprague Dawley rats by intra-carotid infusion. The capillary depletion method was used to elucidate their distribution between the BBB and brain parenchyma.

RESULTS: Anti-PECAM-1 …

Release Of A Wound-Healing Agent From Plga Microspheres In A Thermosensitive Gel, H. A. Machado, J. J. Abercrombie, T. You, Patrick P. Deluca, K. P. Leung

Pharmaceutical Sciences Faculty Publications

The purpose of this research was to develop a topical microsphere delivery system in a thermosensitive 20% poloxamer 407 gel (Pluronic F127) to control release of KSL-W, a cationic antimicrobial decapeptide, for a period of 4-7 days for potential application in combat related injuries. KSL-W loaded microsphere formulations were prepared by a solvent extraction-evaporation method (water-oil-water), with poly (D,L-lactic-co-glycolic acid) (PLGA) (50 : 50, low-weight, and hydrophilic end) as the polymeric system. After optimization of the process, three formulations (A, B, and C) were prepared with different organic to water ratio of the primary emulsion while maintaining other components and …

Psmb9 Codon 60 Polymorphisms Have No Impact On The Activity Of The Immunoproteasome Catalytic Subunit B1i Expressed In Multiple Types Of Solid Cancer, Ji Eun Park, Lin Ao, Zachary Miller, Kyungbo Kim, Ying Wu, Eun Ryoung Jang, Eun Young Lee, Kyung Bo Kim, Wooin Lee

Pharmaceutical Sciences Faculty Publications

The proteasome is a key regulator of cellular protein homeostasis and is a clinically validated anticancer target. The immunoproteasome, a subtype of proteasome expressed mainly in hematopoietic cells, was initially recognized for its role in antigen presentation during the immune response. Recently, the immunoproteasome has been implicated in several disease conditions including cancer and autoimmune disorders, but many of the factors contributing to these pathological processes remain unknown. In particular, the codon 60 polymorphism of the PSMB9 gene encoding the β1i immunoproteasome catalytic subunit has been investigated in the context of a variety of diseases. Despite this, previous studies have …

Combination Of Sirna-Directed Gene Silencing With Cisplatin Reverses Drug Resistance In Human Non-Small Cell Lung Cancer, Shanthi Ganesh, Arun K. Iyer, Jan Weller, David V. Morrissey, Mansoor M. Amiji

Pharmaceutical Sciences Faculty Publications

One of the most challenging aspects of lung cancer therapy is the rapid acquisition of multidrug-resistant (MDR) phenotype. One effective approach would be to identify and downregulate resistance-causing genes in tumors using small interfering RNAs (siRNAs) to increase the sensitivity of tumor cells to chemotherapeutic challenge. After identifying the overexpressed resistance-related antiapoptotic genes (survivin and bcl-2) in cisplatin-resistant cells, the siRNA sequences were designed and screened to select the most efficacious candidates. Modifications were introduced in them to minimize off-target effects. Subsequently, the combination of siRNA and cisplatin that gave the maximum synergy was identified in resistant cells. We then …

Computational And Experimental Insights Into The Mechanism Of Substrate Recognition And Feedback Inhibition Of Protoporphyrinogen Oxidase, Ge-Fei Hao, Ying Tan, Sheng-Gang Yang, Zhi-Fang Wang, Chang-Guo Zhan, Zhen Xi, Guang-Fu Yang

Pharmaceutical Sciences Faculty Publications

Protoporphyrinogen IX oxidase (PPO; EC 1.3.3.4) is an essential enzyme catalyzing the last common step in the pathway leading to heme and chlorophyll biosynthesis. Great interest in PPO inhibitors arises from both its significance to agriculture and medicine. However, the discovery of PPO inhibitors with ultrahigh potency and selectivity is hampered due to lack of structural and mechanistic understanding about the substrate recognition, which remains a longstanding question central in porphyrin biology. To understand the mechanism, a novel binding model of protogen (protoporphyrinogen IX, the substrate) was developed through extensive computational simulations. Subsequently, amino acid residues that are critical for …

Metal-Based Nanoparticle Interactions With The Nervous System: The Challenge Of Brain Entry And The Risk Of Retention In The Organism, Robert A. Yokel, Eric A. Grulke, Robert C. Macphail

Pharmaceutical Sciences Faculty Publications

This review of metal-based nanoparticles focuses on factors influencing their distribution into the nervous system, evidence they enter brain parenchyma, and nervous system responses. Gold is emphasized as a model metal-based nanoparticle and for risk assessment in the companion review. The anatomy and physiology of the nervous system, basics of colloid chemistry, and environmental factors that influence what cells see are reviewed to provide background on the biological, physical–chemical, and internal milieu factors that influence nervous system nanoparticle uptake. The results of literature searches reveal little nanoparticle research included the nervous system, which about equally involved in vitro and in …

Gene Transfer Of Mutant Mouse Cholinesterase Provides High Lifetime Expression And Reduced Cocaine Responses With No Evident Toxicity, Liyi Geng, Yang Gao, Xiabin Chen, Shurong Hou, Chang-Guo Zhan, Zoran Radic, Robin J. Parks, Stephen J. Russell, Linh Pham, Stephen Brimijoin

Pharmaceutical Sciences Faculty Publications

Gene transfer of a human cocaine hydrolase (hCocH) derived from butyrylcholinesterase (BChE) by 5 mutations (A199S/F227A/S287G/A328W/Y332G) has shown promise in animal studies for treatment of cocaine addiction. To predict the physiological fate and immunogenicity of this enzyme in humans, a comparable enzyme was created and tested in a conspecific host. Thus, similar mutations (A199S/S227A/S287G/A328W/Y332G) were introduced into mouse BChE to obtain a mouse CocH (mCocH). The cDNA was incorporated into viral vectors based on: a) serotype-5 helper-dependent adenovirus (hdAD) with ApoE promoter, and b) serotype-8 adeno-associated virus with CMV promoter (AAV-CMV) or multiple promoter and enhancer elements (AAV-VIP). Experiments on …

Block Copolymer Self-Assembled And Cross-Linked Nanoassemblies For Combination Delivery Of Iron Oxide And Doxorubicin, Daniel Scott, Yihwa Beabout, Robert J. Wydra, Mo Dan, Robert A. Yokel, J. Zach Hilt, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

We describe the development of nanoscale polymer drug carriers for the combinational delivery of an anticancer drug (doxorubicin: DOX) along with super paramagnetic iron oxide nanoparticles (IONPs). The drug molecules were electrostatically loaded into both block copolymer self-assembled nanoassemblies (SNAs) and cross-linked nanoassemblies (CNAs). Both nanoassemblies entrapped DOX and IONPs either individually or in tandem, maintaining sub-100 nm diameter. The IONP-loaded nanoassemblies generated heat in the presence of an alternating magnetic field (AMF). Incorporation of the drug payload, DOX, showed no adverse effects on the heating profile. Drug release from the SNAs and CNAs was accelerated as temperature increased from …

Amyloid-Β Probes: Review Of Structure-Activity And Brain-Kinetics Relationships, Todd J. Eckroat, Abdelrahman S. Mayhoub, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

The number of people suffering from Alzheimer's disease (AD) is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloid-β plaques, for diagnosis and monitoring of therapeutic efficacy. …

Biodistribution And Biopersistence Of Ceria Engineered Nanomaterials: Size Dependence, Robert A. Yokel, Michael T. Tseng, Mo Dan, Jason M. Unrine, Uschi M. Graham, Peng Wu, Eric A. Grulke

Pharmaceutical Sciences Faculty Publications

The aims were to determine the biodistribution, translocation, and persistence of nanoceria in the brain and selected peripheral organs. Nanoceria is being studied as an anti-oxidant therapeutic. Five, 15, 30, or 55 nm ceria was iv infused into rats which were terminated 1, 20, or 720 h later. Cerium was determined in blood, brain, liver, and spleen. Liver and spleen contained a large percentage of the dose, from which there was no significant clearance over 720 h, associated with adverse changes. Very little nanoceria entered brain parenchyma. The results suggest brain delivery of nanoceria will be a challenge.

FROM THE …

Physicochemical Characterization And Aerosol Dispersion Performance Of Organic Solution Advanced Spray-Dried Cyclosporine A Multifunctional Particles For Dry Powder Inhalation Aerosol Delivery, Xiao Wu, Weifen Zhang, Don Hayes Jr., Heidi M. Mansour

Pharmaceutical Sciences Faculty Publications

In this systematic and comprehensive study, inhalation powders of the polypeptide immunosuppressant drug - cyclosporine A - for lung delivery as dry powder inhalers (DPIs) were successfully designed, developed, and optimized. Several spray drying pump rates were rationally chosen. Comprehensive physicochemical characterization and imaging was carried out using scanning electron microscopy, hot-stage microscopy, differential scanning calorimetry, powder X-ray diffraction, Karl Fischer titration, laser size diffraction, and gravimetric vapor sorption. Aerosol dispersion performance was conducted using a next generation impactor with a Food and Drug Administration-approved DPI device. These DPIs displayed excellent aerosol dispersion performance with high values in emitted dose, …

Block Copolymer Cross-Linked Nanoassemblies Improve Particle Stability And Biocompatibility Of Superparamagnetic Iron Oxide Nanoparticles, Mo Dan, Daniel F. Scott, Peter A. Hardy, Robert J. Wydra, J. Zach Hilt, Robert A. Yokel, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

PURPOSE: To develop cross-linked nanoassemblies (CNAs) as carriers for superparamagnetic iron oxide nanoparticles (IONPs).

METHODS: Ferric and ferrous ions were co-precipitated inside core-shell type nanoparticles prepared by cross-linking poly(ethylene glycol)-poly(aspartate) block copolymers to prepare CNAs entrapping Fe(3)O(4) IONPs (CNA-IONPs). Particle stability and biocompatibility of CNA-IONPs were characterized in comparison to citrate-coated Fe(3)O(4) IONPs (Citrate-IONPs).

RESULTS: CNA-IONPs, approximately 30 nm in diameter, showed no precipitation in water, PBS, or a cell culture medium after 3 or 30 h, at 22, 37, and 43°C, and 1, 2.5, and 5 mg/mL, whereas Citrate-IONPs agglomerated rapidly (> 400 nm) in all …

Nuclear Envelope Composition Determines The Ability Of Neutrophil-Type Cells To Passage Through Micron-Scale Constrictions, Amy C. Rowat, Diana E. Jaalouk E. Jaalouk, Monika Zwerger, W. Lloyd Ung, Irwin A. Eydelnant, Donald E. Olins, Ada L. Olins, Harald Herrmann, David A. Weitz, Jan Lammerding

Pharmaceutical Sciences Faculty Publications

Neutrophils are characterized by their distinct nuclear shape, which is thought to facilitate the transit of these cells through pore spaces less than one-fifth of their diameter. We used human promyelocytic leukemia (HL-60) cells as a model system to investigate the effect of nuclear shape in whole cell deformability. We probed neutrophil-differentiated HL-60 cells lacking expression of lamin B receptor, which fail to develop lobulated nuclei during granulopoiesis and present an in vitro model for Pelger-Huët anomaly; despite the circular morphology of their nuclei, the cells passed through micron-scale constrictions on similar timescales as scrambled controls. We then investigated the …

Activation Of Thromboxane A2 Receptor (Tp) Increases The Expression Of Monocyte Chemoattractant Protein -1 (Mcp-1)/Chemokine (C-C Motif) Ligand 2 (Ccl2) And Recruits Macrophages To Promote Invasion Of Lung Cancer Cells, Xiuling Li, Hsin-Hsiung Tai

Pharmaceutical Sciences Faculty Publications

Thromboxane synthase (TXAS) and thromboxane A₂ receptor (TP), two critical components for thromboxane A₂ (TXA₂) signaling, have been suggested to be involved in cancer invasion and metastasis. However, the mechanisms by which TXA₂ promotes these processes are still unclear. Here we show that TXA₂ mimetic, I-BOP, induced monocyte chemoattractant protein -1(MCP-1)/chemokine (C-C motif) ligand 2 (CCL2) expression at both mRNA and protein levels in human lung adenocarcinoma A549 cells stably over-expressing TP receptor α isoform (A549-TPα). The induction of MCP-1 was also found in other lung cancer cells H157 and H460 that express relatively …

Design, Physicochemical Characterization, And Optimization Of Organic Solution Advanced Spray-Dried Inhalable Dipalmitoylphosphatidylcholine (Dppc) And Dipalmitoylphosphatidylethanolamine Poly(Ethylene Glycol) (Dppe-Peg) Microparticles And Nanoparticles For Targeted Respiratory Nanomedicine Delivery As Dry Powder Inhalation Aerosols, Samantha Ann Meenach, Frederick G. Vogt, Kimberly W. Anderson, J. Zach Hilt, Ronald C. Mcgarry, Heidi M. Mansour

Pharmaceutical Sciences Faculty Publications

Novel advanced spray-dried and co-spray-dried inhalable lung surfactant-mimic phospholipid and poly(ethylene glycol) (PEG)ylated lipopolymers as microparticulate/nanoparticulate dry powders of biodegradable biocompatible lipopolymers were rationally formulated via an organic solution advanced spray-drying process in closed mode using various phospholipid formulations and rationally chosen spray-drying pump rates. Ratios of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine PEG (DPPE-PEG) with varying PEG lengths were mixed in a dilute methanol solution. Scanning electron microscopy images showed the smooth, spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using the scanning electron micrographs and SigmaScan® software and were determined to be 600 …

Cyclooxygenase-2 Inhibition Attenuates Abdominal Aortic Aneurysm Progression In Hyperlipidemic Mice, Sarbani Ghoshal, Charles D Loftin

Pharmaceutical Sciences Faculty Publications

Abdominal aortic aneurysms (AAAs) are a chronic inflammatory disease that increase the risk of life-threatening aortic rupture. In humans, AAAs have been characterized by increased expression of cyclooxygenase-2 and the inactivation of COX-2 prior to disease initiation reduces AAA incidence in a mouse model of the disease. The current study examined the effectiveness of selective cyclooxygenase-2 (COX-2) inhibition on reducing AAA progression when administered after the initiation of AAA formation. AAAs were induced in hyperlipidemic apolipoprotein E-deficient mice by chronic angiotensin II (AngII) infusion and the effect of treatment with the COX-2 inhibitor celecoxib was examined when initiated at different …

Modeling Of Pharmacokinetics Of Cocaine In Human Reveals The Feasibility For Development Of Enzyme Therapies For Drugs Of Abuse, Fang Zheng, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly …

Brain Microvascular Endothelial Cell Association And Distribution Of A 5 Nm Ceria Engineered Nanomaterial, Mo Dan, Michael T. Tseng, Peng Wu, Jason M. Unrine, Eric A. Grulke, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

PURPOSE: Ceria engineered nanomaterials (ENMs) have current commercial applications and both neuroprotective and toxic effects. Our hypothesis is that ceria ENMs can associate with brain capillary cells and/or cross the blood-brain barrier.

METHODS: An aqueous dispersion of ∼5 nm ceria ENM was synthesized and characterized in house. Its uptake space in the Sprague Dawley rat brain was determined using the in situ brain perfusion technique at 15 and 20 mL/minute flow rates; 30, 100, and 500 μg/mL ceria perfused for 120 seconds at 20 mL/minute; and 30 μg/mL perfused for 20, 60, and 120 seconds at 20 mL/minute. The capillary …

Localization And Functional Characterization Of The Rat Oatp4c1 Transporter In An In Vitro Cell System And Rat Tissues, Kuei-Ling Kuo, Haining Zhu, Patrick J. Mcnamara, Markos Leggas

Pharmaceutical Sciences Faculty Publications

The organic anion transporting polypeptide 4c1 (Oatp4c1) was previously identified as a novel uptake transporter predominantly expressed at the basolateral membrane in the rat kidney proximal tubules. Its functional role was suggested to be a vectorial transport partner of an apically-expressed efflux transporter for the efficient translocation of physiological substrates into urine, some of which were suggested to be uremic toxins. However, our in vitro studies with MDCKII cells showed that upon transfection rat Oatp4c1 polarizes to the apical membrane. In this report, we validated the trafficking and function of Oatp4c1 in polarized cell systems as well as its subcellular …

Distribution, Elimination, And Biopersistence To 90 Days Of A Systemically Introduced 30 Nm Ceria-Engineered Nanomaterial In Rats, Robert A. Yokel, Tu C. Au, Robert Macphail, Sarita S. Hardas, D. Allan Butterfield, Rukhsana Sultana, Michael Goodman, Michael T. Tseng, Mo Dan, Hamed Haghnazar, Jason M. Unrine, Uschi M. Graham, Peng Wu, Eric A. Grulke

Pharmaceutical Sciences Faculty Publications

Nanoceria is used as a catalyst in diesel fuel, as an abrasive in printed circuit manufacture, and is being pursued as an antioxidant therapeutic. Our objective is to extend previous findings showing that there were no reductions of cerium in organs of the mononuclear phagocyte (reticuloendothelial) system up to 30 days after a single nanoscale ceria administration. An ~5% aqueous dispersion of citrate-stabilized 30 nm ceria, synthesized and characterized in-house, or vehicle, was iv infused into rats terminated 1, 7, 30, or 90 days later. Cageside observations were obtained daily, body weight weekly. Daily urinary and fecal cerium outputs were …

Phosphatidylserine Colocalizes With Epichromatin In Interphase Nuclei And Mitotic Chromosomes, Igor Prudovsky, Calvin P.H. Vary, Yolanda Markaki, Ada L. Olins, Donald E. Olins

Pharmaceutical Sciences Faculty Publications

Cycling eukaryotic cells rapidly re-establish the nuclear envelope and internal architecture following mitosis. Studies with a specific anti-nucleosome antibody recently demonstrated that the surface (“epichromatin”) of interphase and mitotic chromatin possesses a unique and conserved conformation, suggesting a role in postmitotic nuclear reformation. Here we present evidence showing that the anionic glycerophospholipid phosphatidylserine is specifically located in epichromatin throughout the cell cycle and is associated with nucleosome core histones. This suggests that chromatin bound phosphatidylserine may function as a nucleation site for the binding of ER and re-establishment of the nuclear envelope.

Aluminum In Food – The Nature And Contribution Of Food Additives, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

No abstract provided.

The Pharmacokinetics And Toxicology Of Aluminum In The Brain, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

The chemical forms (species) of aluminum in blood plasma and brain extracellular fluid are considered, as they are the candidates for brain aluminum uptake and efflux. The blood-brain barrier is the primary site of brain aluminum uptake. The mechanism of brain uptake of aluminum transferrin, long thought to be mediated by transferrin-receptor mediated endocytosis, requires further investigation. Brain Al citrate uptake has been attributed to the sodium-independent Lglutamate/ L-cystine exchanger system, system Xc-. Reports have suggested aluminum can compromise blood-brain barrier integrity, however the studies were conducted with aluminum concentrations greatly exceeding those seen in human blood plasma. Aluminum appeared …

Combination Effects Of Docetaxel And Doxorubicin In Hormone-Refractory Prostate Cancer Cells, Eleftheria Tsakalozou, Allison M. Eckman, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Combination effects of docetaxel (DOC) and doxorubicin (DOX) were investigated in prostate cancer cells (PC3 and DU145). Combination indices (CIs) were determined using the unified theory in various concentrations and mixing ratios (synergy: CI < 0.9, additivity: 0.9 < CI < 1.1, and antagonism: CI > 1.1). DOC showed a biphasic cytotoxicity pattern with the half maximal inhibitory concentration (IC50) at the picomolar range for PC3 (0.598 nM) and DU145 (0.469 nM), following 72 h drug exposure. The IC50s of DOX were 908 nM and 343 nM for PC3 and DU145, respectively. Strong synergy was seen when PC3 was treated with DOC at concentrations lower than its IC50 values (0.125~0.5 nM) plus …

Ceria-Engineered Nanomaterial Distribution In, And Clearance From, Blood: Size Matters, Mo Dan, Peng Wu, Eric A. Grulke, Uschi M. Graham, Jason M. Unrine, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

AIMS: Characterize different sized ceria-engineered nanomaterial (ENM) distribution in, and clearance from, blood (compared to the cerium ion) following intravenous infusion.

MATERIALS & METHODS: Cerium (Ce) was quantified in whole blood, serum and clot (the formed elements) up to 720 h.

RESULTS: Traditional pharmacokinetic modeling showed best fit for 5 nm ceria ENM and the cerium ion. Ceria ENMs larger than 5 nm were rapidly cleared from blood. After initially declining, whole blood 15 and 30 nm ceria increased (results that have not been well-described by traditional pharmacokinetic modeling). The cerium ion and 5 and 55 nm ceria did not …

Nanoparticulate Formulations Of Mithramycin Analogs For Enhanced Cytotoxicity, Daniel Scott, Jürgen Rohr, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Mithramycin (MTM), a natural product of soil bacteria from the Streptomyces genus, displays potent anticancer activity but has been limited clinically by severe side effects and toxicities. Engineering of the MTM biosynthetic pathway has produced the 3-side-chain-modified analogs MTM SK (SK) and MTM SDK (SDK), which have exhibited increased anticancer activity and improved therapeutic index. However, these analogs still suffer from low bioavailability, short plasma retention time, and low tumor accumulation. In an effort to aid with these shortcomings, two nanoparticulate formulations, poly(ethylene glycol)-poly(aspartate hydrazide) self-assembled and cross-linked micelles, were investigated with regard to the ability to load and pH …

Degradable Cross-Linked Nanoassemblies As Drug Carriers For Heat Shock Protein 90 Inhibitor 17-N-Allylamino-17-Demethoxy-Geldanamycin, Andrei G. Ponta, Shanjida Akter, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Cross-linked nanoassemblies (CNAs) with a degradable core were prepared for sustained release of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a potent inhibitor of heat shock protein 90 (HSP90). The particle size of CNAs ranged between 100 and 250 nm, which changed depending on the cross-linking yields and drug entrapment method. CNAs with a 1% cross-linking yield entrapped 17-AAG in aqueous solutions, yet degraded in 3 hrs. CNAs entrapped 5.2 weight% of 17-AAG as the cross-linking yield increased to 10%, retaining more than 80% of particles for 24 hrs. CNAs with drugs entrapped after the cross-linking reactions were 100 nm and remained stable in both …

Histone Deacetylase Inhibitors And Mithramycin A Impact A Similar Neuroprotective Pathway At A Crossroad Between Cancer And Neurodegeneration, Sama F. Sleiman, Jill Berlin, Manuela Basso, Saravanan S. Karuppagounder, Jürgen Rohr, Rajiv R. Ratan

Pharmaceutical Sciences Faculty Publications

Mithramycin A (MTM) and histone deacetylase inhibitors (HDACi) are effective therapeutic agents for cancer and neurodegenerative diseases. MTM is a FDA approved aureolic acid-type antibiotic that binds to GC-rich DNA sequences and interferes with Sp1 transcription factor binding to its target sites (GC box). HDACi, on the other hand, modulate the activity of class I and II histone deacetylases. They mediate their protective function, in part, by regulating the acetylation status of histones or transcription factors, including Sp1, and in turn chromatin accessibility to the transcriptional machinery. Because these two classes of structurally and functionally diverse compounds mediate similar therapeutic …