The University of Maryland School of Pharmacy, founded in 1841, is a thriving center for life sciences research and community service. Through its education, research, and service programs, the School of Pharmacy strives to improve the health and well-being of society by aiding in the discovery, development, and use of medicines.

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  • Immunomodulatory Nanoparticles as a Multimodal Approach to Attenuate Immune Dysregulation in Severe Inflammation and Sepsis

    Truong, Nhu; Pearson, Ryan M. (2023)
    Sepsis, a life-threatening condition triggered by an uncontrolled immune response to infection, currently lacks an FDA-approved therapeutic intervention to enhance patient survival. Severe inflammatory conditions can disrupt the balance of histone acetyltransferase (HAT)/histone deacetylase (HDAC) activity, leading to global cellular hypoacetylation. Histone deacetylase inhibitors (HDACi) restore acetylation profiles and reverse transcriptional silencing. Suberoylanilide hydroxamic acid (SAHA), a pan-HDACi, was modified by para-hydroxymethylation (termed SAHA-OH), which resulted in a favourable reduction in SAHA-associated toxicity under inflammatory lipopolysaccharide (LPS) challenge. SAHA-OH was incorporated into immunomodulatory nanoparticles (iNPs), previously developed by our lab, to form iNP-SAHA using a prodrug approach through the covalent modification with poly(lactic-co-glycolic acid) (PLGA). iNP-SAHA treatment significantly reduced proinflammatory cytokines in vitro and in vivo, improved the viability of LPS-stimulated primary macrophages, and enhanced survival of mice in an LPS-induced endotoxemia model. iNP-SAHA treatment did not significantly improved mice survival compared to the iNP treatment alone; however, the synergistic anti-inflammatory properties of iNP-SAHA are potentially promising for future exploration in alternative models of inflammatory disease. We evaluated the efficacy and cellular mechanism of iNP activity using a clinically relevant cecal ligation and puncture (CLP) murine model of polymicrobial sepsis. iNPs, when administered as an adjuvant to antibiotics, significantly improved survival compared to antibiotics alone. Interestingly, iNP treatment marginally affected local and systemic cytokine profiles, despite mitigating organ dysregulation. Minimal effects on immune cell proportions at local sites were observed, but iNP treatment normalized monocyte levels in peripheral blood and alveolar macrophages in lung tissues. Further studies enumerated that iNPs modulated cellular adhesion and migration surface marker expression as well as apoptotic levels on immune cells. These findings highlight the potential of iNPs as an adjunctive therapy for sepsis, particularly when combined with antibiotics, suggesting promising prospects for future clinical translation. Lastly, a high-throughput microfluidic approach for iNP formulation to enable facile scale-up was developed. We optimized the microfluidic method and the impact of polymer and surfactant concentrations, surfactant chemistry, flow rate ratio (FRR), and anti-inflammatory activity. This work demonstrated a controlled and reproducible microfluidic method for iNP formulation, showcasing their inherent anti-inflammatory properties and offering a promising avenue for inflammation management.
  • Conversion of Small-Molecule Inhibitors into Heterobifunctional Compounds in the Discovery of Novel Chemotherapeutics

    Chan, Alexandria; Fletcher, Steven (2023)
    Heterobifunctional polypharmacologic agents are compounds that have individual pharmacophores for at least two separate biological targets. Our work spans two distinct sets of heterobifunctional molecules: 1. Polypharmacologic agents that inhibit two proteins known to contribute to the disease state, and 2. Protein degraders: Proteolysis targeting chimeras (PROTACs) and molecular glues. Both types of protein degraders function through recruiting an E3 ligase to the protein of interest, resulting in a hijacking of the ubiquitin-proteasome system, and the subsequent destruction of the target protein. The use of type 1 compounds is rapidly growing as such polypharmacologic agents are postulated to exhibit distinct advantages over the monovalent, parent drug compounds from which they are constructed, including the ability to increase therapeutic effect, lower effective dosage, and circumvent treatment resistance. Type 2 compounds – the protein degraders – can eliminate a target of interest, requiring the cell to resynthesize the protein to regain its cellular function. These compounds may have a catalytic mechanism of action wherein the compounds are recycled after mediating the degradation of the target protein, thereby requiring non-stoichiometric amounts of drug while also directly countering resistance that manifests through target protein upregulation. Moreover, such degraders retain activity with resistant proteins where traditional, non-covalent small-molecule drugs fail. Due to these advantages, there is increasing enthusiasm that targeted protein degraders may herald a new class of anti-cancer therapeutics. Herein, our efforts towards the discovery of heterobifunctional pharmaceuticals for the treatment of drug-resistant hematological malignancies are described.
  • Utilizing Pharmacometrics to Facilitate Generic Drug Development of Orally Inhaled Products and Optimize Pharmacotherapy of Antifibrinolytics

    Li, Shuhui; Gobburu, Jogarao (2023)
    This thesis has two parts. The first part is related to the pharmacokinetic (PK) batch-to-batch variability of orally inhaled products, which may pose challenges for generic product development. I applied the techniques of pharmacometrics to propose and evaluate alternative PK bioequivalence (BE) study designs using Advair Diskus as an example product, aiming to facilitate generic development. First, population PK models for Advair Diskus were developed and qualified to simulate PK BE study. Next, the effect of batch-to-batch variability on the establishment of BE was evaluated using the developed models. Batch-to-batch variability substantially elevates the probability of reaching a false conclusion in a PK BE study for equivalent and inequivalent comparisons. Therefore, ignoring batch-to-batch variability when presenting will increase the risk of either patients being treated with an inequivalent formulation or pharmaceutical companies not obtaining approval for an equivalent formulation. This calls for alternative PK BE approaches to account for the batch-to-batch variability. I proposed and evaluated a two-phase study framework that uses a pilot study to select reference and test batches for the pivotal BE study. A parallel design with ≥ 12 patients per sequence or a crossover design with ≥ 6 patients per sequence is recommended for the pilot study design. The proposed criteria for selecting batches based on the pilot study results include (1) 0.9 ≤ T/R ≤ 1.11 and (2) higher conditional power. The two-phase study design offers the flexibility to select batches in a PK study to minimize the impact of batch-to-batch variability on the generics development. The two-phase framework might be applied to other products with similar characteristics and high batch-to-batch variability in the reference products. The second part of this thesis used pharmacometrics to optimize the pharmacotherapy of an anti-fibrinolytic, tranexamic acid (TXA), in special patient populations. The PK and pharmacodynamics (PD) of TXA in special populations are understudied; therefore, the PK/PD-driven optimal doses for them are unknown. First, I characterized the PK and PD of TXA in pregnancy and found that pregnant women have up to 30% higher clearance and volume of distribution than the general non-pregnant population. A dose of 650 mg maintains both PK and PD targets for > 1 hour in most patients, which is recommended as the postpartum prophylactic dose for future confirmatory clinical studies. In addition, I evaluated a current dosing regimen for cardiac surgery patients who use cardiopulmonary bypass (CPB) during their surgeries from a PK perspective. This dosing regimen consists of a long infusion of TXA at 100 mg/hr for 5 hours before CPB initiation, a 1 g bolus of TXA at CPB initiation, and another 1 g bolus at the end of CPB. While kidney function affects the clearance of TXA, and the CPB procedure increases the volume of distribution of TXA, the current dosing regimen was confirmed to provide sufficient TXA exposure (15 mg/L) from CPB initiation till 3 hours post-CPB, achieving the therapeutic goal. Both studies contribute to understanding how TXA dosing can be optimized in special patient populations.
  • Development of Mass Spectrometric Methods for Analysis of Sphingolipids and Oligonucleotides

    Tran, Anh Quan; Jones, Jace W., 1978- (2023)
    Mass Spectrometry (MS) is a powerful method for analysis of biomolecules due to its selective and sensitive analytical benchmarks, providing information about their structures and abundance, further enabling their functions to be studied. This thesis focuses on the analysis of sphingolipids and oligonucleotide therapeutics due to knowledge gaps in their MS analysis. Sphingolipids (SPs) are pivotal membrane lipids with very diverse structures, setting the stage for challenging analysis. To enhance analytical performance, lithium was incorporated into the MS workflow, consolidating adducts and simplifying the mass spectrum and proving informative fragmentation patterns. An extraction protocol was developed that integrated a base hydrolysis step for SP enrichment using lithium hydroxide, which effectively hydrolyzed esterified lipids with the added benefit of lithium adduct consolidation. A high throughput screening method was developed with lithium adduct consolidation, resulting in detection enhancement of low abundant SPs. A multidimensional analytical platform was developed to provide higher structural quality of SPs, utilizing off-line liquid chromatograph (LC), ion mobility and high-resolution tandem MS. The off-line LC provided separation and allowed lithium adduction for further analysis while ion mobility and elevated energy tandem MS are used to structurally characterize and resolve SP isomers. Data processing, analysis and visualizations techniques were also developed, tailored to the specific needs of the workflow. A MS imaging method for spatial localization of SPs was developed with lithium adduction and on tissue hydrolysis to enhance SP analysis of intact tissue. OGN (oligonucleotide) therapeutics are becoming increasingly more popular for complex diseases. Despite this, rigorous analytical techniques to monitor biomanufacturing processes and the final formulation product are lacking. A high-throughput screening method was developed to verify the molecular weight and to scan for non-isomeric impurities while minimizing alkali salt contamination that notoriously adduct to OGNs during ionization. LC methods were developed for both analytical and preparative separation while tandem MS was used to confirm their sequence. For isomeric impurities, ion mobility was utilized to interrogate and compare the extremely complicated diastereomeric composition of various OGN drug products.
  • Integration of Quantitative and Qualitative Mass Spectrometric Workflows to Evaluate the Role of Plasmalogen Glycerophosphoethanolamine in Disease Progression

    Morel, Yulemni; Jones, Jace W., 1978- (2023)
    Lipids encompass the major constituent of cellular membranes and are involved in various cellular processes such as membrane integrity, energy storage, and cellular signaling. Due to their structural composition, lipids are vulnerable to disruptions in redox biology, ultimately leading to lipid peroxidation (LPO) and detrimental alterations to membrane dynamics, interactions with membrane proteins, and signal transduction. Several disease states such as traumatic brain injury (TBI) are plagued by oxidative stress and LPO. Thus, an understanding of the lipid molecular targets is crucial for defining the underlying mechanisms driving pathology. Plasmalogen, a unique glycerophospholipid (GP) characterized by a vinyl ether bond at the sn-1 position, is a lipid structure with noteworthy redox-regulating properties. Reports have highlighted dysregulated levels of plasmalogen lipids following TBI-onset, with oxidative degradation products such as lysoglycerophospholipids accumulating. With their established importance, a comprehensive investigation of their oxidative role within TBI is lacking. Furthermore, the structural diversity of the lipidome and the extended lipid complexity due to LPO introduces challenges with the detection, identification, and quantification of these lipid structures. This research describes the development of analytical methodology for the detection, characterization, and quantification of plasmalogen and its oxidized derivatives across biological samples. Herein, a targeted quantitative assay was established to evaluate plasmalogen and its lysoplasmalogen/glycerophospholipid levels, and confirm its role as an early marker of acute brain injury. To investigate the unique oxidative properties of plasmalogen as compared to other lipid classes, liposomal mixtures were prepared, and displayed a significant vulnerability for lipids with the presence of a vinyl ether bond at the sn-1 position, a polyunsaturated fatty acid (PUFA) at the sn-2 position, and an ethanolamine headgroup (PE). After validating their oxidative potential, we further constructed a comprehensive analytical workflow that combined complementary LC separations, tandem mass spectrometry, and drift-tube ion mobility, which significantly improved our ability to tease apart the isomeric complexity of the oxidative lipidome. To establish their impact on the cellular environment, whole cells, purified lysosomes, and samples isolated from a TBI mouse model were investigated and revealed the formation of oxidized PE products that potentially alter organellular function and propagate disease pathology.
  • HDX-MS, Molecular Dynamics, and Modeling: An Integrative Approach to Model Solution Structural Ensembles

    Kihn, Kyle; Deredge, Daniel D.; Wintrode, Patrick L. (2023)
    Probing the structural equilibrium that proteins and protein complexes can adopt in solution is critical in understanding a multitude their biophysical properties. Two common ways to probe these dynamic structures are hydrogen deuterium exchange coupled mass spectrometry (HDX-MS) and molecular dynamics simulations (MD). HDX-MS is a solution-based technique that reports on a system’s secondary and tertiary structure and dynamics at peptide level resolution. Although informative, the typical information obtained through HDX-MS studies remains largely qualitative and is limited by the attainable resolution. On the other hand, MD takes a static starting high resolution structure with a set of model parameters to simulate the system’s motion over time. The resulting trajectory gives an atomistic view of the system from which a multitude of biophysical properties can be derived. However, the timescales accessible to MD simulations are limited and can lead to an under exploration of the conformational landscape. To overcome this, enhanced computational sampling methods have been developed to more efficiently explore a system’s conformational landscape. The ability to integrate experimental HDX-MS data with MD simulations has the potential to increase the utility of both methods. Such integration rests on the ability to predict deuterium exchange from computationally generated ensembles. Thus far, several physics-based models of HDX exchange have been developed and implemented in the calculation of HDX exchange rates from MD simulations. Whereas the value of any single model remains a subject of debate, studies have not focused on the application of such integration to address unanswered biophysical questions. In this project, I aim to demonstrate the applicability of such integrative approach to a variety of biophysical questions. HDX exchange rates will be calculated from MD simulations and compared to the experimentally observed exchange rates for given systems. Further, utilizing a maximum entropy reweighting method, structural ensembles most consistent with in solution HDX-MS data will be extracted for analysis. In this thesis, I apply enhanced sampling MD, experimental HDX rates, and maximum entropy reweighting to generate realistic structural ensembles of protein and protein complexes in-solution to be used in the characterization of in-solution native state ensembles, protein conformational transitions, and protein-small molecule interactions. This is done using three model systems: the Cytoplasmic Heme Binding Protein (PhuS) from Pseudomonas aeruginosa, Human Plasminogen activator inhibitor-1, and ERK2 and its known type I inhibitors. This thesis develops, optimizes, and validates a workflow which can help shift HDX-MS studies from its current qualitative perspective to a quantitative treatment of HDX-MS which leverages computational simulations and extract atomic resolution interpretations.
  • PTGFRN as a Target for Antibody-Drug Conjugate (ADC) Development in Mesothelioma and Medulloblastoma

    Marquez, Jorge; Serrero, Ginette; Kane, Maureen A. (2023)
    Cancer is a disease that afflicts millions of people each year. While there are many drugs available to treat certain subsets of cancer, there still remain many types of cancer that do not have tailored therapy available to treat them. Mesothelioma and Pediatric Medulloblastoma are two such cancers that the NIH classifies as rare and aggressive neoplasms. As such, both cancers display unmet needs, and are the subject of much research to improve the chemotherapy available for treatment. Our laboratory has found that both cancers express a protein called Prostaglandin F2 Receptor Negative, or PTGFRN. PTGFRN is a member of the Tetraspanin family, which are transmembrane proteins. Previously, PTGFRN expression has been found to correlate with a more aggressive phenotype. Additionally, when its expression is inhibited, cellular processes essential for cancer metastasis were also found to be impacted. To better understand how PTGFRN affects cancer progression, we looked at the effects of PTGFRN with various in vitro functional assays to assess phenotypic changes. We also performed a global proteome and pathway analysis using mass spectrometric methods to better understand what pathways were most affected by PTGFRN expression, and identify proteins that are complexed, or in direct interaction, with PTGFRN. In parallel to these studies, we also developed monoclonal antibodies that are capable of binding cell-surface PTGFRN, and inducing endocytosis to the cytoplasm. Conjugation of our prototype antibody, the mouse mAb 33B7, to the ribosome-inactivating protein Saporin results in an Antibody-Drug Conjugate (ADC) of moderate¬ efficacy. Due to the success of this first ADC attempt, we then developed a fully human antibody, denoted as 8C7, and conjugated it to the payload Duocarmycin via a cleavable linker, resulting in our second generation ADC. This new ADC exhibits improved, highly potent in vitro anti-cancer effect, as well as in in vivo models with mice bearing mesothelioma and medulloblastoma tumors. The work detailed here lays the groundwork for a tailored therapy to treat the aforementioned cancers, and expands our knowledge of proteins and protein interactions involved in cancer metastasis.
  • Centennial March of the School of Pharmacy University of Maryland

    Slama, Frank J. (1941)
    Musical piece celebrating the 100th Anniversary of the Maryland College of Pharmacy, the predecessor of the University of Maryland School of Pharmacy in 1941. Piece is written by Frank J. Slama, then Professor of Botany and Pharmacognosy.
  • University of Maryland School of Pharmacy. Annual Report 2021-2022

    University of Maryland, Baltimore. School of Pharmacy, 2022
  • A pilot study of Cancer Genome Profiling in the African American Population

    Swan, Nikia N.; Wu, Ming, Dr. (2023-12-08)
    As an African American woman, it is imperative that I change the perception that we have on healthcare and the pharmaceuticalindustry. It is a common but respectable misconception that Medicine and research does not work in the African American population. Many of these misconceptions have developed over time from the medical mistreatment in diverse population, specifically African Americans. (T.S.E, Henriette Lacks etc.) Studies show that Breast and Ovarian cancer are two of the most prevalent cancers among women worldwide. African American woman have a lower incidence in both Breast and Ovarian cancers buthave a higher mortality rate compared to their white counterparts. Genetics, Access to care, treatment options, and other healthcare disparities play a vitalrole in overall survival rates among this diverse population. While there has been research on both cancer types, there is limited data and research specially for AfricanAmerican women.
  • Effects of FRS targeted compounds on Regulation of AP-1 Proteins in Human Airway Smooth Muscle Cells

    Gudivada, Himaja; Jateng, Danielle; McClean, Nathaniel; Grogan, Lena; Shapiro, Paul, Ph.D. (2023-12-08)
  • Synthesis and Biological Evaluation of Novel Heterogeneous Ribonucleoprotein A18 Inhibitors

    Badger, Olanza K.; Lowe, Brandon; Solano-Gonzalez, Eduardo; Webber, David J.; MacKerell, Alexander D., Jr.; Carrier, France; Fletcher, Steven (2023-12-08)
    Heterogeneous ribonucleoproteins (hnRNP) are a large family of ribonucleic acid (RNA) binding proteins that contribute to functions involved in transcription and translation regulation 6 . hnRNPs are primarily a nuclear protein but translocate to the cytoplasm in response to cellular stress such as hypoxia, UV-radiation, or cold stress. Elevated levels of hnRNP A18 have been detected in the cytoplasm of tumor cells in different cancers such as melanoma, acute myeloid leukemia, and Ewing Sarcoma. Inhibition of hnRNP A18 has resulted in reduced tumor weight and tumor suppression making hnRNP A18 an ideal target for small molecule inhibition. Through collaborative efforts with Dr. Alexander MacKerell, Jr., and the Computer Aided Drug Design (CADD) group while using SILCS technology, researchers have been able to develop molecular scaffolds with the ability to inhibit hnRNP A18 binding activity. We hypothesize that by using these molecular scaffolds, novel hnRNP A18 inhibitors can be synthesized to inhibit hnRNP A18- RNA binding preventing tumor formation and development.
  • University of Maryland School of Pharmacy Strategic Plan 2022-2026

    University of Maryland, Baltimore. School of Pharmacy (2026)
  • University of Maryland School of Pharmacy Newsletter 2023

    University of Maryland, Baltimore. School of Pharmacy, 2023
  • University of Maryland School of Pharmacy Newsletter 2022

    University of Maryland, Baltimore. School of Pharmacy, 2022
  • Maryland Poison Center Annual Report 2022

    University of Maryland, Baltimore. Maryland Poison Center, 2022
  • Maryland Poison Center Annual Report 2021

    University of Maryland, Baltimore. Maryland Poison Center, 2021
  • Data Snapshot 2022

    University of Maryland, Baltimore. School of Pharmacy. Maryland Poison Center, 2022
  • Data Snapshot 2021

    University of Maryland, Baltimore. School of Pharmacy. Maryland Poison Center, 2021

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