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Formulation And Characterization of Biologics – From siRNA to Monoclonal Antibodies
Get PDFBiologics are a rapidly growing class of therapeutics, encompassing a wide range of modalities, with gene therapy products and monoclonal antibodies (mAbs) constituting the majority. Proper formulation and characterization of these complex therapeutics is crucial to ensure their safety and therapeutic efficacy.
This dissertation focuses on two main areas: the development of a novel renal-targeted siRNA delivery system and the assessment of structural and conformational stability of mAbs in a simulated subcutaneous (SC) environment.
The first part of this dissertation presents the synthesis and characterization of a novel renal-targeted polymer for selective siRNA delivery to injured kidneys. Inulin was modified with α-cyclam-p-toluic acid (CPTA), imparting targeting properties to cells overexpressing the CXCR4 receptor. In a mouse model of cisplatin-induced AKI, self-assembled IC/siRNA polyplexes showed rapid accumulation in injured kidneys, with selective uptake and prolonged retention in renal tubules overexpressing the CXCR4 receptor. Systemically administered polyplexes of IC and siRNA against p53 effectively silenced p53 expression in the injured proximal tubules, leading to positive therapeutic outcomes in a murine model of cisplatin-induced AKI. These results indicate IC\u27s potential as a renal-targeted siRNA delivery system.
The second part of this dissertation investigates the physiochemical stability of mAbs in a simulated SC environment using a novel in vitro instrument, the Subcutaneous Injection Site Simulator (SCISSOR). Limited knowledge exists regarding alterations in the structural stability and integrity of mAbs following injection in the SC space. We utilized the SCISSOR to probe for physicochemical changes in seven mAbs following SC injection using various analytical techniques. After 24 h, all mAbs demonstrated a relative decrease in conformational stability, an increase in fragmentation, and elevated acidic species. Higher order structure analysis revealed a deviation in the secondary structure from the standard and an increase in the number of unordered species. Our findings suggest an overall reduced stability of mAbs after SC administration. Decreased stability could have a potential impact on safety and efficacy. In vitro systems like the SCISSOR, when combined with downstream analyses, offer valuable insights for evaluating the suitability of lead molecules and optimizing formulation design for specific administration in the intended body compartment, thereby enhancing the likelihood of clinical success
DELIVERY OF SMALL MOLECULE USING POLYMERIC NANOPARTICLES FOR THE TREATMENT OF ALCOHOLIC LIVER DISEASE AND ITS PHARMACOKINETICS AND BIODISTRIBUTION IN MICE
No full textAlcoholic liver disease is a challenging chronic disease worldwide. Alcohol abuse and subsequent inflammation, oxidative stress, and disordered lipid metabolism result in liver damage. This dissertation aims to develop a reliable therapeutic strategy for alcoholic liver disease treatment. We have employed polymeric nanoparticles as the delivery system to the liver and utilized PDE4B inhibitor as a novel approach for alcoholic liver disease treatment.
Chapter 1 is an overview of alcoholic liver disease, including the background, pathology, risk factors, and current treatment. In addition, the application of PDE4 inhibitors in alcoholic liver disease was discussed, suggesting a promising avenue for future exploration and development.
Chapter 2 describes the nanoparticles delivery of PDE4B inhibitor for alcoholic liver disease treatment. The results proved that nanoformulation alleviated disease in vivo, as demonstrated by improved inflammation, oxidative stress, and lipid metabolism in the liver. The encouraging results indicated the potential of this approach as a novel therapeutic strategy.
Chapter 3 discussed the pharmacokinetics and biodistribution profile of the nanoformulation in comparison to the free drug. The results suggested that the nanoparticle delivery system enhanced the bioavailability and biodistribution of the loaded small molecule in mice. This finding provides supportive evidence for the improved efficacy of nanoparticle formulation.
Chapter 4 is the summary of the key findings of each chapter and the discussion of current limitations and future directions
Immediate vs Delayed Feedback in a Progressive Musculoskeletal E-module Case for Clinical Reasoning Development
Get PDFIntroduction: Clinical reasoning (CR) skills are essential when preparing healthcare students to transition to clinical practice. The purpose of this study was to evaluate the effects of feedback timing within a case-based learning (CBL) e-module. The secondary aim was to examine the longitudinal impact on student performance within a standardized patient (SP) simulation and their overall course grade at the end of the semester.
Review of Literature: Feedback is a powerful teaching method to improve student learning. However, there are highly conflicting results regarding the best frequency and timing of feedback. This may be influenced by the level of the learner and the complexity of the material. The effect of feedback timing within CBL e-modules teaching CR is unknown.
Methods: Students were randomized to complete one of two variations of the e-module: 1) immediate feedback or 2) delayed feedback. Fisher’s exact test was used to detect differences between student responses within the e-module, the SP simulation, and their overall course grades at the end of the semester.
Results: There was no statistical association for identifying the correct hypothesis, severity rating, or irritability ratings within the e-module. Likewise, there was no association of SP simulation performance or overall course grade with feedback group assignment.
Discussion and Conclusion: The timing of feedback did not have a significant effect on the e-module outcomes, SP simulation performance, or course grades. It is possible that the feedback delay was not long enough to result in differences between groups. Also, the e-module was only a fraction of the materials used during the semester-long course. Regardless of feedback timing, students in both groups valued the opportunity to learn and assess their CR skills within the e-module. These results may support freedom of educators and/or students to choose the feedback they believe will be most beneficial to their learning
Culturally Appropriate Diabetes Education Helps Karen- and Qanjobal-Speaking Patients Lower A1C
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Barriers to a Healthy Diet in an Urban, Underserved Primary Care Clinic and how Food Insecurity Impacts These Barriers
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Dietary Quality in an Urban Primary Care Patient Clinic
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Polygenic and Transcriptional Risk Scores Identify Chronic Obstructive Pulmonary Disease Subtypes in the COPDGene and ECLIPSE Cohort Studies
Get PDFBACKGROUND: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.
METHODS: We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups.
FINDINGS: We examined two high-risk omics-defined groups in non-overlapping test sets (n = 1133 NHW COPDGene, n = 299 African American (AA) COPDGene, n = 468 ECLIPSE). We defined high activity (low PRS, high TRS) and severe risk (high PRS, high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signalling processes compared to a low-risk (low PRS, low TRS) subgroup. High activity but not severe risk participants had greater prospective FEV
INTERPRETATION: Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection.
FUNDING: National Institutes of Health
05 - Pediatric Cancer: Survivor, Physician, Mom
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I am a survivor of high-risk pediatric acute lymphoblastic leukemia and now work as a pediatric hematology-oncology physician. Through my own battle with cancer and long-term side effects, I have felt uniquely gifted with the ability to relate to others, help them feel validated in the myriad feelings they experience, and provide a much-needed aspect of healing: being understood. With just six months left of my pediatric hematology-oncology fellowship training, my firstborn son was diagnosed with brain cancer. I hope that sharing my story will increase the understanding and empathy for pediatric patients and their families.
About Ashleigh
Ashleigh Kussman, MD
Pediatric Hematologist and Oncologist and Blood and Marrow Transplant (BMT) Physician at Children’s Nebraska and UNMChttps://digitalcommons.unmc.edu/livinglibrary2024/1009/thumbnail.jp
Quality of Life among Cancer Survivors: Comparison of Multiple Cancers Using iCaRe2
Get PDFBackground: The number of cancer survivors continues to increase due to dramatic improvements in cancer treatment, accounting for approximately 5% of the entire population. As cancer survivors continue to live longer, it is important to understand their quality of life (QoL) in order to maximize supportive care efforts.
Objectives: In this study, the quality of life (QoL) among patients with different types of cancer was examined. The objectives were to: 1) compare patient-reported outcome measures of QoL using the Short-Form (SF-36) Health Survey scores among patients of different cancer types and 2) identify demographic, oncologic, and clinical factors that are associated with SF-36 QOL scores.
Methods: We performed a retrospective review of prospectively collected data from a multi-center cancer registry data collected between January 2007 and February 2020. Multiple linear regression analysis was conducted to identify demographic and clinical factors that are associated with SF-36 Physical Component Score (PCS) and Mental Component Score (MCS).
Findings: Both mental and physical aspects of QoL were affected in all cancer patients, regardless of the type, prognosis, and time since diagnosis and treatment. Individual, socioeconomic, disease, and treatment-related variables were associated with QoL among different cancer populations and should be addressed as part of shared treatment decision-making
