Research Overview

The Oupicky Lab focuses on the broad field of drug delivery and nanomedicine, with emphasis on delivery of therapeutic nucleic acids and drug/nucleic acid combinations. Our research promises to enable or significantly improve a range of therapeutic approaches investigated in the field of nanomedicine. The research in our lab is highly interdisciplinary and covers all development aspects of delivery systems, including synthesis of novel polymers and nanomaterials, evaluation of the delivery activity in vitro and studies of the pharmacokinetics and activity of the delivery vectors in vivo in disease models. We put emphasis on a synthesis of new materials and on understanding the physicochemical properties of delivery systems and their interactions with living systems. Currently active research projects focus on development of nanomedicines for delivery of various combinations of therapeutic agents, including drug-gene, drug-siRNA, drug-miRNA and drug-drug combinations.

Research Projects

Pancreatic Cancer Anatomy Concept And Pancreas Malignant Tumor Symbol As A Digestive Gland Body Part

Targeting CXCR4 chemokine axis in metastatic cancer

Chemokines and chemokine receptors play key roles in progression and metastasis of most cancers. Although different chemokine receptors are involved, inhibition of CXCR4 emerged as one of the most promising approaches in combination cancer therapy, especially when focused on metastatic disease. The CXCR4 chemokine axis regulates cancer development through a complex network of tumor-stroma interactions, including its role in immune evasion of tumors. Small RNA molecules, such as siRNA and miRNA, represent new class of therapeutics for cancer treatment through RNA interference-mediated gene silencing. However, the clinical applicability of siRNA and miRNA is severely limited by the lack of effective delivery systems. There is a significant therapeutic potential for CXCR4-targeted nanomedicines in combination with the delivery of siRNA and miRNA in metastatic cancer. Our work focuses on the development of novel methods to deliver combination of CXCR4 inhibitors with rationally selected siRNA and miRNA to treat metastatic cancer. We have developed innovative polymers that exhibit intrinsic ability to inhibit CXCR4 and to simultaneously encapsulate therapeutic siRNA and miRNA. We are exploring the potential of these delivery systems in the treatment of metastatic pancreatic cancer, cholangiocarcinoma, pediatric osteosarcoma, and lung cancer.

Support: UNMC startup, Nebraska Department of Health & Human Services

Normal Human Kidney

Treatment of acute kidney injury

Acute kidney injury (AKI) is a major unmet medical need due to the lack of effective pharmacological treatment options and significant healthcare burden of the disease. The fact that AKI mortality remains at 50-80% and has not improved in decades underscores the critical need for better treatments. Ischemia-reperfusion injury (IRI) and nephrotoxic agents (e.g., cisplatin) are critical causative factors in AKI pathophysiology. IRI is a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. A wide range of pathological processes including oxidative stress, inflammation and activation of cell death programs, such as apoptosis and necrosis contribute to tissue injury and renal dysfunction in AKI. This project addresses the urgent need for new renoprotective treatments by developing a novel integrated siRNA delivery platform capable of selective combined inhibition of p53 and CXCR4 in AKI. Our goal is to develop innovative polymer-siRNA conjugates for efficient and safe delivery of CXCR4 antagonist and anti-p53 siRNA (sip53) to proximal tubule cells of the injured kidneys.

Support: R01 DK120533

Collaborator: Prof. Babu Padanilam (UNMC)

DNA Strand And Cancer Cel

Targeting polyamine metabolism and miRNA in cancer

Despite tremendous therapeutic potential, clinical translation of miRNA faces major unsolved pharmaceutical delivery challenges. Due to the involvement of multiple mutations in tumorigenesis and tumor progression, combination of miRNAs with modulators of polyamine metabolism has significant therapeutic potential. The fact that polyamine metabolism is downstream from many oncogenes and tumor suppressor pathways make it a logical target for such combination miRNA therapy approaches. The goal of this project is to develop polyamine prodrugs that can modulate dysregulated polyamine metabolism and encapsulate and systemically deliver anticancer miR-34a. The hypothesis behind this project is that self-immolative polyamine prodrugs based on modulators of polyamine metabolism will deliver miR-34a to the tumors, which will result in enhanced combination effect due to the downregulation of tumor polyamine biosynthesis and upregulation of polyamine catabolism and restoration of important cell growth and death-regulatory functions due to miR-34a. Our work focuses on the development and optimization of formulation of tumor-penetrating nanoparticles that deliver miRNA and modulate polyamine metabolism. We are conducting comprehensive evaluation of anticancer activity, antitumor immune response, and survival advantage of the developed nanoparticles in models of colorectal cancer.

Support: R01 CA235863

Collaborator: Prof. Robert Casero (Johns Hopkins University)

Liver disease

Nanoparticles to treat alcohol-associated liver disease (AALD)

AALD is a major and growing health concern with limited treatment options. The natural history of AALD includes fatty liver disease, alcoholic hepatitis and the development of fibrosis preceding end-stage cirrhosis. MicroRNAs (miRNAs) represent a new class of therapeutics due to their ability to simultaneously affect multiple fibrosis-associated pathways. Among possible targets, miR-155 is involved in inflammatory responses mediated by Kupffer cells (KCs) that affect fibrogenic events in multiple other hepatic cells. Chemokine receptor CXCR4 and its cognate ligand stromal cell-derived factor-1 play important and complex roles in the pathogenesis of AALD, including the coordination of the initial immune reaction upon liver injury and later in controlling the progression of liver fibrosis through its activating effect on hepatic stellate cells (HSCs) and collagen production. The goal of this project is to develop integrated miRNA delivery platform based on self-assembled nanoparticles that deliver anti-miR-155 to activated KCs and in parallel inhibit CXCR4 signaling in activated HSCs in the liver. We are testing the hypothesis that our nanoparticles will lead to enhanced combination effect due to attenuation of profibrogenic signaling of both hepatic macrophages and the matrix-producing HSCs. Overall, this project contributes to the fundamental understanding of the role and therapeutic potential of CXCR4 and miR-155 inhibition in AALD and innovatively addresses targeted delivery of drug/miRNA combinations as an anti-fibrotic treatment.

Support: R01 AA027695

Collaborators: Prof. Benita McVicker (UNMC/VA), Prof. Robert Bennett (UNMC/VA)