NIH Targeted Delivery Interest Group (TDIG) Past Webinars

Amplifying Targetable Surface Areas Through New Delivery Approaches

March 15, 2024
Presenter: Dr. Juliane Nguyen 

While target proteins, binding affinity, and ligand density play crucial roles in directing nanocarriers or therapeutics to disease sites, relying solely on optimizing these factors has proven insufficient for achieving significant accumulation. The challenge arises from the saturation of available binding sites, limiting the effectiveness of delivery systems. To overcome this limitation, we have developed a novel approach that involves engineering each dose of nanoparticles, cells, or other therapeutics as a capturing surface for subsequent doses. By continuously amplifying the targeting surface, drug accumulation at the disease site can be enhanced. In this context, we investigated the utilization of therapeutic cells and bioderived nanovesicles surface-decorated with heterodimerizing leucine zippers. Our studies reveal that these novel Zipper-Therapeutics, administered sequentially in a mouse model of myocardial infarction, exhibit remarkable accumulation in the injured myocardium and demonstrate prolonged retention. This approach not only enhances therapeutic efficacy but also suggests promising implications for improving accumulation at diverse disease sites.

The Present and Future of mRNA Lipid Nanoparticles: From COVID-19 Vaccines to Selective Organ Targeting Tissue-Specific Disease Therapies

February 16, 2024
Presenter: Dr. Daniel J. Siegwart, Professor, UT Southwestern Medical Center

Gene editing and messenger RNA-based protein replacement therapy hold tremendous potential to effectively treat disease-causing mutations with diverse cellular origin. However, it is currently challenging to rationally design nanoparticles that selectively target specific tissues. I will describe a strategy termed selective organ targeting (SORT) wherein multiple classes of lipid nanoparticles (LNPs) are systematically engineered to edit extrahepatic tissues via addition of a supplemental SORT molecule. Lung-, spleen-, and liver-targeting SORT LNPs were designed to selectively edit therapeutically relevant cell types including epithelial cells, endothelial cells, B cells, T cells, and hepatocytes. Mechanistically, the chemical nature of the added SORT molecule controls biodistribution, global/apparent pKa, and serum protein interactions of SORT nanoparticles. SORT LNPs operate using an endogenous targeting mechanism whereby organ targeting occurs via desorption of poly(ethylene glycol) lipids from the LNP surface, binding of distinct proteins to the nanoparticle surface because of recognition of exposed SORT molecules, and subsequent interactions between surface-bound proteins and cognate receptors highly expressed in specific tissues. These findings establish a crucial link between the molecular composition of SORT nanoparticles and their unique and precise organ-targeting properties and suggest that the recruitment of specific proteins to a nanoparticle’s surface can enable drug delivery beyond the liver. SORT is compatible with multiple gene editing techniques, including mRNA, CRISPR/Cas9, base editing, and prime editing. SORT LNPs have enabled CRISPR/Cas based knockout of serum and protein levels of PCSK9, a therapeutically attractive target for treatment of cardiovascular disease. Successful correction of mutations by Homology Directed Repair (HDR) and base editing (BE) will also be discussed if time allows. As SORT LNPs are currently being used in a human clinical trial for mRNA delivery to treat primary ciliary dyskinesia (PCD), it is envisioned that further development of SORT LNPs may yield various protein replacement and gene correction therapeutics in targeted tissues.

Development of Targeted Lipid Nanoparticles for In Vivo Delivery of mRNA Medicines

January 19, 2024
Presenter: Ying Tam, M.Sc., Ph.D., Chief Scientific Officer, Acuitas Therapeutics Inc

Acuitas’ is developing and optimizing a new generation of lipid nanoparticle (LNP) delivery systems to efficiently and safely deliver messenger RNA (mRNA)-based medicines to enable mRNA in a broad range of therapeutic areas. The most advanced therapeutic application is as prophylactic vaccines against infectious disease but anti-cancer and tolerogenic vaccines, passive immunization, genomic engineering through expression of gene editing enzymes such as cas9, ZFNs or TALENs to address genetic diseases and protein expression as protein replacement for monogenic disease and treatment for chronic and acute disease are highly active areas of research.

Our focus is to express mRNA administered in LNP via different routes of administration in target cells to enable a variety of therapeutic applications. While LNP are able to very efficiently deliver their payload to hepatocytes in the liver following intravenous administration, effective delivery to extrahepatic tissues and cells remains a challenge. Strategies to achieve targeted LNP delivery include screening of lipid libraries for variants that exhibit tropism for target cells of interest and incorporation of cognizant ligands with affinity to targets expressed on target cells.

Here, we will present our preclinical work with partners and collaborators validating the use of actively targeted LNP to deliver mRNA to specific target cells and discuss key parameters impacting potency and safety of mRNA LNP as well as considerations regarding clinical translation.

Delivery of Nucleic Acid Therapeutics using Extracellular Vesicles From Red Blood Cells

November 17, 2023
Presenter: Minh Le, Ph.D., Assistant Professor, National University of Singapore

Despite ongoing innovation and a small number of clinically successful applications, the delivery of nucleic acid-based therapeutics (NATs) remains challenging. Between the point of administration and the intended site of action, NATs have to contend with immune activation and clearance, degradation by nucleases, off-target accumulation, and various barriers posed by cellular membranes.

We envision a delivery platform which can help NATs overcome these obstacles and realize their promise of specific and potent therapeutic effects. Nano-sized particles known as “red blood cell-derived extracellular vesicles” (“RBCEVs”) have proven to be an attractive candidate. Our research group has developed an inexpensive and scalable method to produce and purify RBCEVs from RBCs available in blood banks. Thanks to their cellular rather viral or synthetic origin, RBCEVs possess high biocompatibility and low immunogenicity. Our studies have demonstrated robust RBCEV-based delivery of RNAs, including small interfering RNAs and antisense oligonucleotides, to suppress leukemia as well as solid cancers and to treat cancer cachexia. Moreover, we have developed techniques to conjugate antibodies and peptides for enhanced specific targeting. In this talk, I will present the highlights of our works and discuss the unique potential of the RBCEVs as a new versatile drug delivery platform.

Encrypted RNA™: A New Class of RNA for Targeted Therapeutic Delivery 

October 20, 2023
Presenter: Ariel Weinberger, Ph.D., CEO & Founder: Autonomous Therapeutics, Inc.

From vaccines to enzyme replacement therapies, nucleic acid technology enables the immediate development of biological medicines that can translate virtually any therapeutic protein in vivo. Yet, exogenous protein translation carries toxicity risks and dosage limitations—if proteins are produced at uncontrolled levels outside of desired tissues. Previously, the viral vector and nanoparticle fields have aimed to surmount these barriers by developing cell-specific and tissue-specific delivery vectors. In this talk, we will demonstrate an orthogonal approach to targeted therapeutic delivery that is independent of delivery vector: disease-activated therapeutic protein translation. We will describe the development of a new class of RNA, known as encrypted RNA™, that intrinsically limits therapeutic protein translation outside of diseased tissues. Encrypted RNA is a platform technology that can be applied in plug-and-play fashion to develop disease-activated therapeutics against a broad range of viruses and cancers. Strikingly, a single encrypted RNA molecule can be both disease-specific and variant-agnostic. For example, a single encrypted RNA developed against influenza has pan-influenza A&B efficacy, with negligible protein translation in healthy cells that are not influenza-infected. Similarly, a single encrypted RNA developed against SARS-CoV-2 has specific efficacy against every tested COVID-19 variant: from the ancestral Wuhan variant to Omicron. Encrypted RNAs are inhalable, safe, and effective in vivo in multiple preclinical animal models. A single inhaled dose of encrypted RNA protects against SARS-CoV-2 infection in both mice and Syrian hamsters. Ultimately, encrypted RNAs function as auxiliary immune systems that sense and detect infections in cells—and respond to these infections by producing therapeutic proteins in situ. More broadly, the capability to control protein expression offers the prospect of controlling the therapeutic index of virtually any therapeutic protein.

Next Generation Multi Targeted Therapeutics

September 22, 2023
Presenter: Adam Margolin, Ph.D., CEO

This presentation described a novel nanotechnology-based discovery platform developed in Chad Mirkin's group at Northwestern and being brought to clinic by Flashpoint Therapeutics, that enables more potent multi-targeted therapies by co-delivering diverse RNA, DNA, and/or peptide cargo to the right cells with precise control of stoichiometry, optimized structure-function relationship, and synchronized activation kinetics.

In in-vivo mouse models, the platform has transformed immuno-oncology therapeutic components from ineffective to curative, and demonstrates superior product profiles across multiple in vivo and clinical studies.

Advancing Cancer Treatment: Rational Design of Targeted and Stroma Modulating Drug Delivery Systems for Overcoming Therapy-Resistance

June 16, 2023
Presenter: Dr. Lily Yang

Poor drug delivery and therapy resistance pose significant clinical challenges in cancer treatment. The presence of dysfunctional tumor vessels, dense tumor stromal cells, and extracellular matrix contributes to the inefficient delivery of drugs into tumors, limiting the distribution of therapeutic agents within tumor cells. To address these challenges and improve drug delivery efficiency, researchers have focused on developing targeted drug delivery systems that specifically target both the tumor and its stroma. In this presentation, Dr. Yang will highlight recent advancements in the targeted delivery of nanoparticle/drug carriers to stroma-rich tumors. The talk will cover key considerations in the rational design of tumor-targeted and stroma-modulating nanoparticle drug systems, including the selection of targeting ligands and receptors, nanomaterials, surface coating, and payload drugs.  Dr. Yang will also share her insights on the development of relevant mouse tumor models for evaluating targeted nanoparticle/drug delivery, examining interactions between the nanoparticle/drug and tumor and stromal cells, extracellular matrix, as well as assessing therapeutic efficacy in stroma-rich tumors.

Leveraging the Natural Cellular and Biomolecular Interactions in Blood for the Design of Targeted, Anti-Inflammatory Particle Therapeutics

May 19, 2023
Presenter: Dr. Omolola Eniola-Adefeso

Vascular-targeted particle therapeutics offer the possibility of increased drug effectiveness while minimizing side effects often associated with systemic drug administration. Factors that influence the likelihood of targeted particle therapeutics to reach the vascular wall are the ability to identify: 1) a disease-specific target, 2) the appropriate drug carrier type and geometry for efficient interaction with the vascular wall, and 3) a drug-carrier combination that allows for the desired release of the targeted therapeutics. Our work focuses on probing the role of particle geometry, material chemistry, and blood rheology/dynamics on the ability of vascular-targeted drug carriers to interact with the blood vessel wall - an important consideration that will control the effectiveness of drug targeting regardless of the targeted disease or delivered therapeutically. This presentation will highlight the carrier-blood cell interactions that affect drug carrier binding to the vascular wall and alter critical neutrophil functions in disease. The talk will present the material design parameters for optimal drug carriers' design for active and passive use in treating acute lung injury and other inflammatory diseases.

Cargocytes: A Next Generation Biomimetic Drug Delivery Platform

April 21, 2023
Presenter: Dr. Richard Klemke

Our laboratory has developed a unique, precision, drug transporter system (CargocytesTM) with the potential to treat a wide range of diseases. Cargocytes are biocompatible transporters with enhanced genetic and biophysical properties that improve upon the innate tumor trophic properties of disease homing cells. Using our patented process, we then gently remove only the nucleus from these cells, thereby providing a unique, viable and safe drug delivery vehicle that retains all organelles and robustly homes to diseased tissues. Cargocytes possess unique biological properties that enable them to deliver a wide range of therapeutic cargos deep into diseased tissues. I discussed how Cargocyte technology address current challenges in drug delivery including biodistribution, precision disease targeting, and drug tissue penetration after intravenous administration, with a focus on oncology and inflammatory disease indications. 

A New Generation of Targeted Therapies for Cancer, Autoimmune, and Infectious Diseases

March 17, 2023
Presenter: Philip S. Low, Ph.D.

This talk will summarized our development of small molecule ligands for targeting attached drugs selectively to pathologic cells, thereby concentrating the drug in the diseased cell and reducing its uptake into healthy cells. Applications of the technology will be presented for targeted drugs that treat and image cancers, autoimmune and infectious diseases, with our recent research primarily focused on targeting drugs to specific immune cell types for controlling the immune system. Clinical and preclinical data will demonstrate that use of a low molecular weight targeting ligand to deliver an established drug can both reduce its toxicity and enhance its potency, often converting an otherwise unusable drug into an effective drug.

Why Most Anticancer Nanomedicines Do Not Improve Clinical Efficacy and How to Improve It

February 17, 2023
Presenter: Duxin Sun, Ph.D.

Anticancer nanomedicine, which is designed based on tumor EPR effect and long systemic circulation, was an attractive strategy to improve anticancer efficacy and reduce drug's toxicity. Although thousands of anticancer nanomedicines have achieved outstanding efficacy in preclinical animal cancer models, most anticancer nanomedicines failed to show superior clinical efficacy in cancer patients. This low success rate of anticancer nanomedicines in clinical cancer patients has provoked decades of debate for the current nanomedicine design strategy.

Based on extensive studies of current clinical used nanomedicines, we proposed a new anticancer nanomedicine design strategy, which is cancer type specific, cell type specific, drug specific, and nanocarrier specific. The new anticancer nanomedicine design strategy may improve their success in clinical cancer patients and achieve long-term tumor remission. We currently use these new strategies to design anticancer nanomedicines to remodel immune microenvironment in both tumors and lymph nodes for immunotherapy of triple negative breast cancer and pancreatic cancer.

Targeted Nanoparticles: What Do We Really Target In the Tumor Microenvironment?

January 20, 2023
Presenter: Dr. S. Karathanasis

Considering the highly adjustable design of nanoparticles, the biophysical and biochemical properties can be engineered to direct a nanoparticle to distinct tumor microenvironments, especially the tumor’s perivascular regions. First, I will discuss how the shape can govern a nanoparticle’s in vivo journey and targeting of hard-to-reach tumor sites. Specifically, chain-like shapes can enhance targeting of a nanoparticle to tumor-associated vasculature. Then, I will talk about the design of multi-ligand nanoparticles to target more than one receptor associated with the perivascular regions of sites of metastases. Such multi-ligand nanoparticles can account for the dynamic and heterogeneous microenvironment of metastatic disease, which undergoes spatiotemporal changes including the expression of targetable cell-surface biomarkers. Lastly, we ask the question whether targeted nanoparticles can distinguish metastatic cancer from sites of inflammation. Common ligands aim at cancer targets that are often upregulated in general inflammation. This will lead to intriguing findings regarding the cellular uptake of targeted nanoparticles by the intended cells and other cell populations within the tumor microenvironment.

Stathis Karathanasis is Professor and Associate Chair of Biomedical Engineering (BME) at the School of Medicine of Case Western Reserve University, the Director of Graduate Education of the BME Department, and a member of the Case Comprehensive Cancer Center. He is a trained biomedical engineer with undergraduate and doctoral degrees in chemical engineering. A native of Greece, he grew up in Thessaloniki and received his undergraduate degree from Aristotle University. In 2001, he moved to the United States, where he completed his doctoral degree in University of Houston and a postdoctoral fellowship in Georgia Institute of Technology. He joined the Faculty of School of Medicine at Case Western Reserve in 2009, where he directs the Cancer Nanotechnology and Immunotherapy research program. His research interests lie in the integration of nanotechnology with imaging, oncology, and immunology to develop impactful nanomedicines for hard-to-treat cancers.

Targeted Nanocomplexes to Carry Therapeutic Payloads Across the Blood Brain Barrier (BBB) to Address Brain Tumors and Other Neurological Diseases/Conditions

November 18, 2022
Presenter: Esther H. Chang Ph.D.

A targeted nanocomplex(scL) platform technology has proven to be a versatile delivery system with broad application to diverse cancer types as well as to neurological diseases/conditions.

The most advanced products using the scL platform in oncology are SGT-53 and SGT-94 that each carry a gene encoding a powerful tumor suppressor (p53 and RB94, respectively), and both investigational agents have successfully completed Phase I clinical trials, displaying good safety profiles and anti-tumor activity in patients. SGT-53 is now about to finish a Phase II trials for advanced pancreatic cancer. The interim analysis of the trial will be briefly discussed.  Both SGT-53 and an analogous nanocomplex carrying temozolomide have been used in mouse models for glioblastomas.

The ability of the scL delivery to cross the BBB will be shown in selected examples including reduction of neuroinflammation and downmodulation of transgene expression in the brain by scL-siRNAs/ASOs. Harnessing neuroinflammation should have therapeutic benefit in a variety of neurological diseases/conditions wherein neuroinflammation has been implicated. Our scL projects involving medical countermeasures that penetrate the CNS to reactivate AChE inactivated by organophosphate nerve agents will be briefly discussed.

Cellular Hitchhiking for Targeted Drug Delivery

October 21, 2022
Presenter: Dr. Samir Mitragotri

Nanoparticle-based drug delivery systems are widely explored to improve the biological outcome of chemo and immunotherapy. However, poor vascular circulation, limited targeting and the inability to negotiate many biological barriers are key hurdles in their clinical translation. Biology has provided many examples of successful “carriers” in the form of circulatory cells, which routinely overcome the hurdles faced by synthetic nanoparticle systems. Their laboratory has explored blood-cell inspired drug delivery systems that take advantage of the abilities of red blood cells, macrophages and other blood cells. They have explored “cellular hitchhiking” which involves combining nanoparticles with circulatory cells to drastically alter the in vivo fate of the nanoparticles. He provided an overview of the principles and examples of hitchhiking-based drug- and immuno-therapy. 

Samir Mitragotri is the Hiller Professor of Bioengineering and Wyss Professor of Biologically Inspired Engineering at Harvard University and Wyss Institute. His research has provided new insights into biological barriers of skin, blood-brain barrier, immune clearance and gastrointestinal tract, among others. His research has also led to new methods of transdermal, oral, and targeted drug delivery systems. He is an elected member of the National Academy of Engineering, National Academy of Medicine and National Academy of Inventors. He is also an elected fellow of AAAS, CRS, BMES, AIMBE, and AAPS. He received a PhD in Chemical Engineering from the Massachusetts Institute of Technology. 

Role of Extracellular Vesicles in Acute Lung Injury

September 16, 2022
Presenter: Dr. Jae-Woo Lee

Dr. Lee is a clinician-scientist and Professor of Anesthesiology at University of California, San Francisco.  Dr. Lee's research is focused on understanding the role of extracellular vesicles in the pathophysiology of acute lung injury from bacterial pneumonia in hopes of developing novel therapeutics.

The Primal Essence of Targeted Drug Delivery: Can It Deliver Enough Drug to Cure?

May 20, 2022
Presenter: Dr. Kinam Park

Kinam Park, Ph.D. is the Showalter Distinguished Professor of Biomedical Engineering and Professor of Pharmacy at Purdue University. He has studied controlled drug delivery systems for four decades, with a recent focus on understanding the mechanisms of drug release from long-acting injectable formulations. He is the founder of Akina, Inc., specializing in specialty PLGA polymers and new biodegradable plastics.

Targeted Delivery of Immune Therapeutics In Transplantation

June 17, 2022
Presenter: Reza Abdi, M.D.

The application of nanotechnology principles to medicine has created enormous excitement as a transformative approach, permitting the selective delivery of therapeutics to target tissue sites. In the cancer field, which comprises most of the current nanomedicine applications, the initial and current mainstay approach is to increase the delivery of toxic payloads to tumors. Nonetheless, our understanding of the important roles of immune therapeutics and lymphoid tissues in the fight against cancer has grown remarkably. On the other hand, immune-mediated diseases, including transplant rejection, are receiving increasing attention for the development of targeted delivery methods for immune therapeutics (ITs). ITs have been key to the success of organ transplantation and immune-mediated conditions, but a substantial unmet medical need remains to develop novel strategies to increase the efficacy and reduce the toxicity of ITs. In this talk, I will discuss the importance of targeted IT delivery to lymphoid tissues in transplantation as well as in other diseases including cancer.

Dr. Abdi is a transplant nephrologist at Brigham and Women’s Hospital and Professor of Medicine at Harvard Medical School. He is also the Director of the Transplantation Research Center at Brigham and Women’s Hospital. His research is at the forefront of current knowledge in transplantation and immunology, striving to expand understanding of transplant immunology and rejection using a wide range of immunological studies and techniques, and to investigate and introduce new therapies for other conditions, including cancer, type 1 diabetes, allergy, and vaccination.

Lipid Nanoparticles for mRNA Therapeutics, Cancer Immunotherapy and Cell Therapy

July 15, 2022
Presenter: Yizhou Dong, M.S., Ph.D.

Messenger RNA (mRNA) has shown great promise for broad therapeutic applications. However, the efficient and safe delivery of mRNA remains a key challenge for the clinical use of mRNA-based therapeutics. Lipid and lipid-derived nanoparticles possess unique properties for mRNA delivery. In this seminar, I will describe the development of lipid-derived nanomaterials for delivery of multiple types of mRNAs and their potential applications for treating genetic disorders, cancers, and infectious diseases.

Yizhou Dong is an Associate Professor in the Division of Pharmaceutics and Pharmacology, College of Pharmacy at The Ohio State University. He received his B.S. in pharmaceutical sciences from Peking University Health Science Center and M.S. in organic chemistry from Shanghai Institute of Organic Chemistry. In 2009, he received his Ph.D. degree in pharmaceutical sciences from the University of North Carolina at Chapel Hill (UNC-CH) under the supervision of Professor K.-H. Lee. From 2010 to 2014, he was a postdoctoral fellow in the laboratory of Professors Robert Langer and Daniel Anderson at Harvard Medical School and Massachusetts Institute of Technology. His research focuses on the design and development of biotechnology platforms for the treatment of genetic disorders, infectious diseases, and cancers. Dr. Dong has authored over one hundred papers and patents. Several of his inventions have been licensed and are currently under development as drug candidates for clinical trials. He serves as a scientific advisory board member for Oncorus Inc. Dr. Dong is the recipient of multiple awards, such as Young Innovator in Cellular and Molecular Bioengineering from the Biomedical Engineering Society, Maximizing Investigators’ Research Award from the National Institute of General Medical Sciences (NIGMS), Ohio State Early Career Innovator of the Year, and The American Association of Pharmaceutical Scientists (AAPS) Emerging Leader Award. In 2022, Dr. Dong is elected as a fellow of the American Institute for Medical and Biological Engineering (AIMBE).

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