Browsing by Author "McHugh, Kevin J."

Now showing 1 - 9 of 9
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    Dynamic Imine Bonding Facilitates Mannan Release from a Nanofibrous Peptide Hydrogel
    (American Chemical Society, 2023) Pogostin, Brett H.; Saenz, Gabriel; Cole, Carson C.; Euliano, Erin M.; Hartgerink, Jeffrey D.; McHugh, Kevin J.
    Recently, there has been increased interest in using mannan as an immunomodulatory bioconjugate. Despite notable immunological and functional differences between the reduced (R-Man) and oxidized (O-Man) forms of mannan, little is known about the impact of mannan oxidation state on its in vivo persistence or its potential controlled release from biomaterials that may improve immunotherapeutic or prophylactic efficacy. Here, we investigate the impact of oxidation state on the in vitro and in vivo release of mannan from a biocompatible and immunostimulatory multidomain peptide hydrogel, K2(SL)6K2 (abbreviated as K2), that has been previously used for the controlled release of protein and small molecule payloads. We observed that O-Man released more slowly from K2 hydrogels in vitro than R-Man. In vivo, the clearance of O-Man from K2 hydrogels was slower than O-Man alone. We attributed the slower release rate to the formation of dynamic imine bonds between reactive aldehyde groups on O-Man and the lysine residues on K2. This imine interaction was also observed to improve K2 + O-Man hydrogel strength and shear recovery without significantly influencing secondary structure or peptide nanofiber formation. There were no observed differences in the in vivo release rates of O-Man loaded in K2, R-Man loaded in K2, and R-Man alone. These data suggest that, after subcutaneous injection, R-Man naturally persists longer in vivo than O-Man and minimally interacts with the peptide hydrogel. These results highlight a potentially critical, but previously unreported, difference in the in vivo behavior of O-Man and R-Man and demonstrate that K2 can be used to normalize the release of O-Man to that of R-Man. Further, since K2 itself is an adjuvant, a combination of O-Man and K2 could be used to enhance the immunostimulatory effects of O-Man for applications such as infectious disease vaccines and cancer immunotherapy.
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    Employing Drug Delivery Strategies to Overcome Challenges Using TLR7/8 Agonists for Cancer Immunotherapy
    (Springer Nature, 2021) Varshney, Dhruv; Qiu, Sherry Yue; Graf, Tyler P.; McHugh, Kevin J.
    Toll-like receptors (TLRs) are a potential target for cancer immunotherapy due to their role in the activation of the innate immune system. More specifically, TLR7 and TLR8, two structurally similar pattern recognition receptors that trigger interferon and cytokine responses, have proven to be therapeutically relevant targets for cancer in numerous preclinical and clinical studies. When triggered by an agonist, such as imiquimod or resiquimod, the TLR7/8 activation pathway induces cellular and humoral immune responses that can kill cancer cells with high specificity. Unfortunately, TLR7/8 agonists also present a number of issues that must be overcome prior to broad clinical implementation, such as poor drug solubility and systemic toxic effects. To overcome the key limitations of TLR7/8 agonists as a cancer therapy, biomaterial-based drug delivery systems have been developed. These delivery devices are highly diverse in their design and include systems that can be directly administered to the tumor, passively accumulated in relevant cancerous and lymph tissues, triggered by environmental stimuli, or actively targeted to specific physiological areas and cellular populations. In addition to improved delivery systems, recent studies have also demonstrated the potential benefits of TLR7/8 agonist co-delivery with other types of therapies, particularly checkpoint inhibitors, cancer vaccines, and chemotherapeutics, which can yield impressive anti-cancer effects. In this review, we discuss recent advances in the development of TLR7/8 agonist delivery systems and provide perspective on promising future directions.
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    Enhanced stability and clinical absorption of a form of encapsulated vitamin A for food fortification
    (PNAS, 2022) Tang, Wen; Zhuang, Jia; Anselmo, Aaron C.; Xu, Xian; Duan, Aranda; Zhang, Ruojie; Sugarman, James L.; Zeng, Yingying; Rosenberg, Evan; Graf, Tyler; McHugh, Kevin J.; Tzeng, Stephany Y.; Behrens, Adam M.; Freed, Lisa E.; Jing, Lihong; Jayawardena, Surangi; Weinstock, Shelley B.; Le, Xiao; Sears, Christopher; Oxley, James; Daristotle, John L.; Collins, Joe; Langer, Robert; Jaklenec, Ana
    Food fortification is an effective strategy to address vitamin A (VitA) deficiency, which is the leading cause of childhood blindness and drastically increases mortality from severe infections. However, VitA food fortification remains challenging due to significant degradation during storage and cooking. We utilized an FDA-approved, thermostable, and pH-responsive basic methacrylate copolymer (BMC) to encapsulate and stabilize VitA in microparticles (MPs). Encapsulation of VitA in VitA-BMC MPs greatly improved stability during simulated cooking conditions and long-term storage. VitA absorption was nine times greater from cooked MPs than from cooked free VitA in rats. In a randomized controlled cross-over study in healthy premenopausal women, VitA was readily released from MPs after consumption and had a similar absorption profile to free VitA. This VitA encapsulation technology will enable global food fortification strategies toward eliminating VitA deficiency.
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    Multidomain peptide hydrogel adjuvants elicit strong bias towards humoral immunity
    (Royal Society of Chemistry, 2022) Pogostin, Brett H.; Yu, Marina H.; Azares, Alon R.; Euliano, Erin M.; Lai, Cheuk Sun Edwin; Saenz, Gabriel; Wu, Samuel X.; Farsheed, Adam C.; Melhorn, Sarah M.; Graf, Tyler P.; Woodside, Darren G.; Hartgerink, Jeffrey D.; McHugh, Kevin J.
    Adjuvants play a critical role in enhancing vaccine efficacy; however, there is a need to develop new immunomodulatory compounds to address emerging pathogens and to expand the use of immunotherapies. Multidomain peptides (MDPs) are materials composed of canonical amino acids that form injectable supramolecular hydrogels under physiological salt and pH conditions. MDP hydrogels are rapidly infiltrated by immune cells in vivo and have previously been shown to influence cytokine production. Therefore, we hypothesized that these immunostimulatory characteristics would allow MDPs to function as vaccine adjuvants. Herein, we demonstrate that loading antigen into MDP hydrogels does not interfere with their rheological properties and that positively charged MDPs can act as antigen depots, as demonstrated by their ability to release ovalbumin (OVA) over a period of 7–9 days in vivo. Mice vaccinated with MDP-adjuvanted antigen generated significantly higher IgG titers than mice treated with the unadjuvanted control, suggesting that these hydrogels potentiate humoral immunity. Interestingly, MDP hydrogels did not elicit a robust cellular immune response, as indicated by the lower production of IgG2c and smaller populations of tetramer-positive CD8+ T splenocytes compared to mice vaccinated alum-adjuvanted OVA. Together, the data suggest that MDP hydrogel adjuvants strongly bias the immune response towards humoral immunity while evoking a very limited cellular immune response. As a result, MDPs may have the potential to serve as adjuvants for applications that benefit exclusively from humoral immunity.
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    Nanotechnology-enhanced immunotherapy for metastatic cancer
    (Elsevier, 2021) Zhang, Peisen; Meng, Junli; Li, Yingying; Yang, Chen; Hou, Yi; Tang, Wen; McHugh, Kevin J.; Jing, Lihong
    A vast majority of cancer deaths occur as a result of metastasis. Unfortunately, effective treatments for metastases are currently lacking due to the difficulty of selectively targeting these small, delocalized tumors distributed across a variety of organs. However, nanotechnology holds tremendous promise for improving immunotherapeutic outcomes in patients with metastatic cancer. In contrast to conventional cancer immunotherapies, rationally designed nanomaterials can trigger specific tumoricidal effects, thereby improving immune cell access to major sites of metastasis such as bone, lungs, and lymph nodes, optimizing antigen presentation, and inducing a persistent immune response. This paper reviews the cutting-edge trends in nano-immunoengineering for metastatic cancers with an emphasis on different nano-immunotherapeutic strategies. Specifically, it discusses directly reversing the immunological status of the primary tumor, harnessing the potential of peripheral immune cells, preventing the formation of a pre-metastatic niche, and inhibiting the tumor recurrence through postoperative immunotherapy. Finally, we describe the challenges facing the integration of nanoscale immunomodulators and provide a forward-looking perspective on the innovative nanotechnology-based tools that may ultimately prove effective at eradicating metastatic diseases.
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    Novel Vaccine Adjuvants as Key Tools for Improving Pandemic Preparedness
    (MDPI, 2021) Pogostin, Brett H.; McHugh, Kevin J.
    Future infectious disease outbreaks are inevitable; therefore, it is critical that we maximize our readiness for these events by preparing effective public health policies and healthcare innovations. Although we do not know the nature of future pathogens, antigen-agnostic platforms have the potential to be broadly useful in the rapid response to an emerging infection—particularly in the case of vaccines. During the current COVID-19 pandemic, recent advances in mRNA engineering have proven paramount in the rapid design and production of effective vaccines. Comparatively, however, the development of new adjuvants capable of enhancing vaccine efficacy has been lagging. Despite massive improvements in our understanding of immunology, fewer than ten adjuvants have been approved for human use in the century since the discovery of the first adjuvant. Modern adjuvants can improve vaccines against future pathogens by reducing cost, improving antigen immunogenicity, and increasing antigen stability. In this perspective, we survey the current state of adjuvant use, highlight potentially impactful preclinical adjuvants, and propose new measures to accelerate adjuvant safety testing and technology sharing to enable the use of “off-the-shelf” adjuvant platforms for rapid vaccine testing and deployment in the face of future pandemics.
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    Theranostic nanoparticles with disease-specific administration strategies
    (Elsevier, 2022) Zhang, Peisen; Li, Yingying; Tang, Wen; Zhao, Jie; Jing, Lihong; McHugh, Kevin J.
    Recent advances in the synthesis of nanomaterials with diagnostic and therapeutic capabilities have been rapidly reshaping the landscape of precision medicine. Impressive progress has been made toward the design and production of innovative theranostic nanomaterials to treat a variety of diseases, yet their potential is currently limited by low bioavailability, biocompatibility, or undesirable pharmacokinetics, hindering their widespread clinical implementation. Here, we summarize the state of the art for theranostic nanoparticles and discuss the diverse administration routes being used in the diagnosis and treatment of different diseases. In addition to the most commonly used intravenous (IV) administration, newly emerging nanomaterial administration routes are described in depth to explore the potential benefits of these routes that can bypass biological barriers and thereby facilitate the delivery of nanoparticles to boost imaging sensitivity and therapeutic efficacy in specific use cases. Some of the biggest challenges facing nanoparticle delivery systems are site-specific targeting, controlled nanoparticle accumulation, and safe metabolic processing. By providing examples of their in vivo applications for various diseases, we highlight the benefits, challenges, and opportunities of theranostic nanoprobes and routes of administration to inform future nanoparticle design.
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    Translating diagnostics and drug delivery technologies to low-resource settings
    (AAAS, 2022) Euliano, Erin M.; Sklavounos, Alexandros A.; Wheeler, Aaron R.; McHugh, Kevin J.
    Diagnostics and drug delivery technologies engineered for low-resource settings aim to meet their technical design specifications using strategies that are compatible with limited equipment, infrastructure, and operator training. Despite many preclinical successes, very few of these devices have been translated to the clinic. Here, we identify factors that contribute to the clinical success of diagnostics and drug delivery systems for low-resource settings, including the need to engage key stakeholders at an early stage, and provide recommendations for the clinical translation of future medical technologies.