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      Combined ROS Sensitive PEG-PPS-PEG with Peptide Agonist for Effective Target Therapy in Mouse Model

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          Abstract

          Background and Purpose

          Growth hormone-releasing hormone (GHRH) agonist, a 29-amino acid peptide, shows significant potential in treating myocardial infarction (MI) by aiding the repair of injured heart tissue. The challenge lies in the effective on-site delivery of GHRH agonist. This study explores the use of a targetable delivery system employing ROS-responsive PEG-PPS-PEG polymers to encapsulate and deliver GHRH agonist MR409 for enhanced therapeutic efficacy.

          Methods

          We synthesized a self-assembling poly (ethylene glycol)-poly (propylene sulfide)-poly (ethylene glycol) polymer (PEG-PPS-PEG) amphiphilic polymer responsive to reactive oxygen species (ROS). The hydrophilic peptide GHRH agonist MR409 was encapsulated within these polymers to form nano PEG-PPS-PEG@MR409 vesicles (NPs). Cardiomyocyte apoptosis was induced under hypoxia and serum-free culture condition for 24 hours, and their production of ROS was detected by fluorescence dye staining. The cellular uptake of PEG-PPS-PEG@MR409 NPs was observed using fluorescence-labeled MR409. Targeting ability and therapeutic efficacy were evaluated using a mouse MI model.

          Results

          PEG-PPS-PEG@MR409 NPs were efficiently internalized by cardiomyocytes, reducing ROS levels and apoptosis. These NPs exhibited superior targeting to the infarcted heart compared to naked MR409 peptide. With a reduced injection frequency (once every three days), PEG-PPS-PEG@MR409 NPs significantly promoted cardiac function recovery post-MI, matching the efficacy of daily MR409 injections.

          Conclusion

          ROS-responsive PEG-PPS-PEG polymers provide a novel and effective platform for the targeted delivery of GHRH agonist peptides, improving cardiac function and offering a new approach for peptide therapy in MI treatment.

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          Most cited references31

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          Strategies in the design of nanoparticles for therapeutic applications.

          Engineered nanoparticles have the potential to revolutionize the diagnosis and treatment of many diseases; for example, by allowing the targeted delivery of a drug to particular subsets of cells. However, so far, such nanoparticles have not proved capable of surmounting all of the biological barriers required to achieve this goal. Nevertheless, advances in nanoparticle engineering, as well as advances in understanding the importance of nanoparticle characteristics such as size, shape and surface properties for biological interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications. This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.
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            Designer vaccine nanodiscs for personalized cancer immunotherapy

            Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumor exome sequencing have signaled the new era of personalized immunotherapy with patient-specific neo-antigens, but a general methodology for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that high density lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (i.e. CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumor growth. Nanodiscs eliminated established MC-38 and B16F10 tumors when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine.
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              PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect.

              As mortality due to cancer continues to rise, advances in nanotechnology have significantly become an effective approach for achieving efficient drug targeting to tumour tissues by circumventing all the shortcomings of conventional chemotherapy. During the past decade, the importance of polymeric drug-delivery systems in oncology has grown exponentially. In this context, poly(lactic-co-glycolic acid) (PLGA) is a widely used polymer for fabricating 'nanoparticles' because of biocompatibility, long-standing track record in biomedical applications and well-documented utility for sustained drug release, and hence has been the centre of focus for developing drug-loaded nanoparticles for cancer therapy. Such PLGA nanoparticles have also been used to develop proteins and peptides for nanomedicine, and nanovaccines, as well as a nanoparticle-based drug- and gene-delivery system for cancer therapy, and nanoantigens and growth factors. These drug-loaded nanoparticles extravasate through the tumour vasculature, delivering their payload into the cells by the enhanced permeability and retention (EPR) effect, thereby increasing their therapeutic effect. Ongoing research about drug-loaded nanoparticles and their delivery by the EPR effect to the tumour tissues has been elucidated in this review with clarity. Copyright © 2010 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                ijn
                International Journal of Nanomedicine
                Dove
                1176-9114
                1178-2013
                05 September 2024
                2024
                : 19
                : 9109-9120
                Affiliations
                [1 ]Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang Province, 310009, People’s Republic of China
                [2 ]Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education , Hangzhou, Zhejiang Province, People’s Republic of China
                [3 ]Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China
                [4 ]Department of Cardiology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University , Hangzhou, Zhejiang, People’s Republic of China
                [5 ]State Key Laboratory of Transvascular Implantation Devices , Hangzhou, 310009, People’s Republic of China
                [6 ]Binjiang Institute of Zhejiang University , Hangzhou, 310053, People’s Republic of China
                Author notes
                Correspondence: Hong Yu; Yaping Wang, Tel +86-571-87783992, Fax +86-571-88002709, Email yuvascular@zju.edu.cn; yapingwang@zju.edu.cn
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0001-8685-9673
                Article
                471036
                10.2147/IJN.S471036
                11382658
                39253061
                962ec281-6d63-483f-87e4-2eb40bd3b0c1
                © 2024 Xiang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 30 May 2024
                : 13 August 2024
                Page count
                Figures: 6, References: 31, Pages: 12
                Categories
                Original Research

                Molecular medicine
                myocardial infarction,targeted therapy,growth hormone-releasing hormone,reactive oxygen species

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