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      Nanocarriers for pancreatic cancer imaging, treatments, and immunotherapies

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          Abstract

          Pancreatic tumors are highly desmoplastic and immunosuppressive. Delivery and distribution of drugs within pancreatic tumors are compromised due to intrinsic physical and biochemical stresses that lead to increased interstitial fluid pressure, vascular compression, and hypoxia. Immunotherapy-based approaches, including therapeutic vaccines, immune checkpoint inhibition, CAR-T cell therapy, and adoptive T cell therapies, are challenged by an immunosuppressive tumor microenvironment. Together, extensive fibrosis and immunosuppression present major challenges to developing treatments for pancreatic cancer. In this context, nanoparticles have been extensively studied as delivery platforms and adjuvants for cancer and other disease therapies. Recent advances in nanotechnology have led to the development of multiple nanocarrier-based formulations that not only improve drug delivery but also enhance immunotherapy-based approaches for pancreatic cancer. This review discusses and critically analyzes the novel nanoscale strategies that have been used for drug delivery and immunomodulation to improve treatment efficacy, including newly emerging immunotherapy-based approaches. This review also presents important perspectives on future research directions that will guide the rational design of novel and robust nanoscale platforms to treat pancreatic tumors, particularly with respect to targeted therapies and immunotherapies. These insights will inform the next generation of clinical treatments to help patients manage this debilitating disease and enhance survival rates.

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          Most cited references361

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          Cancer Statistics, 2021

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.
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            Engineering precision nanoparticles for drug delivery

            In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers — systemic, microenvironmental and cellular — that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.
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              Tumour exosome integrins determine organotropic metastasis

              Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2022
                1 January 2022
                : 12
                : 3
                : 1030-1060
                Affiliations
                [1 ]Department of Chemical and Biological Engineering, Iowa State University, Ames, IA.
                [2 ]Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE.
                [3 ]Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA.
                [4 ]Department of Veterinary Microbiology & Preventive Medicine, Iowa State University, Ames, IA.
                [5 ]Nanovaccine Institute, Iowa State University, Ames, IA.
                [6 ]Eppley Institute, University of Nebraska Medical Center, Omaha, NE.
                [7 ]Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha NE.
                Author notes
                ✉ Corresponding authors: Maneesh Jain, Ph.D., E-mail: mjain@ 123456unmc.edu , Phone: 402-559-7667; Balaji Narasimhan, Ph.D., E-mail: nbalaji@ 123456iastate.edu , Phone: 515-294-8019; Aliasger K. Salem, Ph. D., E-mail: aliasger-salem@ 123456uiowa.edu , Phone: 319-335-8796.

                #These authors contributed equally to this work.

                Competing Interests: Balaji Narasimhan and Michael J. Wannemuehler are co-founders of ImmunoNanoMed Inc., a start-up with business interests in the development of nano-based vaccines against infectious diseases. Narasimhan also has a financial interest in Degimflex LLC. Surya K. Mallapragada is a co-founder of Degimflex LLC., a start-up with business interests in the development of flexible degradable electronic films for biomedical applications. She also has a financial interest in ImmunoNanoMed Inc. Surinder K. Batra is a co-founder of Sanguine Diagnostics and Therapeutics Inc, a company focused on developing mucin-based diagnostic and therapeutic strategies for human cancers. The other authors disclosed no potential conflicts of interest.

                Article
                thnov12p1030
                10.7150/thno.64805
                8771545
                35154473
                42bdd0fa-08c9-4155-a019-375a9746e425
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 10 July 2021
                : 3 December 2021
                Categories
                Review

                Molecular medicine
                pancreatic ductal adenocarcinoma,solid tumors,nanoparticles,drug delivery,immunotherapy,tumor microenvironment

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