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      Harnessing nanomedicine for enhanced immunotherapy for breast cancer brain metastases

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          Graphical abstract

          Brain metastases (BMs) are the most common type of brain tumor, and the incidence among breast cancer (BC) patients has been steadily increasing over the past two decades. Indeed, ~ 30% of all patients with metastatic BC will develop BMs, and due to few effective treatments, many will succumb to the disease within a year. Historically, patients with BMs have been largely excluded from clinical trials investigating systemic therapies including immunotherapies (ITs) due to limited brain penetration of systemically administered drugs combined with previous assumptions that BMs are poorly immunogenic. It is now understood that the central nervous system (CNS) is an immunologically distinct site and there is increasing evidence that enhancing immune responses to BCBMs will improve patient outcomes and the efficacy of current treatment regimens. Progress in IT for BCBMs, however, has been slow due to several intrinsic limitations to drug delivery within the brain, substantial safety concerns, and few known targets for BCBM IT. Emerging studies demonstrate that nanomedicine may be a powerful approach to overcome such limitations, and has the potential to greatly improve IT strategies for BMs specifically. This review summarizes the evidence for IT as an effective strategy for BCBM treatment and focuses on the nanotherapeutic strategies currently being explored for BCBMs including targeting the blood–brain/tumor barrier (BBB/BTB), tumor cells, and tumor-supporting immune cells for concentrated drug release within BCBMs, as well as use of nanoparticles (NPs) for delivering immunomodulatory agents, for inducing immunogenic cell death, or for potentiating anti-tumor T cell responses.

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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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            A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.

            We previously found that a polymer conjugated to the anticancer protein neocarzinostatin, named smancs, accumulated more in tumor tissues than did neocarzinostatin. To determine the general mechanism of this tumoritropic accumulation of smancs and other proteins, we used radioactive (51Cr-labeled) proteins of various molecular sizes (Mr 12,000 to 160,000) and other properties. In addition, we used dye-complexed serum albumin to visualize the accumulation in tumors of tumor-bearing mice. Many proteins progressively accumulated in the tumor tissues of these mice, and a ratio of the protein concentration in the tumor to that in the blood of 5 was obtained within 19 to 72 h. A large protein like immunoglobulin G required a longer time to reach this value of 5. The protein concentration ratio in the tumor to that in the blood of neither 1 nor 5 was achieved with neocarzinostatin, a representative of a small protein (Mr 12,000) in all time. We speculate that the tumoritropic accumulation of these proteins resulted because of the hypervasculature, an enhanced permeability to even macromolecules, and little recovery through either blood vessels or lymphatic vessels. This accumulation of macromolecules in the tumor was also found after i.v. injection of an albumin-dye complex (Mr 69,000), as well as after injection into normal and tumor tissues. The complex was retained only by tumor tissue for prolonged periods. There was little lymphatic recovery of macromolecules from tumor tissue. The present finding is of potential value in macromolecular tumor therapeutics and diagnosis.
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              CTLA-4 and PD-1 Pathways

              Supplemental Digital Content is available in the text.
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                Author and article information

                Contributors
                jwinkles@som.umaryland.edu
                akim@som.umaryland.edu
                Journal
                Drug Deliv Transl Res
                Drug Deliv Transl Res
                Drug Delivery and Translational Research
                Springer US (New York )
                2190-393X
                2190-3948
                30 October 2021
                30 October 2021
                2021
                : 11
                : 6
                : 2344-2370
                Affiliations
                [1 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Department of Neurosurgery, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                [2 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Marlene and Stewart Greenebaum Comprehensive Cancer Center, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                [3 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Department of Surgery, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                [4 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Center for Vascular and Inflammatory Diseases, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                [5 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Department of Pharmacology, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                [6 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Department of Pharmaceutical Sciences, , University of Maryland School of Pharmacy, ; Baltimore, MD 21201 USA
                [7 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Department of Surgery and Neurosurgery, , University of Maryland School of Medicine, ; 800 West Baltimore St., Baltimore, MD 21201 USA
                [8 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Departments of Neurosurgery, Pharmacology, and Pharmaceutical Sciences, , University of Maryland School of Medicine, ; 655 W Baltimore St., Baltimore, MD 21201 USA
                Author information
                http://orcid.org/0000-0002-3402-0603
                http://orcid.org/0000-0002-6560-6893
                http://orcid.org/0000-0002-0154-5171
                http://orcid.org/0000-0001-9663-0768
                http://orcid.org/0000-0002-3305-1424
                http://orcid.org/0000-0002-8733-6046
                Article
                1039
                10.1007/s13346-021-01039-9
                8568876
                34716900
                ce238b24-972a-4159-8b4f-3ac27edae80a
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 July 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA218617
                Award ID: NS108813
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © Controlled Release Society 2021

                Pharmacology & Pharmaceutical medicine
                breast cancer brain metastases,nanoparticles,nanotechnology,immunotherapy,nanoimmunotherapies,immune checkpoint inhibitors,blood–brain barrier

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