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      Perlecan-targeted nanoparticles for drug delivery to triple-negative breast cancer

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          Abstract

          Aim:

          We previously developed two antibodies that bind to a cell surface protein, perlecan, overexpressed in triple-negative breast cancer (TNBC). The goal of this study was to investigate these antibodies as targeting ligands for nanoparticle-mediated drug delivery.

          Methods:

          Paclitaxel-loaded poly(D,L-lactide-co-glycolide) nanoparticles were functionalized with antibodies using thiol–maleimide chemistry. Effect of antibody functionalization on therapeutic efficacy of drug-loaded nanoparticles was investigated using in vitro and in vivo models of TNBC.

          Results:

          The antibodies were covalently conjugated to nanoparticles without affecting antibody binding affinity or nanoparticle properties. Perlecan-targeted nanoparticles showed improved cell uptake, retention, cytotoxicity in vitro and enhanced tumor growth inhibition in vivo.

          Conclusion:

          The data presented here indicates that perlecan-targeted nanoparticles can improve tumor drug delivery to TNBC.

          Most cited references27

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          Matrix proteoglycans: from molecular design to cellular function.

          R Iozzo (1998)
          The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions. Proteoglycans act as tissue organizers, influence cell growth and the maturation of specialized tissues, play a role as biological filters and modulate growth-factor activities, regulate collagen fibrillogenesis and skin tensile strength, affect tumor cell growth and invasion, and influence corneal transparency and neurite outgrowth. Additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant. The review focuses on the most recent genetic and molecular biological studies of the matrix proteoglycans, broadly defined as proteoglycans secreted into the pericellular matrix. Special emphasis is placed on the molecular organization of the protein core, the utilization of protein modules, the gene structure and transcriptional control, and the functional roles of the various proteoglycans. When possible, proteoglycans have been grouped into distinct gene families and subfamilies offering a simplified nomenclature based on their protein core design. The structure-function relationship of some paradigmatic proteoglycans is discussed in depth and novel aspects of their biology are examined.
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            Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models.

            Dmitri B. Kirpotin, Daryl C Drummond, Yi Shao … (2006)
            We describe evidence for a novel mechanism of monoclonal antibody (MAb)-directed nanoparticle (immunoliposome) targeting to solid tumors in vivo. Long-circulating immunoliposomes targeted to HER2 (ErbB2, Neu) were prepared by the conjugation of anti-HER2 MAb fragments (Fab' or single chain Fv) to liposome-grafted polyethylene glycol chains. MAb fragment conjugation did not affect the biodistribution or long-circulating properties of i.v.-administered liposomes. However, antibody-directed targeting also did not increase the tumor localization of immunoliposomes, as both targeted and nontargeted liposomes achieved similarly high levels (7-8% injected dose/g tumor tissue) of tumor tissue accumulation in HER2-overexpressing breast cancer xenografts (BT-474). Studies using colloidal gold-labeled liposomes showed the accumulation of anti-HER2 immunoliposomes within cancer cells, whereas matched nontargeted liposomes were located predominantly in extracellular stroma or within macrophages. A similar pattern of stromal accumulation without cancer cell internalization was observed for anti-HER2 immunoliposomes in non-HER2-overexpressing breast cancer xenografts (MCF-7). Flow cytometry of disaggregated tumors posttreatment with either liposomes or immunoliposomes showed up to 6-fold greater intracellular uptake in cancer cells due to targeting. Thus, in contrast to nontargeted liposomes, anti-HER2 immunoliposomes achieved intracellular drug delivery via MAb-mediated endocytosis, and this, rather than increased uptake in tumor tissue, was correlated with superior antitumor activity. Immunoliposomes capable of selective internalization in cancer cells in vivo may provide new opportunities for drug delivery.
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              Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging.

              Helen Su, Jonathan Bartlett, I. Hildebrandt … (2007)
              Targeted delivery represents a promising approach for the development of safer and more effective therapeutics for oncology applications. Although macromolecules accumulate nonspecifically in tumors through the enhanced permeability and retention (EPR) effect, previous studies using nanoparticles to deliver chemotherapeutics or siRNA demonstrated that attachment of cell-specific targeting ligands to the surface of nanoparticles leads to enhanced potency relative to nontargeted formulations. Here, we use positron emission tomography (PET) and bioluminescent imaging to quantify the in vivo biodistribution and function of nanoparticles formed with cyclodextrin-containing polycations and siRNA. Conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid to the 5' end of the siRNA molecules allows labeling with (64)Cu for PET imaging. Bioluminescent imaging of mice bearing luciferase-expressing Neuro2A s.c. tumors before and after PET imaging enables correlation of functional efficacy with biodistribution data. Although both nontargeted and transferrin-targeted siRNA nanoparticles exhibit similar biodistribution and tumor localization by PET, transferrin-targeted siRNA nanoparticles reduce tumor luciferase activity by approximately 50% relative to nontargeted siRNA nanoparticles 1 d after injection. Compartmental modeling is used to show that the primary advantage of targeted nanoparticles is associated with processes involved in cellular uptake in tumor cells rather than overall tumor localization. Optimization of internalization may therefore be key for the development of effective nanoparticle-based targeted therapeutics.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Future Drug Discov
                Journal ID (iso-abbrev): Future Drug Discov
                Journal ID (publisher-id): FDD
                Title: Future Drug Discovery
                Publisher: Newlands Press Ltd (London, UK )
                ISSN (Electronic): 2631-3316
                Publication date (Electronic, pub): 01 July 2019
                Publication date (Electronic, collection): July 2019
                Publication date PMC-release: 01 July 2019
                Volume: 1
                Issue: 1
                Electronic Location Identifier: FDD8
                Affiliations
                [1 ]Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA
                [2 ]Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
                Author notes
                [* ]Author for correspondence: Tel.: +1 612 624 0951; Fax: +1 612 626 2125; jpanyam@ 123456umn.edu
                Article
                DOI: 10.4155/fdd-2019-0005
                PMC ID: 6700713
                PubMed ID: 31448368
                SO-VID: e2bf7a7d-cccc-48a6-a2b6-f5e130dfe3b9
                Copyright © © 2019 Jayanth Panyam
                License:

                This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License

                History
                Date received : 18 January 2019
                Date accepted : 07 May 2019
                Date: 01 July 2019
                Page count
                Pages: 12
                Categories
                Subject: Research Article

                Keywords: antibody,perlecan,polymeric nanoparticles,targeted drug delivery,triple-negative breast cancer
                Data availability:
                Keywords: antibody, perlecan, polymeric nanoparticles, targeted drug delivery, triple-negative breast cancer

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