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      Development and evaluation of a new modular nanotransporter for drug delivery into nuclei of pathological cells expressing folate receptors

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          Abstract

          Purpose

          Modular nanotransporters (MNTs) are artificial multifunctional systems designed to facilitate receptor-specific transport from the cell surface into the cell nucleus through inclusion of polypeptide domains for accomplishing receptor binding and internalization, as well as sequential endosomal escape and nuclear translocation. The objective of this study was to develop a new MNT targeted at folate receptors (FRs) for precise delivery of therapeutic cargo to the nuclei of FR-positive cells and to evaluate its potential, particularly for delivery of therapeutic agents (eg, the Auger electron emitter 111In) into the nuclei of target cancer cells.

          Methods

          A FR-targeted MNT was developed by site-specific derivatization of ligand-free MNT with maleimide-polyethylene glycol-folic acid. The ability of FR-targeted MNT to accumulate in target FR-expressing cells was evaluated using flow cytometry, and intracellular localization of this MNT was assessed using confocal laser scanning microscopy of cells. The cytotoxicity of the 111In-labeled FR-targeted MNT was evaluated on HeLa and U87MG cancer cell lines expressing FR. In vivo micro-single-photon emission computed tomography/CT imaging and antitumor efficacy studies were performed with intratumoral injection of 111In-labeled FR-targeted MNT in HeLa xenograft-bearing mice.

          Results

          The resulting FR-targeted MNT accumulated in FR-positive HeLa cancer cell lines specifically and demonstrated the ability to reach its target destination – the cell nuclei. 111In-labeled FR-targeted MNT demonstrated efficient and specific FR-positive cancer cell eradication. A HeLa xenograft in vivo model revealed prolonged retention of 111In delivered by FR-targeted MNT and significant tumor growth delay (up to 80% growth inhibition).

          Conclusion

          The FR-targeted MNT met expectations of its ability to deliver active cargo into the nuclei of target FR-positive cells efficiently and specifically. As a result of this finding the new FR-targeted MNT approach warrants broad evaluation.

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          Most cited references 39

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          Folate-mediated delivery of macromolecular anticancer therapeutic agents.

          The receptor for folic acid constitutes a useful target for tumor-specific drug delivery, primarily because: (1) it is upregulated in many human cancers, including malignancies of the ovary, brain, kidney, breast, myeloid cells and lung, (2) access to the folate receptor in those normal tissues that express it can be severely limited due to its location on the apical (externally-facing) membrane of polarized epithelia, and (3) folate receptor density appears to increase as the stage/grade of the cancer worsens. Thus, cancers that are most difficult to treat by classical methods may be most easily targeted with folate-linked therapeutics. To exploit these peculiarities of folate receptor expression, folic acid has been linked to both low molecular weight drugs and macromolecular complexes as a means of targeting the attached molecules to malignant cells. Conjugation of folic acid to macromolecules has been shown to enhance their delivery to folate receptor-expressing cancer cells in vitro in almost all situations tested. Folate-mediated macromolecular targeting in vivo has, however, yielded only mixed results, largely because of problems with macromolecule penetration of solid tumors. Nevertheless, prominent examples do exist where folate targeting has significantly improved the outcome of a macromolecule-based therapy, leading to complete cures of established tumors in many cases. This review presents a brief mechanistic background of folate-targeted macromolecular therapeutics and then summarizes the successes and failures observed with each major application of the technology. Copyright 2002 Elsevier Science B.V.
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            Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis.

            Difficulties with the nondestructive delivery of macromolecules into living cells have limited the potential applications of antibodies, genes, enzymes, peptides, and antisense oligonucleotides in biology and medicine. We have found, however, that the natural endocytosis pathway for the vitamin folate can be exploited to nondestructively introduce macromolecules into cultured cells if the macromolecule is first covalently linked to folate. Thus, treatment of KB cells with folate-conjugated ribonuclease, horseradish peroxidase, serum albumin, IgG, or ferritin allowed delivery of greater than 10(6) copies of the macromolecules within a 2-hr period. Cytochemical staining using 4-chloro-1-naphthol further demonstrated that the horseradish peroxidase retained activity for at least 6 hr after internalization. Since folate is an essential vitamin required in substantial quantities by virtually all cells, these observations may open the possibility of scientific and medical applications for many of the above macromolecules.
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              A Novel Tumor-Specific Agent for Intraoperative Near-Infrared Fluorescence Imaging: A Translational Study in Healthy Volunteers and Patients with Ovarian Cancer.

              Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                26 April 2017
                : 11
                : 1315-1334
                Affiliations
                [1 ]Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences
                [2 ]Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
                Author notes
                Correspondence: Alexander S Sobolev, Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, 34/5 Vavilov St, 119334, Moscow, Russia, Tel +7499 135 3100, Fax +7499 135 4105, Email alsobolev@ 123456yandex.ru
                Article
                dddt-11-1315
                10.2147/DDDT.S127270
                5413543
                © 2017 Slastnikova 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.

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                Original Research

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