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      Lysine-mediated hydroxyethyl starch-10-hydroxy camptothecin micelles for the treatment of liver cancer

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          Abstract

          Liver cancer is a malignant tumor with extremely high morbidity and mortality. At present, traditional chemotherapy is still the most commonly used therapeutic approach. However, serious side effects lead to the treatment of liver cancer is not ideal. Therefore, it is imperative to develop a new drug delivery system based on nanotechnology and liver cancer microenvironment. In this study, a pH/reduction/α-amylase multi-sensitive hydroxyethyl starch-10-hydroxy camptothecin micelles (HES-10-HCPT-SS-Ly) targeting over-expressed amino acid (AA) transporters on the surface of liver cancer cell by applying lysine were successfully synthesized. The prepared micelles showed regular structure, suitable particle size, and intelligent drug release property. Compared with conventional HES-10-HCPT micelles and 10-HCPT injection, HES-10-HCPT-SS-Ly micelles demonstrated better in vitro anti-proliferative capability toward human liver cancer Hep-G2 cells and greater antitumor efficiency against nude mouse with Hep-G2 tumor. These findings suggest that HES-10-HCPT-SS-Ly micelles may be a promising nanomedicine for treatment of liver cancer.

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          Most cited references23

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          Polymer therapeutics and the EPR effect

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            Redox-Sensitive Hydroxyethyl Starch–Doxorubicin Conjugate for Tumor Targeted Drug Delivery

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              Dextran-based doxorubicin nanocarriers with improved tumor penetration.

              Drug delivery systems with improved tumor penetration are valuable assets as anticancer agents. A dextran-based nanocarrier system with aldehyde functionalities capable of forming an acid labile linkage with the chemotherapy drug doxorubicin was developed. Aldehyde dextran nanocarriers (ald-dex-dox) demonstrated efficacy as delivery vehicles with an IC50 of ∼300 nM against two-dimensional (2D) SK-N-BE(2) monolayers. Confocal imaging showed that the ald-dex-dox nanocarriers were rapidly internalized by SK-N-BE(2) cells. Fluorescence lifetime imaging microscopy (FLIM) analysis indicated that ald-dex-dox particles were internalized as intact complexes with the majority of the doxorubicin released from the particle four hours post uptake. Accumulation of the ald-dex-dox particles was significantly enhanced by ∼30% in the absence of glucose indicating a role for glucose and its receptors in their endocytosis. However, inhibition of clathrin dependent and independent endocytosis and macropinocytosis as well as membrane cholesterol depletion had no effect on ald-dex-dox particle accumulation. In three-dimensional (3D) SK-N-BE(2) tumor spheroids, which more closely resemble a solid tumor, the ald-dex-dox nanoparticles showed a significant improvement in efficacy over free doxorubicin, as evidenced by decreased spheroid outgrowth. Drug penetration studies in 3D demonstrated the ability of the ald-dex-dox nanocarriers to fully penetrate into a SK-N-BE(2) tumor spheroids, while doxorubicin only penetrates to a maximum distance of 50 μM. The ald-dex-dox nanocarriers represent a promising therapeutic delivery system for the treatment of solid tumors due to their unique enhanced penetration ability combined with their improved efficacy over the parent drug in 3D.
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                Author and article information

                Journal
                Drug Deliv
                Drug Deliv
                IDRD
                idrd20
                Drug Delivery
                Taylor & Francis
                1071-7544
                1521-0464
                2020
                31 March 2020
                : 27
                : 1
                : 519-529
                Affiliations
                Department of Pharmacy, Shengjing Hospital, China Medical University , Shenyang, China
                Author notes
                CONTACT Limei Zhao ligfpharm@ 123456sina.com Department of Pharmacy, Shengjing Hospital, China Medical University , No. 36, Sanhao Street, Shenyang, 110004, China
                Author information
                http://orcid.org/0000-0001-6194-541X
                Article
                1745329
                10.1080/10717544.2020.1745329
                7170360
                32228107
                32b181e5-b098-4ca1-a666-60a59a248bf4
                © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 03 February 2020
                : 09 March 2020
                : 17 March 2020
                Page count
                Figures: 7, Tables: 3, Pages: 11, Words: 6138
                Categories
                Research Article

                Pharmacology & Pharmaceutical medicine
                hydroxyethyl starch conjugate,chemotherapy,liver cancer therapy,targeted drug delivery,amino acid transporters

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