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Cell-penetrating peptide-based nanovehicles potentiate lymph metastasis targeting and deep penetration for anti-metastasis therapy

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      Abstract

      Lymph metastasis is a vital pathway of cancer cell dissemination, and insidious lymph node metastasis increases the risk of distant cancer metastasis. Current therapies for lymph metastasis are largely restricted by limited targeting and penetration capacity. Herein, we report that an r9 cell-penetrating peptide-based cabazitaxel nanovehicle (r9-CN) displays prominent lymph metastasis targeting and deep penetration ability after intravenous injection for effective anti-metastasis therapy.

      Methods: The r9-CN and CN nanovehicles were prepared by thin film dispersion, using DSPE-PEG2000 as the nano-carrier material and cabazitaxel as the model drug to fabricate r9-modified nano-micelles by self-assembly. The morphology, size, and stability in physiological solutions of r9-CN and CN were characterized. The targeting, biodistribution, deep penetration, and therapeutic efficacy of r9-CN and CN were systematically explored in vitro and in vivo.

      Results: The r9-CN nanovehicle consists of homogeneous particles with a mean diameter of 13 nm and zeta potential of +0.75 mV. Compared with the nanovehicle lacking the r9 peptide (CN), r9-CN exhibits long retention and deep penetration in the tumor mass, and considerably enhances accumulation and flexible permeation in metastatic lymph nodes, thereby notably suppressing primary tumor growth, lymph node metastasis, and distant lung metastasis.

      Conclusion: The cumulative findings reveal that r9-CN offers a promising delivery platform, enabling efficient lymph metastasis targeting and deep penetration for effective anti-metastasis therapy.

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      Most cited references 53

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      Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
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          Metastasis to distant organs is an ominous feature of most malignant tumours but the natural history of this process varies in different cancers. The cellular origin, intrinsic properties of the tumour, tissue affinities and circulation patterns determine not only the sites of tumour spread, but also the temporal course and severity of metastasis to vital organs. Striking disparities in the natural progression of different cancers raise important questions about the evolution of metastatic traits, the genetic determinants of these properties and the mechanisms that lead to the selection of metastatic cells.
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            Author and article information

            Affiliations
            [1 ]School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, Shandong, China.
            [2 ]State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
            Author notes
            ✉ Corresponding authors: Prof. Kaoxiang Sun ( sunkaoxiang@ 123456luye.cn ), Prof. Yaping Li ( ypli@ 123456simm.ac.cn ), and Prof. Zhiwen Zhang ( zwzhang0125@ 123456simm.ac.cn ). Tel/Fax: +86-21-20231979

            #These authors contributed equally to this work.

            Competing Interests: The authors have declared that no competing interest exists.

            Journal
            Theranostics
            Theranostics
            thno
            Theranostics
            Ivyspring International Publisher (Sydney )
            1838-7640
            2018
            7 June 2018
            : 8
            : 13
            : 3597-3610
            6037037 10.7150/thno.25608 thnov08p3597
            © Ivyspring International Publisher

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

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