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      Self-crosslinkable chitosan-hyaluronic acid dialdehyde nanoparticles for CD44-targeted siRNA delivery to treat bladder cancer

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          Abstract

          Bladder cancer is one of the concerning malignancies worldwide, which is lacking effective targeted therapy. Gene therapy is a potential approach for bladder cancer treatment. While, a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo. In this study, we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs (siRNA) with high interfere to Bcl2 oncogene were designed and screened. Then hyaluronic acid dialdehyde (HAD) was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles (CS-HAD NPs) to achieve CD44 targeted siRNA delivery. The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs (siRNA@CS-HAD NPs) were approximately 100 nm in size, with improved stability, high siRNA encapsulation efficiency and low cytotoxicity. CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer. Overall, a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment, which could be more conducive to clinical application due to its simple preparation and high biological safety.

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          Ligand-directed active tumor-targeting polymeric nanoparticles for cancer chemotherapy.

          Yinan Zhong, Fenghua Meng, Chao Deng … (2014)
          In recent years, polymeric nanoparticles have appeared as a most viable and versatile delivery system for targeted cancer therapy. Various in vivo studies have demonstrated that virus-sized stealth particles are able to circulate for a prolonged time and preferentially accumulate in the tumor site via the enhanced permeability and retention (EPR) effect (so-called "passive tumor-targeting"). The surface decoration of stealth nanoparticles by a specific tumor-homing ligand, such as antibody, antibody fragment, peptide, aptamer, polysaccharide, saccharide, folic acid, and so on, might further lead to increased retention and accumulation of nanoparticles in the tumor vasculature as well as selective and efficient internalization by target tumor cells (termed as "active tumor-targeting"). Notably, these active targeting nanoparticulate drug formulations have shown improved, though to varying degrees, therapeutic performances in different tumor models as compared to their passive targeting counterparts. In addition to type of ligands, several other factors such as in vivo stability of nanoparticles, particle shape and size, and ligand density also play an important role in targeted cancer chemotherapy. In this review, concept and recent development of polymeric nanoparticles conjugated with specific targeting ligands, ranging from proteins (e.g., antibodies, antibody fragments, growth factors, and transferrin), peptides (e.g., cyclic RGD, octreotide, AP peptide, and tLyp-1 peptide), aptamers (e.g., A10 and AS1411), polysaccharides (e.g., hyaluronic acid), to small biomolecules (e.g., folic acid, galactose, bisphosphonates, and biotin), for active tumor-targeting drug delivery in vitro and in vivo are highlighted and discussed. With promise to maximize therapeutic efficacy while minimizing systemic side effects, ligand-mediated active tumor-targeting treatment modality has become an emerging and indispensable platform for safe and efficient cancer therapy.
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            Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective.

            Kenneth Yip, Martin Götte (2006)
            Glycosaminoglycans are major constituents of the cancer cell surface and the tumor stroma. The heparan sulfate degrading enzyme heparanase, hyaluronan, and its receptor CD44 are up-regulated in breast cancer, generating a microenvironment that promotes tumor progression and metastasis. Recent experimental and clinical evidence shows that heparanase, hyaluronan, and CD44 regulate cancer cell proliferation, migration, and invasion, as well as tumor-associated angiogenesis and are correlated with patient survival. These findings suggest that they may be used as prognostic factors and targets for breast cancer treatment.
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              CD44 in cancer progression: adhesion, migration and growth regulation.

              R Marhaba, M Zöller (2004)
              It is well established that the large array of functions that a tumour cell has to fulfil to settle as a metastasis in a distant organ requires cooperative activities between the tumour and the surrounding tissue and that several classes of molecules are involved, such as cell-cell and cell-matrix adhesion molecules and matrix degrading enzymes, to name only a few. Furthermore, metastasis formation requires concerted activities between tumour cells and surrounding cells as well as matrix elements and possibly concerted activities between individual molecules of the tumour cell itself. Adhesion molecules have originally been thought to be essential for the formation of multicellular organisms and to tether cells to the extracellular matrix or to neighbouring cells. CD44 transmembrane glycoproteins belong to the families of adhesion molecules and have originally been described to mediate lymphocyte homing to peripheral lymphoid tissues. It was soon recognized that the molecules, under selective conditions, may suffice to initiate metastatic spread of tumour cells. The question remained as to how a single adhesion molecule can fulfil that task. This review outlines that adhesion is by no means a passive task. Rather, ligand binding, as exemplified for CD44 and other similar adhesion molecules, initiates a cascade of events that can be started by adherence to the extracellular matrix. This leads to activation of the molecule itself, binding to additional ligands, such as growth factors and matrix degrading enzymes, complex formation with additional transmembrane molecules and association with cytoskeletal elements and signal transducing molecules. Thus, through the interplay of CD44 with its ligands and associating molecules CD44 modulates adhesiveness, motility, matrix degradation, proliferation and cell survival, features that together may well allow a tumour cell to proceed through all steps of the metastatic cascade.
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                Author and article information

                Contributors
                Xuecheng Yang
                Hongbo Zhang
                Haitao Niu
                Journal
                Journal ID (nlm-ta): Bioact Mater
                Journal ID (iso-abbrev): Bioact Mater
                Title: Bioactive Materials
                Publisher: KeAi Publishing
                ISSN (Electronic): 2452-199X
                Publication date PMC-release: 08 September 2020
                Publication date Collection: February 2021
                Publication date (Electronic): 08 September 2020
                Volume: 6
                Issue: 2
                Pages: 433-446
                Affiliations
                [a ]Key Laboratory of Urology and Andrology, Medical Research Centre, Affiliated Hospital of Qingdao University, Qingdao, 266003, China
                [b ]Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, 266003, China
                [c ]Pharmaceutical Sciences Laboratory and Turku Bioscience Centre, Åbo Akademi University, Turku, 20520, Finland
                Author notes
                [∗ ]Corresponding author. Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, 266003, China niuht0532@ 123456126.com
                [∗∗ ]Corresponding author. hongbo.zhang@ 123456abo.fi
                [∗∗∗ ]Corresponding author. m18661805062@ 123456163.com
                [1]

                Y. L. and Y. H. W. contributed equally to this work.

                Article
                Publisher ID: S2452-199X(20)30194-8
                DOI: 10.1016/j.bioactmat.2020.08.019
                PMC ID: 7490593
                PubMed ID: 32995671
                SO-VID: 3c278eb8-4359-4571-9244-77d8eae8c401
                Copyright © © 2020 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 16 June 2020
                Date revision received : 7 August 2020
                Date accepted : 23 August 2020
                Categories
                Subject: Article

                Keywords: sirna delivery,chitosan,hyaluronic acid dialdehyde,cd44 targeting,bladder cancer
                Data availability:
                Keywords: sirna delivery, chitosan, hyaluronic acid dialdehyde, cd44 targeting, bladder cancer

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