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      Codelivery of GRP78 siRNA and docetaxel via RGD-PEG-DSPE/DOPA/CaP nanoparticles for the treatment of castration-resistant prostate cancer

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          Abstract

          Background: Castration-resistant prostate cancer (CRPC) accounts for the majority of prostate cancer deaths, and patients with CRPC are prone to developing drug resistance. Therefore, there is a need to develop effective therapeutics to treat CRPC, especially drug-resistant CRPC. Although various nanoparticles have been developed for drug or gene delivery and control release, approaches to reproducibly formulate the optimal treatment with nanoparticles that could effectively target CRPC and bone metastasis remain suboptimal. Recently, codelivery of a chemotherapeutic agent and a small interfering RNA (siRNA) has become a promising strategy for the treatment of drug-resistant prostate cancer.

          Methods: In a previous study, we prepared a novel RGD-PEG-DSPE/CaP nanoparticle as an effective and biocompatible drug and gene delivery system. In this study, we further modify the nanoparticle to obtain the LCP-RGD nanoparticle, which contains a calcium phosphate (CaP) core, dioleoyl phosphatidic acid (DOPA) and RGD modified poly(ethylene glycol)-conjugated distearoyl phosphatidylethanolamine (RGD-PEG-DSPE). This drug delivery system was used for codelivery of GRP78 siRNA and docetaxel (DTXL) for the treatment of the PC-3 CRPC.

          Results: The nanoparticles contain the CaP core, which can effectively compress the negatively charged siRNA, while the DOPA and RGD-PEG-DSPE component can effectively carry DTXL. The arginine-glycine-aspartic acid (RGD) segment can target the prostate cancer site, as the cancer site is neovascularized. This novel nanoparticle has good stability, excellent biocompatibility, high drug and siRNA loading capacity, and an in vitro sustainable release profile.

          Conclusion: Codelivery of DTXL and GRP78 siRNA has enhanced in vitro and in vivo anti-prostate cancer effects which are much greater than using free DTXL and free GRP78 siRNA together. Our study also indicated that codelivery of DTXL and GRP78 siRNA have an in vitro and in vivo combinational anti-prostate cancer effect and also could effectively sensitize the cell-killing effect of DTXL; this method may be especially suitable for drug-resistant CRPC treatment.

          Most cited references34

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          Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile.

          We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.
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            The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies.

            B. Luo, A Lee (2013)
            Cancer progression is characterized by rapidly proliferating cancer cells that are in need of increased protein synthesis. Therefore, enhanced endoplasmic reticulum (ER) activity is required to facilitate the folding, assembly and transportation of membrane and secretory proteins. These functions are carried out by ER chaperones. It is now becoming clear that the ER chaperones have critical functions outside of simply facilitating protein folding. For example, cancer progression requires glucose regulated protein (GRP) 78 for cancer cell survival and proliferation, as well as angiogenesis in the microenvironment. GRP78 can translocate to the cell surface acting as a receptor regulating oncogenic signaling and cell viability. Calreticulin, another ER chaperone, can translocate to the cell surface of apoptotic cancer cells and induce immunogenic cancer cell death and antitumor responses in vivo. Tumor-secreted GRP94 has been shown to elicit antitumor immune responses when used as antitumor vaccines. Protein disulfide isomerase is another ER chaperone that demonstrates pro-oncogenic and pro-survival functions. Because of intrinsic alterations of cellular metabolism and extrinsic factors in the tumor microenvironment, cancer cells are under ER stress, and they respond to this stress by activating the unfolded protein response (UPR). Depending on the severity and duration of ER stress, the signaling branches of the UPR can activate adaptive and pro-survival signals, or induce apoptotic cell death. The protein kinase RNA-like ER kinase signaling branch of the UPR has a dual role in cancer proliferation and survival, and is also required for ER stress-induced autophagy. The activation of the inositol-requiring kinase 1α branch promotes tumorigenesis, cancer cell survival and regulates tumor invasion. In summary, perturbance of ER homeostasis has critical roles in tumorigenesis, and therapeutic modulation of ER chaperones and/or UPR components presents potential antitumor treatments.
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              RNAi therapeutics: principles, prospects and challenges.

              RNA interference (RNAi) was discovered less than a decade ago and already there are human clinical trials in progress or planned. A major advantage of RNAi versus other antisense based approaches for therapeutic applications is that it utilizes cellular machinery that efficiently allows targeting of complementary transcripts, often resulting in highly potent down-regulation of gene expression. Despite the excitement about this remarkable biological process for sequence specific gene regulation, there are a number of hurdles and concerns that must be overcome prior to making RNAi a real therapeutic modality, which include off-target effects, triggering of type I interferon responses, and effective delivery in vivo. This review discusses mechanistic aspects of RNAi, the potential problem areas and solutions and therapeutic applications. It is anticipated that RNAi will be a major therapeutic modality within the next several years, and clearly warrants intense investigation to fully understand the mechanisms involved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                29 April 2019
                2019
                : 13
                : 1357-1372
                Affiliations
                [1 ]Department of Pathology, Jining First People’s Hospital, Jining Medical University , Jining 272000, People’s Republic of China
                [2 ]Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical University & Tumor Hospital Affiliated to Bengbu Medical University , Bengbu 233004, People’s Republic of China
                Author notes
                Correspondence: Fanzhong Lin; Hongying Cao Department of Pathology, Jining First People’s Hospital, Jining Medical University , No. 6, Jiankang Road, Jining272000, People’s Republic of ChinaTel +86 537 605 1547Fax +86 537 605 1547Email linfanzhong1@ 123456126.com ; caohongying001@ 123456126.com
                [*]

                These authors contributed equally to this work

                Article
                198400
                10.2147/DDDT.S198400
                6499149
                58cde794-40a3-4432-843a-8e2194d8d011
                © 2019 Zhang 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 16 December 2018
                : 05 March 2019
                Page count
                Figures: 9, Tables: 3, References: 44, Pages: 16
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                codelivery,docetaxel,rank,sirna,nanoparticles
                Pharmacology & Pharmaceutical medicine
                codelivery, docetaxel, rank, sirna, nanoparticles

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