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      Development and evaluation of novel tumor-targeting paclitaxel-loaded nano-carriers for ovarian cancer treatment: in vitro and in vivo

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          Abstract

          Background

          Ovarian cancer is the most leading cause of death and the third most common gynecologic malignancy in women. Traditional chemotherapy has inevitable drawbacks of nonspecific tumor targeting, high toxicity, and poor therapeutic efficiency. In order to overcome such shortcomings, we prepared a novel nano-carrier drug-delivery system to enhance the anti-tumor efficiency.

          Methods

          In vitro characterizations of nano-carriers were determined by TEM, DLS. Cell viability was measured by MTT method. RT-PCR was performed to measure the expression of FARα in three ovarian cancer cell lines. The drug-release study and the uptaken study were measured in vitro. The pharmacokinetic and the drug distribution study were verified by HPLC methods in vivo. The enhanced anti-tumor efficiency of FA-NP was evaluated by the tumor inhibitory rate in vivo.

          Results

          Paclitaxel (PTX)-loaded nanoparticles (NPs) (PTX-PEG-PLA-NP and PTX-PEG-PLA-FA-NP) were prepared successfully, and the drug-release study showed that the cumulative release rates of NP groups were much less than free PTX group. The pharmacokinetic study showed that the elimination phase of two kinds of NP groups were much longer than that of PTX group. The drug distribution in different tissues showed that the peak-reach time was 2 h in the PTX group and 6 h in both NP groups. All of these results confirmed the excellent slow-release effects of both kinds of nano-carriers. More importantly, we confirmed that PTX-PEG-PLA-FA-NP had greater uptake by SK-OV-3 cells than PTX-PEG-PLA-NP and free PTX in vitro. A drug-distribution study of tumor-bearing mice demonstrated that the PTX concentration of tumor tissues in the PTX-PEG-PLA-FA-NP group was 3 times higher than the other two groups. PTX-PEG-PLA-FA-NP was uptaken much more by SK-OV-3 cells than PTX-PEG-PLA-NP and free PTX. Eventually, based on the slow-release effect and tumor-targeting characteristics of PTX-PEG-PLA-FA-NP, a cytotoxicity test indicated that PTX-PEG-PLA-FA-NP was much more toxic to SK-OV-3 cells than the controls. The tumor inhibitory rate in the PTX-PEG-PLA-FA-NP group of tumor-bearing mice was about 1.5 times higher than the controls. The tumor targeting and anti-tumor efficiency of PTX-PEG-PLA-FA-NP were confirmed both in vitro and in vivo.

          Conclusions

          We developed an ovarian cancer targeting nano-carrier drug delivery system successfully, which showed perfect ovarian cancer targeting and anti-tumor effect, thus have the potential to be a new therapy strategy for ovarian cancer patients.

          Electronic supplementary material

          The online version of this article (10.1186/s13046-018-0700-z) contains supplementary material, which is available to authorized users.

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          Most cited references25

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          Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications.

          Cancer is a leading cause of death worldwide. Currently available therapies are inadequate and spur demand for improved technologies. Rapid growth in nanotechnology towards the development of nanomedicine products holds great promise to improve therapeutic strategies against cancer. Nanomedicine products represent an opportunity to achieve sophisticated targeting strategies and multi-functionality. They can improve the pharmacokinetic and pharmacodynamic profiles of conventional therapeutics and may thus optimize the efficacy of existing anti-cancer compounds. In this review, we discuss state-of-the-art nanoparticles and targeted systems that have been investigated in clinical studies. We emphasize the challenges faced in using nanomedicine products and translating them from a preclinical level to the clinical setting. Additionally, we cover aspects of nanocarrier engineering that may open up new opportunities for nanomedicine products in the clinic.
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            Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles.

            Nanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided. © 2013.
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              Folate-targeted therapeutic and imaging agents for cancer.

              Cancer therapies that exploit targeting ligands to deliver attached cytotoxic drugs selectively to malignant cells are currently receiving significant attention. While antibody-targeted drugs have been the first to enter the clinic, recent studies demonstrate that the vitamin folic acid can also be used to deliver attached imaging and therapeutic agents selectively to malignant cells in both animal tumor models and human cancer patients. Thus, folate conjugates bind to folate receptors that are overexpressed on approximately 40% of human cancers and mediate internalization of their attached drugs by receptor-mediated endocytosis. With the use of proper linkers, folate-targeted drugs can be released inside their target cells where they can perform their desired cytotoxic functions. Based on this strategy, six folate-targeted drugs are currently in human clinical trials.
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                Author and article information

                Contributors
                songkun2001226@sdu.edu.cn
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                26 February 2018
                26 February 2018
                2018
                : 37
                : 29
                Affiliations
                [1 ]ISNI 0000 0004 1761 1174, GRID grid.27255.37, Department of Obstetrics and Gynecology, Qilu Hospital, , Shandong University, ; 107 Wenhua Xi Road, Jinan, Shandong 250012 People’s Republic of China
                [2 ]ISNI 0000 0004 1761 1174, GRID grid.27255.37, Gynecology Oncology Key Laboratory, Qilu Hospital, , Shandong University, ; Jinan, Shandong 250012 China
                [3 ]ISNI 0000 0004 1761 1174, GRID grid.27255.37, Department of Biomedical Engineering, School of Control Science and Engineering, , Shandong University, ; Jinan, Shandong 250012 China
                [4 ]ISNI 0000 0004 1761 1174, GRID grid.27255.37, Department of Chemistry and Chemical Engineering, , Shandong University, ; Jinan, Shandong 250012 China
                Article
                700
                10.1186/s13046-018-0700-z
                6389131
                29478415
                5e2413cc-5e15-4531-b852-6116eb7d24cd
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 12 October 2017
                : 7 February 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81172488
                Funded by: Fundamental Research Funds of Shandong University
                Award ID: 2014QLKY24
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                nano-carriers,ovarian cancer,paclitaxel,tumor targeting,folic acid
                Oncology & Radiotherapy
                nano-carriers, ovarian cancer, paclitaxel, tumor targeting, folic acid

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