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  • br DOX induced hepatotoxicity involves not only hepatic inju


    DOX-induced hepatotoxicity involves not only hepatic injury but also the induction of oxidative stress, and thus we examined the levels of glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and su-peroxide dismutase (SOD) in serum (Fig. 10C). MDA is a typical marker of oxidative stress and elevated concentrations in the serum are seen after DOX treatment. However, the combinational delivery of OA and DOX from the NPs significantly reduced the MDA level (P < 0.01). This is consistent with a previous study [57]. GSH-Px and SOD are two enzymes which protect organisms from oxidative damage. DOX treat-ment reduced the levels of both GSH-Px and SOD in the serum, but [email protected] NPs reversed this because of the protective action of OA (Fig. 10C) [58].
    Finally, to evaluate the effect of OA on inflammation in DOX-treated mice, serum levels of IL-1β, IL-6 and TNF-a were determined. From Fig. 10D, it is clear that DOX treated mice exhibited high levels of serum IL-1β, IL-6 and TNF-α, but these are much reduced upon si-multaneous OA administration with the [email protected] NPs.
    4. Conclusions
    In this work, we report the synthesis, characterization and an in vitro and in vivo anti-tumor evaluation of a pH-responsive nanomedicine for the targeted co-delivery of oleanolic L-Glutamine (OA) and doxorubicin (DOX). Chitosan was first functionalized with folic acid (FA) to allow active targeting to FA-receptor positive cancer cells, and the FA-CS composite
    (caption on next page)
    Fig. 9. The effect of treatment with saline, free DOX, free OA, FA-CS-g-OA, and [email protected] on the protein expression profile of MDA-MB-231 breast tumors.
    further modified with OA to give FA-CS-g-OA. The latter self-assembled into nanoparticles upon addition to an aqueous medium, and DOX could be effectively trapped in the core (drug loading: 15.6% w/w). Drug release is accelerated at the slightly acidic pHs which typify the tumor microenvironment. Enhanced cytotoxicity and cellular uptake of the [email protected] NPs into MDA-MB-231 cells in vitro was noted compared with free DOX, while the NPs were less toxic than DOX to healthy HUVEC cells. In vivo studies demonstrated prolonged phar-macokinetics with the NPs, and reduced hemolysis. In a murine MDA-MB-231 tumor model, the [email protected] NPs became localized in the tumor, and caused significantly greater reductions in tumor volume than pure DOX. Systemic toxicity was reduced, and survival times in-creased, when using the nanoparticle formulations. The NPs caused downregulation of the P-gp and MRP-1 proteins associated with multi-drug resistance, and reduced tumor fibrosis. The presence of OA could mitigate DOX-induced tissue damage by inhibiting hepatic/renal injury, and also through anti-oxidant and anti-inflammatory activities. Taken together, our results demonstrate that the [email protected] NPs comprise a powerful therapeutic platform for treating multi-drug re-sistant breast cancers.
    The authors have no conflict of interest to declare.
    This research was financially supported by grant 16410723700 from the Science and Technology Commission of Shanghai Municipality, the Biomedical Textile Materials “111 Project” of the Ministry of Education of L-Glutamine China (No. B07024), the UK China Joint 
    Laboratory for Therapeutic Textiles (based at Donghua University), the Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Project on Applied Basic Research (2018FE001 (-162)), and the National Natural Science Foundation of China (81460647).
    Appendix A. Supplementary data
    G. Nie, An MMP-2 responsive liposome integrating antifibrosis and chemother-apeutic drugs for enhanced drug perfusion and efficacy in pancreatic cancer, ACS Appl. Mater. Interfaces 8 (2016) 3438–3445.