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Research Article

An efficient injectable formulation with block copolymer micelles for hydrophobic antitumor candidate-pyridazinone derivatives

    XiuXiu Jin

    State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy. Chengdu, China

    Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, China

    ,
    YaLi Wang

    State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy. Chengdu, China

    ,
    LiWei Tan

    State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy. Chengdu, China

    ,
    Yun He

    Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, China

    ,
    JinRong Peng

    State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy. Chengdu, China

    ,
    Li Hai

    Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, China

    ,
    Yong Wu

    **Author for correspondence:

    E-mail Address: wyong@scu.edu.cn

    Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, China

    &
    ZhiYong Qian

    *Author for correspondence:

    E-mail Address: anderson-qian@163.com

    State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy. Chengdu, China

    Published Online:https://doi.org/10.2217/nnm.15.66

    Aim: To make delivery improvements via delivery systems for 6-(4-morpholino-3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (DZO) – a model compound of hydrophobic antitumor candidate pyridazinone derivatives. Materials & methods: Methoxy poly(ethylene glycol)-poly(d,l-lactide) (MPEG-PDLLA) micelle was employed as a vector, and DZO was encapsulated in. The DZO-loaded micelles were characterized in detail and its cytotoxicity, maximum tolerated dose (MTD) and pharmacokinetic experiments were done. In vivo anticancer activity was studied through a subcutaneous 4T1 tumor model. Results: Compared with free DZO, the DZO-loaded micelles possessed a sustained release property, an improved MTD, better pharmacokinetic parameters and an enhanced antitumor activity for subcutaneous 4T1 model in vivo. Conclusion: An effective injectable delivery system for DZO was developed successfully.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 World Health Organization. Cancer (Media centre). www.who.int/mediacentre/factsheets/fs297/en/.
    • 2 Nicola F, Peter S, Alberto C et al. Drug attrition during pre-clinical and clinical development: understanding and managing drug-induced cardiotoxicity. Pharmacol. Ther. 138(3), 470–484 (2013).
    • 3 David JA. The valley of death in anticancer drug development: a reassessment. Trends Pharmacol. Sci. 33(4), 173–180 (2012).
    • 4 Akahane A, Katayama H, Mitsunaga T. Discovery of 6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinebutanoic acid (FK 838): a novel non-xanthine adenosine A1 receptor antagonist with potent diuretic activity. J. Med. Chem. 42(5), 779–783 (1999).
    • 5 Meade EA, Wotrin LL, Drach JC, Townsend LB. Synthesis and antiproliferative and antiviral activity of carbohydrate-modified Pyrrolo[2,3-d]pyridazin-7-one nucleosides. J. Med. Chem. 40(5), 794–801 (1997).
    • 6 Refaat HM, Khalil OM, Kadry H. Synthesis and anti-inflammatory activity of certain piperazinylthienylpyridazine derivatives. Arch. Pharm. Res. 30(7), 803–811 (2007).
    • 7 Siddiqui AA, Mishra R, Shaharyar M. Synthesis and characterization of new types of halogenated and alkylated imidazolidineiminothiones and a comparative study of their antitumor, antibacterial, and antifungal activities. Eur. J. Med. Chem. 46(6), 2280–2289 (2011).
    • 8 Osamu T, Frank MC. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3(3), 233–245 (2003).
    • 9 Liu SC, Hitoshi Y. P27-Associated G1 arrest induced by hinokitiol in human malignant melanoma cells is mediated via down-regulation of pRb, Skp2 ubiquitin ligase, and impairment of cdk2 function. Cancer Lett. 286(2), 240–249 (2009).• Demonstrated the potential of pyridazinone derivatives in antitumor activity.
    • 10 Zhou SG, Liao HM, Chao H et al. Design, synthesis and structure activity relationships of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety as potential antitumor agents. Eur. J. Med. Chem. 83(18), 581–593 (2014).
    • 11 Csókás D, Zupkó I, Károlyi BI et al. Synthesis, spectroscopy, x-ray analysis and in vitro antiproliferative effect of ferrocenylmethylene-hydrazinylpyridazin- -3(2H)-ones and related ferroceno[d]pyridazin-1(2H)-ones. J. Organomet. Chem. 743(15), 130–138 (2013).
    • 12 Taleb H, Al T. Design and synthesis of novel tetrahydro-2H-pyrano-[3,2- -c]pyridazin-3(6H)-one derivatives as potential anticancer agents. Eur. J. Med. Chem. 45(12), 5724–5731 (2010).
    • 13 Ovais S, Javed K, Yaseen S et al. Synthesis, antiproliferative and anti-inflammatory activities of some novel 6-aryl-2-(p-(methanesulfonyl)phenyl)- -4,5-dihydropyridazi-3(2H)-ones. Eur. J. Med. Chem. 67, 352–358 (2013).
    • 14 Rathish IG, Javed K, Ahmad S et al. Synthesis and evaluation of anticancer activity of some novel 6-aryl-2-(p-sulfamylphenyl)-pyridazin-3(2H)-ones. Eur. J. Med. Chem. 49, 304–309 (2012).
    • 15 Nahren MM, Dhananjay B, Nanda G. Why pyridine containing pyrido[2,3-d]pyrimidin-7-ones selectively inhibit CDK4 than CDK2: insights from molecular dynamics simulation. J. Mol. Graphics Modeling 28, 695–706 (010).
    • 16 AVENTIS CO. WO2004/046130 (2004).•• Data showed the antitumor activity of 6-(4-morpholino-3-[trifluoromethyl]phenyl)pyridazin-3(2H)-one (DZO) and its synthetic methods.
    • 17 Hu YH, Lou LG, Lin SJ et al. US2013/0281426 (2013).
    • 18 Wu Y, Zhu Y, Hai L, Li J, Yu YG, Liu WJ. CN201410018618.0 (2014).
    • 19 Wu Y, Wang YQ, Hai L, Qi TL, Yu YG, Lei F. CN201210192036.5 (2012).
    • 20 Carr C, Julia N, Wigmore T. The side effects of chemotherapeutic agents. Curr. Anaesth. Crit. Care 19(2), 70–79 (2008).
    • 21 Aggarwal P, Hall JB, McLeland CB, Dobrovolskaia MA, Mcneil SE. Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv. Drug Deliv. Rev. 61(6), 428–437 (2009).
    • 22 Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 44(1), 235–249 (2000).
    • 23 Le Garrec D, Gori S, Luo L, Lessard D et al. Poly(N-vinylpyrrolidone)-block-poly(D,L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation. J. Control. Release 99(1), 83–101 (2004).
    • 24 Chiappetta DA, Sosnik A. Poly(ethylene oxide)-poly-(propylene oxide) block copolymer micelles as drug delivery agents: improved hydrosolubility, stability and bioavailability of drugs. Eur. J. Pharm. Biopharm. 66(3), 303–317 (2007).
    • 25 Fuhrmann K, Jessica D, Schulz, Marc A, Gauthier, Jean-Christophe L. PEG nanocages as non-sheddable stabilizers for drug nanocrystals. ACS Nano 6(2), 1667–1676 (2012).•• Demonstrated the advantage of biodegrable nanomicelles on anticancer drug delivery.
    • 26 Farokhzad OC, Langer R. Impact of nanotechnology on drug delivery. ACS Nano 3(1), 16–20 (2009).
    • 27 Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat. Rev. Cancer 5, 161–171 (2005).
    • 28 Service RF. Nanotechnology takes aim at cancer. Science 310, 1132–1134 (2005).
    • 29 Alexis F, Rhee JW, Richie JP et al. New frontiers in nanotechnology for cancer treatment. Urol. Oncol. Semin. Ori. Invest. 26(1), 74–85 (2008).
    • 30 Wang X, Yang L, Chen Z, Shin DM. Application of nanotechnology in cancer therapy and imaging. CA Cancer J. Clin. 58(2), 97–110 (2008).
    • 31 Wang YJ, Chen LJ, Tan LW et al. PEG-PCL based micelle hydrogels as oral docetaxel delivery systems for breast cancer therapy. Biomaterials 35(25), 6972–6985 (2014).
    • 32 Wang C, Long CF, Xie CS et al. Two novel nanoscale preparations of micelle and thermosensitive hydrogel for docetaxel to treat malignant tumor. J. Biomed. Nanotechnol. 9(3), 357–366 (2013).
    • 33 Wang YJ, Wang C, Wang YJ, Luo F, Yan X, Qian ZY. Micelles of methoxy poly(ethylene glycol)-poly(ε-caprolactone) as a novel drug delivery vehicle for Tacrolimus. J. Biomed. Nanotechnol. 9(2), 147–157 (2013).
    • 34 Xue BX, Wang YJ, Tang XH et al. Biodegradable self-assembled MPEG-PCL micelles for hydrophobic oridonin delivery in vitro. J. Biomed. Nanotechnol. 8(1), 80–89 (2012).
    • 35 Gou ML, Men K, Shi HS et al. Curcumin-loaded biodegradable polymeric micelles for colon cancer therapy in vitro and in vivo. Nanoscale 3, 1558–1567 (2011).
    • 36 Gong CY, Xie YM, Wu QJ et al. Improving anti-tumor activity with polymeric micelles entrapping paclitaxel in pulmonary carcinoma. Nanoscale 4, 6004–6017 (2012).
    • 37 Gou ML, Zheng XL, Ke M et al. Poly(ε-caprolactone)/poly(ethylene glycol)/poly(ε-caprolactone) nanoparticles: preparation, characterization, and application in doxorubicin delivery. J. Phys. Chem. B 113(39), 12928–12933 (2009).
    • 38 Wang YJ, Wang C, Fu SZ et al. Preparation of tacrolimus loaded micelles based on poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone). Int. J. Pharm. 407(1–2), 184–189 (2011).
    • 39 Gou ML, Zheng L, Peng XY et al. Poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone) (PCL–PEG–PCL) nanoparticles for honokiol delivery in vitro. Int. J. Pharm. 375(1–2), 170–176 (2009).
    • 40 Mei L, Zhang ZP, Zhao LY, Huang LQ. Pharmaceutical nanotechnology for oral delivery of anticancer drugs. Adv. Drug Deliv. Rev. 65(6), 880–890 (2013).•• Demonstrated the method to synthesize methoxy poly(ethylene glycol)-poly(lactide) and how to prepare the drug-loaded micelles and evaluate them.
    • 41 Dong YC, Feng SS. Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs. Biomaterials 25(14), 2843–2849 (2004).
    • 42 Zheng XL, Kan B, Gou M et al. Preparation of MPEG-PLA nanoparticle for honokiol delivery in vitro. Int. J. Pharm. 386(1–2), 262–267 (2010).• Demonstrated the prominent property of the polymetric micelles in antitumor drug delivery.
    • 43 Croy SR, Kwon GS. Polymeric micelles for drug delivery. Curr. Pharm. Des. 12(36), 4669–4684 (2006).
    • 44 Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Release 65(1–2), 271–284 (2000).
    • 45 Takahashi, Taisuke, Maeda, Jun, Inagaki, Yusuke: WO 2014133056 A1 (2014).
    • 46 Gou ML, Li XY, Dai M et al. A novel injectable local hydrophobic drug delivery system: biodegradable nanoparticles in thermo-sensitive hydrogel. Int. J. Pharm. 359(1–2), 228–233 (2008).
    • 47 Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother. Rep. 50, 219–44 (1966).
    • 48 Zheng XL, Kan B, Gou ML et al. Preparation of MPEG–PLA nanoparticle for honokiol delivery in vitro. Int. J. Pharm. 386(1–2), 262–267 (2010).