c(RGDyk)环肽修饰纳米胶束逆转脑胶质瘤对多西他赛的耐药性

doi:10.3969/j.issn.2095-9400.2019.11.001

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Abstract

Objective: To prepare c(RGDyk) cyclic peptide modified Nano-micelles encapsulating docetaxel (DTX) and to evaluate its ability to reverse the resistance of U87 glioma cells against DTX. Methods: Using Poloxamer 188 (PL-188) as raw material, after carboxylation of succinic anhydride, the c(RGDyk) cyclic peptide was bonded to synthesize c(RGDyk)-PL-188 targeting material and its structure was confirmed by 1H-NMR and FT-IR. c(RGDyk)-PL-188 was used as the coating material; the Nano-micelles encapsulating DTX [c(RGDyk)DTX-NPs] were prepared by Nano coprecipitation method and the prescription was optimized. Transmission electron microscope (TEM), differential scanning calorimetry (DSC) and dynamic dialysis method were used to characterize the morphology, drug crystal form and drug release behavior of c(RGDyk)DTX-NPs in vitro. CCK8 cellular viability assay in vitro, cellular uptake and U87 cells spheroids growth inhibition test were applied to evaluate the reversal effect of c(RGDyk)DTX-NPs on human glioma U87 cells resistance to DTX. Results: 1H-NMR and FT-IR showed that c(RGDyk)-PL-188 was successfully synthesized, which could be spontaneously assembled into micelles with mean particle diameter of (115.6±0.2) nm. When the mass ratio of c(RGDyk)-PL-188/DTX is 10:1, drug loading content and drug loading efficiency for DTX-loaded micelles were high up to 7.88%±0.02% and 85.5%±2.78%, respectively. DTX-loaded micelles had a mean diameter of (159.2±0.2) nm and zeta potential of (-16.8±0.8) mV, exhibiting the spherical shape determined by TEM. In vitro DTX release showed that c(RGDyk)DTX-NPs exhibited sustained-release behavior and the cumulative release of DTX was only 78% within 24 hours. Cellular uptake indicated that c(RGDyk)-NPs could specifically target drug-resistant human glioma U87 cells, which significantly increased the intracellular fluorescence distribution of fluorescent probe ICG, and its targetability was inhibited by free c(RGDyk) solution. Compared with DTX solution and DTX-NPs, c(RGDyk)DTX-NPs had the stronger cytotoxicity to drug-resistant human glioma U87 cells. The study of U87 human glioma cells spheroids model in vitro showed that c(RGDyk)DTX-NPs could penetrate into the deep part of the tumor spheroids more effectively and inhibit the growth of the tumor spheroids. Conclusion: DTX is efficiently encapsulated in c(RGDyk) cyclic peptide modified Nano-micelles with high drug loading content and drug loading efficiency, specifically targeting U87 human glioma cells and reversing their resistance against docetaxel

Key words： docetaxel micelles poloxamer glioma;cells spheroids;multi-drugs resistance

Received: 09 April 2019

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	Articles by authors
	WU Qilong
	CAI Jinhua
	XU Helin
	LI Hui
	ZHAO Yingzheng
	CHEN Bin

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https://xb.wmu.edu.cn/EN/10.3969/j.issn.2095-9400.2019.11.001 OR https://xb.wmu.edu.cn/EN/Y2019/V49/I11/781

[1] HERBST R S, KHURI F R. Mode of action of docetaxel-a basis for combination with novel anticancer agents[J]. Cancer Treat Rev, 2003, 29(5): 407-415.
[2] GUÉRITTE-VOEGELEIN F, GUÉNARD D, LAVELLE F, et al. Relationships between the structure of taxol analogues and their antimitotic activity[J]. J Med Chem, 1991, 34(3): 992-998.
[3] OGAWA C, YATABE M, INOUE M, et al. Comparison of chemical behavior of original and generic docetaxel formulations as non-alcoholic preparations: discussion about diluent solvents for docetaxel[J]. Yakugaku Zasshi, 2018, 138(7): 973-984.
[4] LUO Z, JIANG L, DING C, et al. Surfactant free delivery of docetaxel by poly[(r)-3-hydroxybutyrate-(r)-3-hydroxyhexanoate]-based polymeric micelles for effective melanoma treatments[J]. Adv Healthc Mater, 2018, 7(23): e1801221.
[5] RAFIEI P, HADDADI A. Docetaxel-loaded PLGA and PLGA-PEG nanoparticles for intravenous application: pharmacokinetics and biodistribution profile[J]. Int J Nanomedicine, 2017, 12: 935-947.
[6] SIM T, KIM J E, HOANG N H, et al, Development of a docetaxel micellar formulation using poly(ethylene glycol)-polylactide-poly(ethylene glycol) (PEG-PLA-PEG) with successful reconstitution for tumor targeted drug delivery[J]. Drug Deliv, 2018, 25(1): 1362-1371.
[7] ALSHRAIM M O, SANGI S, HARISA G I, et al, Chitosan-coated flexible liposomes magnify the anticancer activity and bioavailability of docetaxel: impact on composition[J]. Molecules, 2019, 24(2). pii: E250.
[8] QU N, SUN Y, LI Y, et al, Docetaxel-loaded human serum albumin (HSA) nanoparticles: synthesis, characterization, and evaluation[J]. Biomed Eng Online, 2019, 18(1): 11.
[9] LI C, REN S, DAI Y, et al, Efficacy, pharmacokinetics, and biodistribution of thermosensitive chitosan/beta-glycerophosphate hydrogel loaded with docetaxel[J]. AAPS Pharm Sci Tech, 2014, 15(2): 417-424.
[10] ALAKHOV V, MOSKALEVA E, BATRAKOVA E V, et al, Hypersensitization of multidrug resistant human ovarian carcinoma cells by pluronic P85 block copolymer[J]. Bioconjug Chem, 1996, 7(2): 209-216.
[11] VENNE A, LI S, MANDEVILLE R, et al. Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells[J]. Cancer Res, 1996, 56(16): 3626-3629.
[12] GAO H, XIONG Y, ZHANG S, et al. RGD and interleukin-13 peptide functionalized nanoparticles for enhanced glioblastoma cells and neovasculature dual targeting delivery and elevated tumor penetration[J]. Mol Pharm, 2014, 11(3): 1042-1052.
[13] BELHADJ Z, ZHAN C, YING M, et al. Multifunctional targeted liposomal drug delivery for efficient glioblastoma treatment[J]. Oncotarget, 2017, 8(40): 66889-66900.
[14] ZHANG L, HU Y, JIANG X, et al. Camptothecin derivative-loaded poly(caprolactone-co-lactide)-b-PEG-b-poly(caprolactone-co-lactide) nanoparticles and their biodistribution in mice[J]. J Control Release, 2004, 96(1): 135-148.
[15] XU H L, MAO K L, LU C T , et al. An injectable acellular matrix scaffold with absorbable permeable nanoparticles improves the therapeutic effects of docetaxel on glioblastoma [J]. Biomaterials, 2016, 107: 44-60.
[16] ZHANG L, XIA Y, LI L, et al. Cancer stem cell-like cells exist in mucoepidermoid carcinoma cell line MC3[J]. Oncol Res, 2012, 20(12): 589-600.
[17] RAHIMI K, FUCHTBAUER A C, FATHI F, et al. Isolation of cancer stem cells by selection for miR-302 expressing cells[J]. Peer J, 2019, 7: e6635.
[18] GAO H, QIAN J, YANG Z, et al. Whole-cell SELEX aptamer-functionalised poly(ethyleneglycol)-poly(epsilon-caprolactone) nanoparticles for enhanced targeted glioblastoma therapy[J]. Biomaterials, 2012, 33(26): 6264-6272.
[19] YANG Z Z, LI J Q, WANG Z Z, et al. Tumor-targeting dual peptides-modified cationic liposomes for delivery of siRNA and docetaxel to gliomas[J]. Biomaterials, 2014, 35(19): 5226-5239.
[20] GAO H, YANG Z, CAO S, et al. Tumor cells and neovasculature dual targeting delivery for glioblastoma treatment[J]. Biomaterials, 2014, 35(7): 2374-2382.