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2000
Volume 23, Issue 1
  • ISSN: 1567-2018
  • E-ISSN: 1875-5704

Abstract

Introduction

Multidrug resistance (MDR) is a key challenge in clinical chemotherapy. The combination of drugs can effectively reverse multi-drug resistance.

Objective

In this study, doxorubicin (DOX) was capsulated into nanoparticles formed by an amphiphilic PEGylated-poly (α-lipoic acid)-methanamide analogue of celastrol (mPEG-PαLA-CEN) prodrug polymer. CEN was linked to the branched chain of poly (α-lipoic acid) by forming ester bonds. DOX was physically trapped inside the nanoparticles electrostatic interaction. Both drugs can be simultaneously released in response to low pH and high GSH in order to overcome DOX resistance.

Methods

The chemical structure of the mPEG-PαLA-CEN-DOX NPs was confirmed through 1H NMR, FT-IR spectroscopy, UV-Vis spectrum, DLS, and TEM. Drug-loading content, efficacy, and drug release were measured using HPLC. Cell toxicity was examined using an MTT assay.

Results

CEN/DOX-loaded nanoparticles were found to have spherical shapes with diameters of around 229.7 nm. The NPs exhibited high biocompatibility and released 92% DOX and 71.8% CEN in response to low pH and high GSH of tumor microenvironments. As dual drug-loaded nanoparticles, the efficacy of mPEG-PαLA-CEN-DOX NPs against tumor cell lines was enhanced for both MCF-7 and MCF-7/ADR compared to free DOX. Compared to free DOX, the IC50 of mPEG-PαLA-CEN-DOX NPs reduced from 46.10 μM to 8.36 μM for the MCF-7/ADR cell line.

Conclusion

In conclusion, this study demonstrated that PEGylated poly (α-lipoic acid)-CEN copolymers can be used not only as biocompatible, stimulation-responsive anticancer drug nanocarriers but also as chemosensitizers to overcome multidrug resistance, which provide a theoretical base for clinical application of CEN/DOX nanodrug.

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References

  1. PribludaA. de la CruzC.C. JacksonE.L. Intratumoral heterogeneity: From diversity comes resistance.Clin. Cancer Res.201521132916292310.1158/1078‑0432.CCR‑14‑121325838394
     [Google Scholar]
  2. AmbudkarS.V. Kimchi-SarfatyC. SaunaZ.E. GottesmanM.M. P-glycoprotein: from genomics to mechanism.Oncogene200322477468748510.1038/sj.onc.120694814576852
     [Google Scholar]
  3. MaoJ. QiuL. GeL. ZhouJ. JiQ. YangY. LongM. WangD. TengL. ChenJ. Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer.Biomed. Pharmacother.2021134711110810.1016/j.biopha.2020.11110833341670
     [Google Scholar]
  4. LiuJ. HuangY. KumarA. TanA. JinS. MozhiA. LiangX.J. pH-Sensitive nano-systems for drug delivery in cancer therapy.Biotechnol. Adv.201432469371010.1016/j.biotechadv.2013.11.00924309541
     [Google Scholar]
  5. FachM. RadiL. WichP.R. Nanoparticle assembly of surface-modified proteins.J. Am. Chem. Soc.201613845148201482310.1021/jacs.6b0624327490262
     [Google Scholar]
  6. QureshiW.A. ZhaoR. WangH. JiT. DingY. IhsanA. MujeebA. NieG. ZhaoY. Co-delivery of doxorubicin and quercetin via mPEG–PLGA copolymer assembly for synergistic anti-tumor efficacy and reducing cardio-toxicity.Sci. Bull.201661211689169810.1007/s11434‑016‑1182‑z
     [Google Scholar]
  7. TangF. LiL. ChenD. Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery.Adv. Mater.201224121504153410.1002/adma.20110476322378538
     [Google Scholar]
  8. LinB. SuH. JinR. LiD. WuC. JiangX. XiaC. GongQ. SongB. AiH. Multifunctional dextran micelles as drug delivery carriers and magnetic resonance imaging probes.Sci. Bull. (Beijing)201560141272128010.1007/s11434‑015‑0840‑x
     [Google Scholar]
  9. FrangvilleC. LiY. BilloteyC. TalhamD.R. TalebJ. RouxP. MartyJ.D. MingotaudC. Assembly of double-hydrophilic block copolymers triggered by gadolinium ions: New colloidal mri contrast agents.Nano Lett.20161674069407310.1021/acs.nanolett.6b0066427224089
     [Google Scholar]
  10. ZhangH. HuH. ZhangH. DaiW. WangX. WangX. ZhangQ. Effects of PEGylated paclitaxel nanocrystals on breast cancer and its lung metastasis.Nanoscale2015724107901080010.1039/C4NR07450E26038337
     [Google Scholar]
  11. ZhouH. HouX. LiuY. ZhaoT. ShangQ. TangJ. LiuJ. WangY. WuQ. LuoZ. WangH. ChenC. Superstable magnetic nanoparticles in conjugation with near-infrared dye as a multimodal theranostic platform.ACS Appl. Mater. Interfaces2016874424443310.1021/acsami.5b1130826821997
     [Google Scholar]
  12. ErgenC. HeymannF. Al RawashdehW. GremseF. BartneckM. PanzerU. PolaR. PecharM. StormG. MohrN. BarzM. ZentelR. KiesslingF. TrautweinC. LammersT. TackeF. Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles.Biomaterials201711410612010.1016/j.biomaterials.2016.11.00927855336
     [Google Scholar]
  13. OishiM SugiyamaS. An efficient particle-based DNA circuit system: Catalytic disassembly of DNA/peg-modified gold nanoparticle-magnetic bead composites for colorimetric detection of mirna.Small 2016123751535158
     [Google Scholar]
  14. HeB. SuiX. YuB. WangS. ShenY. CongH. Recent advances in drug delivery systems for enhancing drug penetration into tumors.Drug Deliv.20202711474149010.1080/10717544.2020.183110633100061
     [Google Scholar]
  15. MaedaH. BharateG.Y. DaruwallaJ. Polymeric drugs for efficient tumor-targeted drug delivery based on epr-effect.2009713409419
     [Google Scholar]
  16. TorchilinV. Tumor delivery of macromolecular drugs based on the EPR effect.Adv. Drug Deliv. Rev.201163313113510.1016/j.addr.2010.03.01120304019
     [Google Scholar]
  17. CabralH. MatsumotoY. MizunoK. ChenQ. MurakamiM. KimuraM. TeradaY. KanoM.R. MiyazonoK. UesakaM. NishiyamaN. KataokaK. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size.Nat. Nanotechnol.201161281582310.1038/nnano.2011.16622020122
     [Google Scholar]
  18. ChengR. MengF. DengC. ZhongZ. Bioresponsive polymeric nanotherapeutics for targeted cancer chemotherapy.Nano Today201510565667010.1016/j.nantod.2015.09.005
     [Google Scholar]
  19. ChengR. MengF. DengC. ZhongZ. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery.Biomaterials2013341436473657
     [Google Scholar]
  20. LiM. SongW. TangZ. LvS. LinL. SunH. LiQ. YangY. HongH. ChenX. Nanoscaled poly(L-glutamic acid)/doxorubicin-amphiphile complex as pH-responsive drug delivery system for effective treatment of nonsmall cell lung cancer.ACS Appl. Mater. Interfaces2013551781179210.1021/am303073u23410916
     [Google Scholar]
  21. DuJ.Z. DuX.J. MaoC.Q. WangJ. Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery.J. Am. Chem. Soc.201113344175601756310.1021/ja207150n21985458
     [Google Scholar]
  22. DuJ.Z. SunT.M. SongW.J. WuJ. WangJ. A tumor-acidity-activated charge-conversional nanogel as an intelligent vehicle for promoted tumoral-cell uptake and drug delivery.Angew. Chem. Int. Ed.201049213621362610.1002/anie.20090721020391548
     [Google Scholar]
  23. LiuJ. IqbalS. DuX.J. YuanY. YangX. LiH.J. WangJ. Ultrafast charge-conversional nanocarrier for tumor-acidity-activated targeted drug elivery.Biomater. Sci.20186235035510.1039/C7BM01025G29265134
     [Google Scholar]
  24. ChenD. ZhangG. LiR. GuanM. WangX. ZouT. ZhangY. WangC. ShuC. HongH. WanL.J. Biodegradable, hydrogen peroxide, and glutathione dual responsive nanoparticles for potential programmable paclitaxel release.J. Am. Chem. Soc.2018140247373737610.1021/jacs.7b1202529799737
     [Google Scholar]
  25. YuanF. LiJ.L. ChengH. ZengX. ZhangX.Z. A redox-responsive mesoporous silica based nanoplatform for in vitro tumor-specific fluorescence imaging and enhanced photodynamic therapy.Biomater. Sci.2018619610010.1039/C7BM00793K29186237
     [Google Scholar]
  26. ChenK. LiaoS. GuoS. ZhangH. CaiH. GongQ. GuZ. LuoK. Enzyme/pH-sensitive dendritic polymer-DOX conjugate for cancer treatment.Sci. China Mater.201861111462147410.1007/s40843‑018‑9277‑8
     [Google Scholar]
  27. ZhangP. WuJ. XiaoF. ZhaoD. LuanY. Disulfide bond based polymeric drug carriers for cancer chemotherapy and relevant redox environments in mammals.Med. Res. Rev.20183851485151010.1002/med.2148529341223
     [Google Scholar]
  28. KuangG. ZhangQ. HeS. WuY. HuangY. Reduction-responsive disulfide linkage core-cross-linked polymeric micelles for site-specific drug delivery.Polym. Chem.202011447078708610.1039/D0PY00987C
     [Google Scholar]
  29. MizuharaT. SahaK. MoyanoD.F. KimC.S. YanB. KimY.K. RotelloV.M. Acylsulfonamide-functionalized zwitterionic gold nanoparticles for enhanced cellular uptake at tumor ph.Angew. Chem. Int. Ed.201554226567657010.1002/anie.20141161525873209
     [Google Scholar]
  30. LiuZ. ShenN. TangZ. ZhangD. MaL. YangC. ChenX. Correction: An eximious and affordable GSH stimulus-responsive poly(α-lipoic acid) nanocarrier bonding combretastatin A4 for tumor therapy.Biomater. Sci.20208102977297710.1039/D0BM90037K32322862
     [Google Scholar]
  31. SongJ. YangX. JacobsonO. HuangP. SunX. LinL. YanX. NiuG. MaQ. ChenX. Ultrasmall gold nanorod vesicles with enhanced tumor accumulation and fast excretion from the body for cancer therapy.Adv. Mater.201527334910491710.1002/adma.20150248626198622
     [Google Scholar]
  32. BentleyE.R. LittleS.R. Local delivery strategies to restore immune homeostasis in the context of inflammation.Adv. Drug Deliv. Rev.202117811397110.1016/j.addr.2021.11397134530013
     [Google Scholar]
  33. SongY.H. AgrawalN.K. GriffinJ.M. SchmidtC.E. Recent advances in nanotherapeutic strategies for spinal cord injury repair.Adv. Drug Deliv. Rev.2019148385910.1016/j.addr.2018.12.01130582938
     [Google Scholar]
  34. DouY. LiC. LiL. GuoJ. ZhangJ. Bioresponsive drug delivery systems for the treatment of inflammatory diseases.J. Control. Release202032764166610.1016/j.jconrel.2020.09.00832911014
     [Google Scholar]
  35. ChenC.K. LawW.C. AalinkeelR. YuY. NairB. WuJ. MahajanS. ReynoldsJ.L. LiY. LaiC.K. TzanakakisE.S. SchwartzS.A. PrasadP.N. ChengC. Biodegradable cationic polymeric nanocapsules for overcoming multidrug resistance and enabling drug–gene co-delivery to cancer cells.Nanoscale2014631567157210.1039/C3NR04804G24326457
     [Google Scholar]
  36. WangJ.Q. YangY. CaiC.Y. TengQ.X. CuiQ. LinJ. AssarafY.G. ChenZ.S. Multidrug resistance proteins (MRPs): Structure, function and the overcoming of cancer multidrug resistance.Drug Resist. Updat.20215410074310.1016/j.drup.2021.10074333513557
     [Google Scholar]
  37. SantiM.D. OrtegaM.G. PeraltaM.A. Daniela. Santi M, Gabriela. Ortega M, and Peralta M A. A state-of-the-art review and prospective therapeutic applications of prenyl flavonoids as chemosensitizers against antifungal multidrug resistance in candida albicans.Curr. Med. Chem.202229244251428110.2174/092986732966622020910353835139777
     [Google Scholar]
  38. BeheshtiM. Different strategies to overcome multidrug resistance in cancer research review.Biotechnol. Adv.201820188889
     [Google Scholar]
  39. LinH. QiaoY. YangH. NanQ. QuW. FengF. LiuW. ChenY. SunH. Small molecular Nrf2 inhibitors as chemosensitizers for cancer therapy.Future Med. Chem.202012324326710.4155/fmc‑2019‑028531950858
     [Google Scholar]
  40. ChenM. RoseA.E. DoudicanN. OsmanI. OrlowS.J. Celastrol synergistically enhances temozolomide cytotoxicity in melanoma cells.Mol. Cancer Res.20097121946195310.1158/1541‑7786.MCR‑09‑024319934274
     [Google Scholar]
  41. XiaoY. LiuJ. GuoM. ZhouH. JinJ. LiuJ. LiuY. ZhangZ. ChenC. Synergistic combination chemotherapy using carrier-free celastrol and doxorubicin nanocrystals for overcoming drug resistance.Nanoscale20181026126391264910.1039/C8NR02700E29943786
     [Google Scholar]
  42. WangY. LiuQ. ChenH. YouJ. PengB. CaoF. ZhangX. ChenQ. UzanG. XuL. ZhangD. Celastrol improves the therapeutic efficacy of EGFR-TKIs for non-small-cell lung cancer by overcoming EGFR T790M drug resistance.Anticancer Drugs201829874875510.1097/CAD.000000000000064729927769
     [Google Scholar]
  43. KannaiyanR. ShanmugamM.K. SethiG. Molecular targets of celastrol derived from Thunder of God Vine: Potential role in the treatment of inflammatory disorders and cancer.Cancer Lett.2011303192010.1016/j.canlet.2010.10.02521168266
     [Google Scholar]
  44. YangH. ChenD. CuiQ.C. YuanX. DouQ.P. Celastrol, a triterpene extracted from the Chinese “Thunder of God Vine,” is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice.Cancer Res.20066694758476510.1158/0008‑5472.CAN‑05‑452916651429
     [Google Scholar]
  45. Li-WeberM. Targeting apoptosis pathways in cancer by Chinese medicine.Cancer Lett.2013332230431210.1016/j.canlet.2010.07.01520685036
     [Google Scholar]
  46. SalminenA. LehtonenM. PaimelaT. KaarnirantaK. Celastrol: Molecular targets of thunder god vine.Biochem. Biophys. Res. Commun.2010394343944210.1016/j.bbrc.2010.03.05020226165
     [Google Scholar]
  47. BufuT. DiX. YilinZ. GegeL. XiC. LingW. Celastrol inhibits colorectal cancer cell proliferation and migration through suppression of MMP3 and MMP7 by the PI3K/AKT signaling pathway.Anticancer Drugs201829653053810.1097/CAD.000000000000062129553945
     [Google Scholar]
  48. NabekuraT. HiroiT. KawasakiT. UwaiY. Effects of natural nuclear factor-kappa B inhibitors on anticancer drug efflux transporter human P-glycoprotein.Biomed. Pharmacother.20157014014510.1016/j.biopha.2015.01.00725776492
     [Google Scholar]
  49. TanY. ZhuY. ZhaoY. Wen L. MengT. Liu X. Yang X. Dai S. Yuan HH. Hu F. Mitochondrial alkaline ph-responsive drug release mediated by celastrol loaded glycolipid-like micelles for cancer therapy.Biomaterials2018154169181
     [Google Scholar]
  50. ChoiJ.Y. RamasamyT. KimS.Y. KimJ. KuS.K. YounY.S. KimJ.R. JeongJ.H. ChoiH.G. YongC.S. KimJ.O. PEGylated lipid bilayer-supported mesoporous silica nanoparticle composite for synergistic co-delivery of axitinib and celastrol in multi-targeted cancer therapy.Acta Biomater.2016399410510.1016/j.actbio.2016.05.01227163403
     [Google Scholar]
  51. GuoL. LuoS. DuZ. ZhouM. LiP. FuY. SunX. HuangY. ZhangZ. Targeted delivery of celastrol to mesangial cells is effective against mesangioproliferative glomerulonephritis.Nat. Commun.20178187887910.1038/s41467‑017‑00834‑829026082
     [Google Scholar]
  52. SunH. LiuX. XiongQ. ShikanoS. LiM. Chronic inhibition of cardiac Kir2.1 and HERG potassium channels by celastrol with dual effects on both ion conductivity and protein trafficking.J. Biol. Chem.200628195877588410.1074/jbc.M60007220016407206
     [Google Scholar]
  53. KusyS. GhosnE.E.B. HerzenbergL.A. ContagC.H. Development of B cells and erythrocytes is specifically impaired by the drug celastrol in mice.PLoS One201274e3573310.1371/journal.pone.003573322545133
     [Google Scholar]
  54. ZhangH.J. ZhangG.R. PiaoH.R. QuanZ.S. Synthesis and characterisation of celastrol derivatives as potential anticancer agents.J. Enzyme Inhib. Med. Chem.201833119019810.1080/14756366.2017.140459029231066
     [Google Scholar]
  55. HeQ.W. FengJ.H. HuX.L. LongH. HuangX.F. JiangZ.Z. ZhangX.Q. YeW.C. WangH. Synthesis and biological evaluation of celastrol derivatives as potential immunosuppressive agents.J. Nat. Prod.20208392578258610.1021/acs.jnatprod.0c0006732822186
     [Google Scholar]
  56. JokerstJ.V. LobovkinaT. ZareR.N. GambhirS.S. Nanoparticle PEGylation for imaging and therapy.Nanomedicine (Lond.)20116471572810.2217/nnm.11.1921718180
     [Google Scholar]
  57. PasutG. VeroneseF.M. State of the art in PEGylation: The great versatility achieved after forty years of research.J. Control. Release2012161246147210.1016/j.jconrel.2011.10.03722094104
     [Google Scholar]
  58. VeroneseF.M. PasutG. PEGylation, successful approach to drug delivery.Drug Discov. Today200510211451145810.1016/S1359‑6446(05)03575‑016243265
     [Google Scholar]
  59. YangH. ShenW. LiuW. ChenL. ZhangP. XiaoC. ChenX. Pegylated poly(α-lipoic acid) loaded with doxorubicin as a ph and reduction dual responsive nanomedicine for breast cancer therapy.Biomacromolecules201819114492450310.1021/acs.biomac.8b0139430346147
     [Google Scholar]
  60. LiuZ. TangZ. ZhangD. WuJ. SiX. ShenN. ChenX. A novel GSH responsive poly(alpha-lipoic acid) nanocarrier bonding with the honokiol-DMXAA conjugate for combination therapy.Sci. China Mater.202063230731510.1007/s40843‑019‑1183‑0
     [Google Scholar]
  61. LiuZ. ShenN. TangZ. ZhangD. MaL. YangC. ChenX. An eximious and affordable GSH stimulus-responsive poly(α-lipoic acid) nanocarrier bonding combretastatin A4 for tumor therapy.Biomater. Sci.2019772803281110.1039/C9BM00002J31062006
     [Google Scholar]
  62. LinF. LiuY. LuoW. LiuS. WangY. GuR. LiuW. XiaoC. Minocycline-loaded poly(α-lipoic acid)–methylprednisolone prodrug nanoparticles for the combined anti-inflammatory treatment of spinal cord injury.Int. J. Nanomedicine2022179110410.2147/IJN.S34449135027828
     [Google Scholar]
  63. MengF. HenninkW.E. ZhongZ. Reduction-sensitive polymers and bioconjugates for biomedical applications.Biomaterials200930122180219810.1016/j.biomaterials.2009.01.02619200596
     [Google Scholar]
  64. JiangF. WangH.J. BaoQ.C. WangL. JinY.H. ZhangQ. JiangD. YouQ.D. XuX.L. Optimization and biological evaluation of celastrol derivatives as Hsp90–Cdc37 interaction disruptors with improved druglike properties.Bioorg. Med. Chem.201624215431543910.1016/j.bmc.2016.08.07027647369
     [Google Scholar]
  65. KisanukiA. KimparaY. OikadoY. KadoN. MatsumotoM.I.T.S.U.A.K.I. EndoK. Ring‐opening polymerization of lipoic acid and characterization of the polymer.J. Polym. Sci. A Polym. Chem.201048225247525310.1002/pola.24325
     [Google Scholar]
  66. LiY. YangH. YaoJ. YuH. ChenX. ZhangP. XiaoC. Glutathione-triggered dual release of doxorubicin and camptothecin for highly efficient synergistic anticancer therapy.Colloids Surf. B Biointerfaces201816927327910.1016/j.colsurfb.2018.05.02529787951
     [Google Scholar]
  67. LvS. SongW. TangZ. LiM. YuH. HongH. ChenX. Charge-conversional PEG-polypeptide polyionic complex nanoparticles from simple blending of a pair of oppositely charged block copolymers as an intelligent vehicle for efficient antitumor drug delivery.Mol. Pharm.20141151562157410.1021/mp400738724606535
     [Google Scholar]
  68. ZhuJ. WangJ. ChenR. FengQ. ZhanX. Cellular process of polystyrene nanoparticles entry into wheat roots.Environ. Sci. Technol.202256106436644410.1021/acs.est.1c0850335475335
     [Google Scholar]
  69. RoshanzadehA. ParkS. GanjbakhshS.E. ParkJ. LeeD.H. LeeS. KimE.S. Surface charge-dependent cytotoxicity of plastic nanoparticles in alveolar cells under cyclic stretches.Nano Lett.202020107168717610.1021/acs.nanolett.0c0246332876460
     [Google Scholar]
  70. ZhangX. HanL. LiuM. WangK. TaoL. WanQ. WeiY. Recent progress and advances in redox-responsive polymers as controlled delivery nanoplatforms.Mater. Chem. Front.20171580782210.1039/C6QM00135A
     [Google Scholar]
  71. MoR. GuZ. Tumor microenvironment and intracellular signal-activated nanomaterials for anticancer drug delivery.Mater. Today201619527428310.1016/j.mattod.2015.11.025
     [Google Scholar]
  72. ZhangY. DingJ. LiM. ChenX. XiaoC. ZhuangX. HuangY. ChenX. One-step “click chemistry”-synthesized cross-linked prodrug nanogel for highly selective intracellular drug delivery and upregulated antitumor efficacy.ACS Appl. Mater. Interfaces2016817106731068210.1021/acsami.6b0042627077549
     [Google Scholar]
  73. ZhangY. XiaoC. DingJ. LiM. ChenX. TangZ. ZhuangX. ChenX. A comparative study of linear, Y-shaped and linear-dendritic methoxy poly(ethylene glycol)-block-polyamidoamine-block-poly(l-glutamic acid) block copolymers for doxorubicin delivery in vitro and in vivo.Acta Biomater.20164024325310.1016/j.actbio.2016.04.00727063495
     [Google Scholar]
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Celastrol Derivative/DOX Co-Assembled Nanodrug for Enhanced Antitumor Therapy
Curr. Drug Deliv. 23, 88 (2026); https://doi.org/10.2174/0115672018298512240819101159
/content/journals/cdd/10.2174/0115672018298512240819101159
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  • Article Type:     Research Article
Keyword(s): chemosensitizers; chemotherapy; GSH responsive; Multidrug resistance; nanoparticles; pH; poly (α-lipoic acid)

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