Highly Water-Soluble Methotrexate-Polyethyleneglycol-Rhodamine Prodrug Micelle for High Tumor Inhibition Activity

Abstract

Highly water-soluble prodrug micelle (50-fold compared with free MTX) of methotrexate-polyethyleneglycol-rhodamine (MTX-PEG-rhodamine) and MTX-mPEG was synthesized by the esterification reaction. The stability of the prodrug micelles was evaluated in phosphate buffer saline (PBS) with 10% fetal bovine serum (FBS). The tumor volume of the saline, MTX, and MTX-PEG-rhodamine groups was increased 3.7-fold, 2.8-fold, and 1.8-fold, respectively, compared with the initial tumor volume. TUNEL and drug distribution results further confirmed that the micelle of MTX-PEG-rhodamine possessed fewer side effects on the normal tissue compared with MTX. The prodrug micelle showed four advantages: retention of the drug activity site, higher water solubility of methotrexate (MTX), ease of preparation and application, and preferential accumulation in tumor tissues. These advantages of MTX-mPEG make it a promising drug delivery system (DDS) for clinical use.

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References

  1. 1.

    Shen J, Song G, An M, Li X, Wu N, Ruan K, et al. The use of hollow mesoporous silica nanospheres to encapsulate bortezomib and improve efficacy for non-small cell lung cancer therapy. Biomaterials. 2014;35:316–26.

    CAS  PubMed  Google Scholar 

  2. 2.

    Fiore M, Forli S, Manetti FJ. Targeting mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, MK2): medicinal chemistry efforts to lead small molecule inhibitors to clinical trials. J Med Chem. 2016;59:3609–34.

    CAS  PubMed  Google Scholar 

  3. 3.

    Zhang J, Wang L, You X, Xian T, Wu J, Pang J. Nanoparticle therapy for prostate cancer: overview and perspectives. Curr Top Med Chem. 2019;19:57–73.

    PubMed  Google Scholar 

  4. 4.

    You X, Kang Y, Hollett G, Chen X, Zhao W, Gu Z, et al. Polymeric nanoparticles for colon cancer therapy: overview and perspectives. J Mater Chem B. 2016;4:7779–92.

    CAS  PubMed  Google Scholar 

  5. 5.

    Liu K, Xu Z, Yin M. Perylenediimide-cored dendrimers and their bioimaging and gene delivery applications. Prog Polym Sci. 2015;46:25–54.

    Google Scholar 

  6. 6.

    Guo XL, Kang XX, Wang YQ, Zhang XJ, Li CJ, Liu Y, et al. Co-delivery of cisplatin and doxorubicin by covalently conjugating with polyamidoamine dendrimer for enhanced synergistic cancer therapy. Acta Biomater. 2019;84:367–77.

    CAS  PubMed  Google Scholar 

  7. 7.

    Hadjidemetriou M, McAdam S, Garner G, Thackeray C, Knight D, Smith D, et al. The human in vivo biomolecule corona onto PEGylated liposomes: a proof-of-concept clinical study. Adv Mater. 2019;31:1803335.

    Google Scholar 

  8. 8.

    Cai X, Mao D, Wang C, Kong D, Cheng X, Liu B. Multifunctional liposome: a bright AIEgen–lipid conjugate with strong photosensitization. Angew Chem. 2018;130:16634–8.

    Google Scholar 

  9. 9.

    Wan X, Beaudoin JJ, Vinod N, Min Y, Makita N, Bludau H, et al. Co-delivery of paclitaxel and cisplatin in poly(2-oxazoline) polymeric micelles: implications for drug loading, release, pharmacokinetics and outcome of ovarian and breast cancer treatments. Biomaterials. 2019;192:1–14.

    CAS  PubMed  Google Scholar 

  10. 10.

    Woraphatphadung T, Sajomsang W, Rojanarata T, Ngawhirunpat T, Tonglairoum P, Opanasopit P. Development of chitosan-based pH-sensitive polymeric micelles containing curcumin for colon-targeted drug delivery. AAPS Pharm Sci Tech. 2018;19:991–1000.

    CAS  Google Scholar 

  11. 11.

    Ahmed N, Fessi H, Elaissari A. Theranostic applications of nanoparticles in cancer. Drug Discov Today. 2012;17:928–34.

    CAS  PubMed  Google Scholar 

  12. 12.

    Lu GH, Shang WT, Deng H, Han ZY, Hu M, Liang XY, et al. Targeting carbon nanotubes based on IGF-1R for photothermal therapy of orthotopic pancreatic cancer guided by optical imaging. Biomaterials. 2019;195:13–22.

    CAS  PubMed  Google Scholar 

  13. 13.

    Soldano C. Hybrid metal-based carbon nanotubes: novel platform for multifunctional applications. Prog Mater Sci. 2015;69:183–212.

    CAS  Google Scholar 

  14. 14.

    Yue J, Luo S, Lu M, Shao D, Wang Z, Dong W. A comparison of mesoporous silica nanoparticles and mesoporous organosilica nanoparticles as drug vehicles for cancer therapy. Chem Biol Drug Des. 2018;92:1435–44.

    CAS  PubMed  Google Scholar 

  15. 15.

    Lu J, Chen Q, Ding X, Wen J, Zhang Y, Li H, et al. BSA modified, disulfide-bridged mesoporous silica with low biotoxicity for dual-responsive drug delivery. Microporous Mesoporous Mater. 2019;278:257–66.

    CAS  Google Scholar 

  16. 16.

    Zhang X, Zhang R, Jun H, Luo M, Chen X, Kang Y, et al. Albumin enhances PTX delivery ability of dextran NPs and therapeutic efficacy of PTX for colorectal cancer. J Mater Chem B. 2019;7:3537–45. https://doi.org/10.1039/C9TB00181F.

    CAS  Article  Google Scholar 

  17. 17.

    Zhao Z, Li Y, Jain A, Chen Z, Liu H, Jin W, et al. Development of a peptide-modified siRNA nanocomplex for hepatic stellate cells. Nanomed-Nanotechnol. 2018;14:51–61.

    CAS  Google Scholar 

  18. 18.

    Zhang X, Li D, Huang J, Ou K, Yan B, Shi F, et al. Screening of pH-responsive long-circulating polysaccharide-drug conjugate nanocarriers for antitumor applications. J Mater Chem B. 2019;7:251–64.

    PubMed  Google Scholar 

  19. 19.

    Ou K, Kang Y, Chen L, Zhang X, Chen X, Zheng Y, et al. H2O2-responsive nano-prodrug for podophyllotoxin delivery. Biomater Sci. 2019;7:2491–8. https://doi.org/10.1039/C9BM00344.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Lee J, Kim J, Jeong M, Lee H, Goh U, Kim H, et al. Liposome-based engineering of cells to package hydrophobic compounds in membrane vesicles for tumor penetration. Nano Lett. 2015;15:2938–44.

    CAS  PubMed  Google Scholar 

  21. 21.

    Maeda H. The tumor blood vessel as an ideal target for macromolecular anticancer agents. J Control Release. 1992;19:315–24.

    CAS  Google Scholar 

  22. 22.

    Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev. 2014;66:2–25.

    CAS  PubMed  Google Scholar 

  23. 23.

    Chauhan VP, Stylianopoulos T, Martin JD, Popovic Z, Chen O, Kamoun WS, et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol. 2012;7:383–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Chung JE, Tan S, Gao SJ, Yongvongsoontorn N, Kim SH, Lee JH, et al. Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy. Nat Nanotechnol. 2014;9:907–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Zheng Y, You X, Guan S, Huang J, Wang L, Zhang J, et al. Poly(ferulic acid) with an anticancer effect as a drug nanocarrier for enhanced colon cancer therapy. Adv Funct Mater. 2019;29:1808646.

    Google Scholar 

  26. 26.

    You X, Gu Z, Huang J, Kang Y, Chu CC, Wu J. Arginine-based poly(ester amide) nanoparticle platform: from structure–property relationship to nucleic acid delivery. Acta Biomater. 2018;74:180–91.

    CAS  PubMed  Google Scholar 

  27. 27.

    Qu Y, Chu B, Wei X, Lei M, Hu D, Zha R, et al. Redox/pH dual-stimuli responsive camptothecin prodrug nanogels for “on demand” drug delivery. J Control Release. 2019;296:93–106.

    CAS  PubMed  Google Scholar 

  28. 28.

    Zhu Y, Zhang J, Meng F, Deng C, Cheng R, Feijen J, et al. cRGD-functionalized reduction-sensitive shell-sheddable biodegradable micelles mediate enhanced doxorubicin delivery to human glioma xenografts in vivo. J Control Release. 2016;233:29–38.

    CAS  PubMed  Google Scholar 

  29. 29.

    Ling X, Chen X, Riddell IA, Wei T, Wang J, Hollett G, et al. Glutathione-scavenging poly(disulfide amide) nanoparticles for the effective delivery of Pt(IV) prodrugs and reversal of cisplatin resistance. Nano Lett. 2018;18(7):4618–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Gasparik V, Daubeuf F, Hachet-Haas M, Rohmer F, Gizzi P, Haiech J, et al. Prodrugs of a CXC chemokine-12 (CXCL12) neutralig and prevent inflammatory reactions in an asthma model in vivo. ACS Med Chem Lett. 2012;3:10–4.

    CAS  PubMed  Google Scholar 

  31. 31.

    Wang G, Deval J, Hong J, Dyatkina N, Prhavc M, Taylor J, et al. Discovery of 4’-Chloromethyl-2’-deoxy-3’,5’-di-O-isobutyryl-2′-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection. J Med Chem. 2015;58:1862–78.

    CAS  PubMed  Google Scholar 

  32. 32.

    Bai Y, Liu CP, Song X, Zhuo L, Bu H, Tian W. Photo-and pH-dual-responsive b-cyclodextrin-based supramolecular prodrug complex self-assemblies for programmed drug delivery. Chem Asian J. 2018;13:3903–11.

    CAS  PubMed  Google Scholar 

  33. 33.

    Pan Z, Ren Y, Song N, Song Y, Li J, He X, et al. Multifunctional mixed micelles cross-assembled from various polyurethanes for tumor therapy. Biomacromolecules. 2016;17:2148–59.

    CAS  PubMed  Google Scholar 

  34. 34.

    Vinciguerra D, Denis S, Mougin J, Jacobs M, Guillaneuf Y, Mura S, et al. A facile route to heterotelechelic polymer prodrug nanoparticles for imaging, drug delivery and combination therapy. J Control Release. 2018;286:425–38.

    CAS  PubMed  Google Scholar 

  35. 35.

    Brennen WN, Rosen DM, Wang H, Isaacs JT, Denmeade SR. Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst. 2012;104:1320–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Li Y, Lin J, Huang Y, Li Y, Yang X, Wu H, et al. Self-targeted, shape-assisted, and controlled-release self-delivery nanodrug for synergistic targeting/anticancer effect of cytoplasm and nucleus of cancer cells. ACS Appl Mater Interfaces. 2015;7:25553–9.

    CAS  PubMed  Google Scholar 

  37. 37.

    Liu G, Ma J, Li Y, Li Q, Tan C, Song H, et al. Core-interlayer-shell Fe3O4@mSiO2@lipid-PEG-methotrexate nanoparticle for multimodal imaging and multistage targeted chemo-photodynamic therapy. Int J Pharm. 2017;521:19–32.

    CAS  PubMed  Google Scholar 

  38. 38.

    Suksiriworapong J, Taresco V, Ivanov DP, Styliari ID, Sakchaisri K, Junyaprasert VB, et al. Synthesis and properties of a biodegradable polymer-drug conjugate: methotrexate-poly(glycerol adipate). Colloid Surface B. 2018;167:115–25.

    CAS  Google Scholar 

  39. 39.

    Guo Y, Zhang Y, Ma J, Li Q, Li Y, Zhou X, et al. Light/magnetic hyperthermia triggered drug released from multi-functional thermo-sensitive magnetoliposomes for precise cancer synergetic theranostics. J Control Release. 2018;272:145–58.

    CAS  PubMed  Google Scholar 

  40. 40.

    Lammers T, Kiessling F, Hennink WE, Storm G. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J Control Release. 2012;161:175–87.

    CAS  PubMed  Google Scholar 

  41. 41.

    Li W, Zhan P, De Clercq E, Lou H, Liu X. Current drug research on PEGylation with small molecular agents. Prog Polym Sci. 2013;38:421–44.

    CAS  Google Scholar 

  42. 42.

    Riebeseel K, Biedermann E, Löser R, Breiter N, Hanselmann R, lhaupt RM, et al. Polyethylene glycol conjugates of methotrexate varying in their molecular weight from MW 750 to MW 40000 synthesis, characterization, and structure-activity relationships in vitro and in vivo. Bioconjug Chem. 2002;13:773–85.

    CAS  PubMed  Google Scholar 

  43. 43.

    Bao Y, Yin M, Hu X, Zhuang X, Sun Y, Guo Y, et al. A safe, simple and efficient doxorubicin prodrug hybrid micelle for overcoming tumor multidrug resistance and targeting delivery. J Control Release. 2016;235:182–94.

    CAS  PubMed  Google Scholar 

  44. 44.

    Jain A, Barve A, Zhao Z, Jin W, Cheng K. Comparison of avidin, neutravidin, and streptavidin as nanocarriers for efficient siRNA delivery. Mol Pharm. 2017;14:1517–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Talath S, Shirote PJ, Lough WJ, Gadad AK. Stability studies of some glycolamide ester prodrugs of niflumic acid in aqueous buffers and human plasma by HPLC with UV detection. Arzneim-Forsch/Drug Res. 2006;56(9):631–9.

    CAS  Google Scholar 

  46. 46.

    Barve A, Jain A, Liu H, Jin W, Cheng K. An enzyme-responsive conjugate improves the delivery of a PI3K inhibitor to prostate cancer. Nanomed-Nanotechnol. 2016;12:2373–81.

    CAS  Google Scholar 

  47. 47.

    Destache CJ, Mandal S, Yuan Z, Kang G, Date AA, Lu W, et al. Topical tenofovir disoproxil fumarate nanoparticles prevent HIV-1 vaginal transmission in a humanized mouse model. Antimicrob Agents Chemother. 2016;60(6):3633–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov Today. 2005;10:1451–8.

    CAS  PubMed  Google Scholar 

  49. 49.

    Chen Z, Liu H, Jain A, Zhang L, Liu C, Cheng K. Discovery of aptamer ligands for hepatic stellate cells using SELEX. Theranostics. 2017;7(12):2982–95.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors express their sincere gratitude to the Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University and Professor Jie Kong for providing the experimental platform and funding.

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Correspondence to Xiao Duan or Lihua Song.

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All animal experimental procedures followed the institutional guidelines for the care and use of laboratory animals, and protocols were approved by the animal ethical and committee in the animal center of Changzhi Medical College, Shanxi, China.

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Duan, X., Yang, X., Li, C. et al. Highly Water-Soluble Methotrexate-Polyethyleneglycol-Rhodamine Prodrug Micelle for High Tumor Inhibition Activity. AAPS PharmSciTech 20, 245 (2019). https://doi.org/10.1208/s12249-019-1462-4

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KEY WORDS

  • prodrug micelle
  • biocompatible
  • drug activity
  • cancer therapy