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A Combinational Approach Towards Treatment of Breast Cancer: an Analysis of Noscapine-Loaded Polymeric Nanoparticles and Doxorubicin

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Abstract

Our aim in this study was to clarify the combination anticancer effect of Noscapine (Nos) loaded in a polymeric nanocarrier with Doxorubicin (Dox) on breast cancer cells. Nanoprecipitation method was used to prepare methoxy polyethylene glycol (mPEG), poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) containing Nos. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to characterize the prepared Nos NPs. The anticancer activity of Nos NPs alone and in combination with Dox was assessed on 4T1 breast cancer cell line and in mice model. Spherical-shaped Nos NPs were prepared, with size of 101 ± 4.80 nm and zeta potential of − 15.40 ± 1 mV. Fourier transform infrared (FTIR) spectroscopy results demonstrated that Nos chemical structure was kept stable during preparation process. However, differential scanning calorimetric (DSC) thermogram proved that crystalline state of Nos changed to amorphous state in Nos NPs. The entrapment efficacy % (EE%) and drug loading % (DL%) of Nos NPs were about 87.20 ± 3.50% and 12.50 ± 2.30%, respectively. Synergistic anticancer effects of Nos both in free form (in hydrochloride form, Nos HCl) and Nos NPs form with Dox hydrochloride (Dox HCl) were observed on 4T1 cells. Combination of Nos NPs and Dox HCl inhibited tumor growth (68.50%) in mice more efficiently than Nos NPs (55.10%) and Dox HCl (32%) alone. Immunohistochemical (IHC) analysis of the tumor tissues confirmed antiangiogenic effect of Nos NPs. The findings highlighted efficacy of Nos NPs alone and in combination with Dox HCl on breast cancer tumors.

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References

  1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin D, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941–53. https://doi.org/10.1002/ijc.31937.

    Article  CAS  PubMed  Google Scholar 

  2. Bijnsdorp IV, Giovannetti E, Peters GJ. Analysis of drug interactions. In: Cree IA, editor. Cancer cell culture methods in molecular biology (methods and protocols): Springer; 2011. p. 421–34.

  3. Zhang RX, Wong HL, Xue HY, Eoh JY, Wu XY. Nanomedicine of synergistic drug combinations for cancer therapy—strategies and perspectives. J Control Release. 2016;240:489–503. https://doi.org/10.1016/j.jconrel.2016.06.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pemovska T, Bigenzahn JW, Superti-Furga G. Recent advances in combinatorial drug screening and synergy scoring. Curr Opin Pharmacol. 2018;42:102–10. https://doi.org/10.1016/j.coph.2018.07.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Li J, Wu Y, Wang D, Zou L, Fu C, Zhang J, et al. Oridonin synergistically enhances the anti-tumor efficacy of doxorubicin against aggressive breast cancer via pro-apoptotic and anti-angiogenic effects. Pharmacol Res. 2019;146:104313. https://doi.org/10.1016/j.phrs.2019.104313.

    Article  CAS  PubMed  Google Scholar 

  6. Šírová M, Strohalm J, Chytil P, Lidický O, Tomala J, Říhová B, et al. The structure of polymer carriers controls the efficacy of the experimental combination treatment of tumors with HPMA copolymer conjugates carrying doxorubicin and docetaxel. J Control Release. 2017;246:1–11. https://doi.org/10.1016/j.jconrel.2016.12.004.

    Article  CAS  PubMed  Google Scholar 

  7. Blank N, Laskov I, Kessous R, Kogan L, Lau S, Sebag I, et al. Absence of cardiotoxicity with prolonged treatment and large accumulating doses of pegylated liposomal doxorubicin. Cancer Chemother Pharmacol. 2017;80(4):737–43. https://doi.org/10.1007/s00280-017-3412-8.

    Article  CAS  PubMed  Google Scholar 

  8. Gheybi F, Alavizadeh SH, Rezayat SM, Zendedel E, Jaafari M. Chemotherapeutic activity of Silymarin combined with doxorubicin liposomes in 4T1 breast cancer cells. Nanomed Res J. 2019;4(1):29–34. https://doi.org/10.22034/NMRJ.2019.01.005.

    Article  CAS  Google Scholar 

  9. Zhong Z-F, Tan W, Tian K, Yu H, Qiang W-A, Wang Y-T. Combined effects of furanodiene and doxorubicin on the migration and invasion of MDA-MB-231 breast cancer cells in vitro. Oncol Rep. 2017;37(4):2016–24. https://doi.org/10.3892/or.2017.5435.

    Article  CAS  PubMed  Google Scholar 

  10. Frión-Herrera Y, Gabbia D, Díaz-García A, Cuesta-Rubio O, Carrara M. Chemosensitizing activity of Cuban propolis and nemorosone in doxorubicin resistant human colon carcinoma cells. Fitoterapia. 2019;136:104173.doi: 0.1016/j.fitote.2019.104173.

  11. Gaonkar RH, Ganguly S, Dewanjee S, Sinha S, Gupta A, Ganguly S, et al. Garcinol loaded vitamin E TPGS emulsified PLGA nanoparticles: preparation, physicochemical characterization, in vitro and in vivo studies. Sci Rep. 2017;7(1):530. https://doi.org/10.1038/s41598-017-00696-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Godugu C, Doddapaneni R, Singh M. Honokiol nanomicellar formulation produced increased oral bioavailability and anticancer effects in triple negative breast cancer (TNBC). Colloids Surf B Biointerfaces. 2017;153:208–19. https://doi.org/10.1016/j.colsurfb.2017.01.038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Woo SM, Kim AJ, Choi YK, Shin YC, Cho SG, Ko SG. Synergistic effect of SH003 and doxorubicin in triple-negative breast cancer. Phytother Res. 2016;30(11):1817–23. https://doi.org/10.1002/ptr.5687.

    Article  CAS  PubMed  Google Scholar 

  14. Chen X, Dang T-TT, Facchini PJ. Noscapine comes of age. Phytochemistry. 2015;111:7–13. https://doi.org/10.1016/j.phytochem.2014.09.008.

    Article  CAS  PubMed  Google Scholar 

  15. Manchukonda NK, Naik PK, Santoshi S, Lopus M, Joseph S, Sridhar B, et al. Rational design, synthesis, and biological evaluation of third generation α-noscapine analogues as potent tubulin binding anti-cancer agents. PLoS One. 2013;8(10):e77970. https://doi.org/10.1371/journal.pone.0077970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mahmoudian M, Rahimi-Moghaddam P. The anti-cancer activity of noscapine: a review. Recent Pat Anticancer Drug Discov. 2009;4(1):92–7. https://doi.org/10.2174/157489209787002524.

    Article  CAS  PubMed  Google Scholar 

  17. Landen JW, Lang R, McMahon SJ, Rusan NM, Yvon A-M, Adams AW, et al. Noscapine alters microtubule dynamics in living cells and inhibits the progression of melanoma. Cancer Res. 2002;62(14):4109–14.

    CAS  PubMed  Google Scholar 

  18. Quisbert-Valenzuela EO, Calaf GM. Apoptotic effect of noscapine in breast cancer cell lines. Int J Oncol. 2016;48(6):2666–74. https://doi.org/10.3892/ijo.2016.3476.

    Article  CAS  PubMed  Google Scholar 

  19. Aneja R, Vangapandu SN, Lopus M, Chandra R, Panda D, Joshi HC. Development of a novel nitro-derivative of noscapine for the potential treatment of drug-resistant ovarian cancer and T-cell lymphoma. Mol Pharmacol. 2006;69(6):1801–9. https://doi.org/10.1124/mol.105.021899.

    Article  CAS  PubMed  Google Scholar 

  20. Andey T, Patel A, Marepally S, Chougule M, Spencer SD, Rishi AK, et al. Formulation, pharmacokinetic, and efficacy studies of mannosylated self-emulsifying solid dispersions of Noscapine. PLoS One. 2016;11(1):e0146804. https://doi.org/10.1371/journal.pone.0146804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chougule MB, Patel AR, Jackson T, Singh M. Antitumor activity of Noscapine in combination with doxorubicin in triple negative breast cancer. PLoS One. 2011;6(3):e17733. https://doi.org/10.1371/journal.pone.0017733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chougule MB, Patel A, Sachdeva P, Jackson T, Singh M. Enhanced anticancer activity of gemcitabine in combination with noscapine via antiangiogenic and apoptotic pathway against non-small cell lung cancer. PLoS One. 2011;6(11):e27394. https://doi.org/10.1371/journal.pone.0027394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chougule M, Patel AR, Sachdeva P, Jackson T, Singh M. Anticancer activity of Noscapine, an opioid alkaloid in combination with Cisplatin in human non-small cell lung cancer. Lung Cancer. 2011;71(3):271–82. https://doi.org/10.1016/j.lungcan.2010.06.002.

    Article  PubMed  Google Scholar 

  24. Qi Q, Liu X, Li S, Joshi HC, Ye K. Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth. Acta Pharmacol Sin. 2013;34(7):930–8. https://doi.org/10.1038/aps.2013.40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Erguven M, Bilir A, Yazihan N, Ermis E, Sabanci A, Aktas E, et al. Decreased therapeutic effects of noscapine combined with imatinib mesylate on human glioblastoma in vitro and the effect of midkine. Cancer Cell Int. 2011;11(1):18. https://doi.org/10.1186/1475-2867-11-18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Madani F, Esnaashari SS, Mujokoro B, Dorkoosh F, Khosravani M, Adabi M. Investigation of effective parameters on size of Paclitaxel loaded PLGA nanoparticles. Ad Pharm Bull. 2018;8(1):77. https://doi.org/10.15171/apb.2018.010.

    Article  CAS  Google Scholar 

  27. Mujokoro B, Madani F, Esnaashari SS, Khosravani M, Adabi M. Combination and co-delivery of methotrexate and curcumin: preparation and in vitro cytotoxic investigation on glioma cells. J Pharm Innov. 2019:1–10. https://doi.org/10.1007/s12247-019-09406-3.

  28. Esnaashari SS, Amani A. Optimization of Noscapine-loaded mPEG-PLGA nanoparticles and release study: a response surface methodology approach. J Pharm Innov. 2018;13:237–46. https://doi.org/10.1007/s12247-018-9318-0.

    Article  Google Scholar 

  29. Mattheolabakis G, Taoufik E, Haralambous S, Roberts ML, Avgoustakis K. In vivo investigation of tolerance and antitumor activity of cisplatin-loaded PLGA-mPEG nanoparticles. Eur J Pharm Biopharm. 2009;71(2):190–5. https://doi.org/10.1016/j.ejpb.2008.09.011.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang X, Li J, Yan M. Targeted hepatocellular carcinoma therapy: transferrin modified, self-assembled polymeric nanomedicine for co-delivery of cisplatin and doxorubicin. Drug Dev Ind Pharm. 2016;42(10):1590–9. https://doi.org/10.3109/03639045.2016.1160103.

    Article  CAS  PubMed  Google Scholar 

  31. Yadav K, Yadav D, Yadav M, Kumar S. Noscapine loaded PLGA nanoparticles prepared using oil-in-water emulsion solvent evaporation method. J Nanopharm Drug Deliv. 2016;3(1):97–105. https://doi.org/10.1166/jnd.2015.1074.

    Article  Google Scholar 

  32. Shalaby KS, Soliman ME, Casettari L, Bonacucina G, Cespi M, Palmieri GF, et al. Determination of factors controlling the particle size and entrapment efficiency of noscapine in PEG/PLA nanoparticles using artificial neural networks. Int J Nanomedicine. 2014;9:4953. https://doi.org/10.2147/IJN.S68737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang H, Zhao Y, Wu Y, Hu Y-l, Nan K, Nie G, et al. Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles. Biomaterials. 2011;32(32):8281–90. https://doi.org/10.1016/j.biomaterials.2011.07.032.

    Article  CAS  PubMed  Google Scholar 

  34. Kozlov N, Natashina U, Tamarov K, Gongalsky M, Solovyev V, Kudryavtsev A, et al. Recycling of silicon: from industrial waste to biocompatible nanoparticles for nanomedicine. Mater Res Express. 2017;4(9):095026. https://doi.org/10.1088/2053-1591/aa8c33.

    Article  CAS  Google Scholar 

  35. Chou T, Martin N. CompuSyn software for drug combinations and for general dose-effect analysis, and user's guide. Paramus: ComboSyn Inc2007.

  36. Chou T-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010:0008–5472. CAN-09-1947.https://doi.org/10.1158/0008-5472.CAN-09-1947.

  37. Sepehri N, Rouhani H, Tavassolian F, Montazeri H, Khoshayand MR, Ghahremani MH, et al. SN38 polymeric nanoparticles: in vitro cytotoxicity and in vivo antitumor efficacy in xenograft balb/c model with breast cancer versus irinotecan. Int J Pharm. 2014;471(1–2):485–97. https://doi.org/10.1016/j.ijpharm.2014.05.046.

    Article  CAS  PubMed  Google Scholar 

  38. Prihantono P, Hatta M, Binekada C, Sampepajung D, Haryasena H, Nelwan B, et al. Ki-67 expression by immunohistochemistry and quantitative real-time polymerase chain reaction as predictor of clinical response to neoadjuvant chemotherapy in locally advanced breast cancer. J Oncol. 2017;2017:1–8. https://doi.org/10.1155/2017/6209849.

    Article  CAS  Google Scholar 

  39. Shi P, Zhong J, Hong J, Huang R, Wang K, Chen Y. Automated ki-67 quantification of immunohistochemical staining image of human nasopharyngeal carcinoma xenografts. Sci Rep. 2016;6:32127. https://doi.org/10.1038/srep32127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Musaei M, Mokhtari J, Nouri M, Pedram RZ. Fabrication and characterization of nanocapsules of PLGA containing BSA using electrospray technique. Nanomed Res J. 2017;2(3):158–64. https://doi.org/10.22034/NMRJ.2017.03.003.

    Article  CAS  Google Scholar 

  41. Matteucci ME, Brettmann BK, Rogers TL, Elder EJ, Williams Iii RO, Johnston KP. Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Mol Pharm. 2007;4(5):782–93. https://doi.org/10.1021/mp0700211.

    Article  CAS  PubMed  Google Scholar 

  42. Madan J, Dhiman N, Parmar VK, Sardana S, Bharatam PV, Aneja R, et al. Inclusion complexes of noscapine in β-cyclodextrin offer better solubility and improved pharmacokinetics. Cancer Chemother Pharmacol. 2010;65(3):537–48. https://doi.org/10.1007/s00280-009-1060-3.

    Article  CAS  PubMed  Google Scholar 

  43. Yadav H, Kumar P, Sharma V, Sharma G, Raza K, Katare O. Enhanced efficacy and a better pharmacokinetic profile of tamoxifen employing polymeric micelles. RSC Adv. 2016;6(58):53351–7. https://doi.org/10.1039/C6RA10874A.

    Article  CAS  Google Scholar 

  44. Mujokoro B, Adabi M, Sadroddiny E, Adabi M, Khosravani M. Nano-structures mediated co-delivery of therapeutic agents for glioblastoma treatment: a review. Mater Sci Eng C. 2016;69:1092–102. https://doi.org/10.1016/j.ejpb.2008.09.011.

    Article  CAS  Google Scholar 

  45. Singh B, Reddy PG, Goberdhan A, Walsh C, Dao S, Ngai I, et al. p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas. Genes Dev. 2002;16(8):984–93. https://doi.org/10.1101/gad.973602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Johnson A, DiPietro LA. Apoptosis and angiogenesis: an evolving mechanism for fibrosis. FASEB J. 2013;27(10):3893–901. https://doi.org/10.1096/fj.12-214189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chen C-C, Lau LF. Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines. J Cell Commun Signal. 2010;4(1):63–9. https://doi.org/10.1007/s12079-009-0080-4.

    Article  CAS  PubMed  Google Scholar 

  48. Li LT, Jiang G, Chen Q, Zheng JN. Ki67 is a promising molecular target in the diagnosis of cancer. Mol Med Rep. 2015;11(3):1566–72. https://doi.org/10.3892/mmr.2014.2914.

    Article  CAS  PubMed  Google Scholar 

  49. Wakaskar RR. Promising effects of nanomedicine in cancer drug delivery. J Drug Target. 2018;26(4):319–24. https://doi.org/10.1080/1061186X.2017.1377207.

    Article  CAS  PubMed  Google Scholar 

  50. Adabi M, Naghibzadeh M, Adabi M, Zarrinfard MA, Esnaashari SS, Seifalian AM, et al. Biocompatibility and nanostructured materials: applications in nanomedicine. Artif Cells Nanomed Biotechnol. 2017;45(4):833–42. https://doi.org/10.1080/21691401.2016.1178134.

    Article  CAS  PubMed  Google Scholar 

  51. Schädlich A, Caysa H, Mueller T, Tenambergen F, Rose C, Göpferich A, et al. Tumor accumulation of NIR fluorescent PEG–PLA nanoparticles: impact of particle size and human xenograft tumor model. ACS Nano. 2011;5(11):8710–20. https://doi.org/10.1021/nn2026353.

    Article  CAS  PubMed  Google Scholar 

  52. Yhee JY, Son S, Son S, Joo MK, Kwon IC. The EPR effect in cancer therapy. In: Bae Y. MR, Park K., editor. Cancer targeted drug delivery: Springer; 2013. p. 621–632

  53. Feng S-S, Zhao L, Zhang Z, Bhakta G, Win KY, Dong Y, et al. Chemotherapeutic engineering: vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168 h in vivo. Chem Eng Sci. 2007;62(23):6641–8. https://doi.org/10.1016/j.ces.2007.08.006.

    Article  CAS  Google Scholar 

  54. Madan J, Pandey RS, Jain V, Katare OP, Chandra R, Katyal A. Poly (ethylene)-glycol conjugated solid lipid nanoparticles of noscapine improve biological half-life, brain delivery and efficacy in glioblastoma cells. Nanomedicine. 2013;9(4):492–503. https://doi.org/10.1016/j.nano.2012.10.003.

    Article  CAS  PubMed  Google Scholar 

  55. Madan J, Dhiman N, Sardana S, Aneja R, Chandra R, Katyal A. Long-circulating poly (ethylene glycol)-grafted gelatin nanoparticles customized for intracellular delivery of noscapine: preparation, in-vitro characterization, structure elucidation, pharmacokinetics, and cytotoxicity analyses. Anti-Cancer Drugs. 2011;22(6):543–55. https://doi.org/10.1097/CAD.0b013e32834159b8.

    Article  CAS  PubMed  Google Scholar 

  56. Doddapaneni R, Patel K, Chowdhury N, Singh M. Noscapine chemosensitization enhances docetaxel anticancer activity and nanocarrier uptake in triple negative breast cancer. Exp Cell Res. 2016;346(1):65–73. https://doi.org/10.1016/j.yexcr.2016.05.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gao Z-G, Tian L, Hu J, Park I-S, Bae YH. Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles. J Control Release. 2011;152(1):84–9. https://doi.org/10.1016/j.jconrel.2011.01.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Luo K-W, Yue GG-L, Ko C-H, Lee JK-M, Gao S, Li L-F, et al. In vivo and in vitro anti-tumor and anti-metastasis effects of Coriolus versicolor aqueous extract on mouse mammary 4T1 carcinoma. Phytomedicine. 2014;21(8–9):1078–87. https://doi.org/10.1016/j.phymed.2014.04.020.

    Article  PubMed  Google Scholar 

  59. Aneja R, Ghaleb AM, Zhou J, Yang VW, Joshi HC. p53 and p21 determine the sensitivity of noscapine-induced apoptosis in colon cancer cells. Cancer Res. 2007;67(8):3862–70. https://doi.org/10.1158/0008-5472.CAN-06-4282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Newcomb EW, Lukyanov Y, Schnee T, Ali MA, Lan L, Zagzag D. Noscapine inhibits hypoxia-mediated HIF-1α expression andangiogenesis in vitro: a novel function for an old drug. Int J Oncol. 2006;28(5):1121–30. https://doi.org/10.3892/ijo.28.5.1121.

    Article  CAS  PubMed  Google Scholar 

  61. Su W, Huang L, Ao Q, Zhang Q, Tian X, Fang Y, et al. Noscapine sensitizes chemoresistant ovarian cancer cells to cisplatin through inhibition of HIF-1α. Cancer Lett. 2011;305(1):94–9. https://doi.org/10.1016/j.canlet.2011.02.031.

    Article  CAS  PubMed  Google Scholar 

  62. Jhaveri N, Cho H, Torres S, Wang W, Schönthal AH, Petasis NA, et al. Noscapine inhibits tumor growth in TMZ-resistant gliomas. Cancer Lett. 2011;312(2):245–52. https://doi.org/10.1016/j.canlet.2011.08.015.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to acknowledge Dr. Masood Khosravani and Mr. Seyed Mohammad Reza Hosseini Najafabadi for help on cell culture studies.

Funding

This study was supported by Tehran University of Medical Science and Health Services Grant No. 94-01-87-28482.

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Esnaashari, S.S., Muhammadnejad, S., Amanpour, S. et al. A Combinational Approach Towards Treatment of Breast Cancer: an Analysis of Noscapine-Loaded Polymeric Nanoparticles and Doxorubicin. AAPS PharmSciTech 21, 166 (2020). https://doi.org/10.1208/s12249-020-01710-3

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