Seyed Mohammad Motevalli, Ahmed Shaker Eltahan, Lu Liu, Andrea Magrini, Nicola Rosato, Weisheng Guo, Massimo Bottini, Xing-Jie Liang. Co-encapsulation of curcumin and doxorubicin in albumin nanoparticles blocks the adaptive treatment tolerance of cancer cells. Biophysics Reports, 2019, 5(1): 19-30. doi: 10.1007/s41048-018-0079-6
Citation: Seyed Mohammad Motevalli, Ahmed Shaker Eltahan, Lu Liu, Andrea Magrini, Nicola Rosato, Weisheng Guo, Massimo Bottini, Xing-Jie Liang. Co-encapsulation of curcumin and doxorubicin in albumin nanoparticles blocks the adaptive treatment tolerance of cancer cells. Biophysics Reports, 2019, 5(1): 19-30. doi: 10.1007/s41048-018-0079-6

Co-encapsulation of curcumin and doxorubicin in albumin nanoparticles blocks the adaptive treatment tolerance of cancer cells

doi: 10.1007/s41048-018-0079-6
Funds:  The authors gratefully acknowledge that this work was financially supported by the National Natural Science Foundation of China (31430031, 51373117, and 51573128) and National Distinguished Young Scholars grant (31225009). The authors also appreciate the support by the external cooperation program of BIC, Chinese Academy of Science (121D11KYSB20130006), the“Strategic Priority Research Program”of the Chinese Academy of Sciences (XDA09030301), and the NanOArt grant of the“Mission Sustainability”of the University of Rome Tor Vergata.
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  • Corresponding author: Massimo Bottini, Xing-Jie Liang
  • Received Date: 17 May 2018
  • Rev Recd Date: 27 August 2018
  • Publish Date: 28 February 2019
  • The adaptive treatment tolerance (ATT) of cancer cells is the main encumbrance to cancer chemotherapy. A potential solution to this problem is to treat cancer cells with multiple drugs using nanoparticles (NPs). In this study, we tested the co-administration of curcumin (Cur) and doxorubicin (Dox) to MCF-7 resistant breast cancer cells to block the ATTand elicit efficient cell killing. Drugs were co-administered to cells both sequentially and simultaneously. Sequential drug co-administration was carried out by pre-treating the cells with albumin nanoparticles (ANPs) loaded with Cur (Cur@ANPs) followed by treatment with Dox-loaded ANPs (Dox@ANPs). Simultaneous drug co-administration was carried out by treating the cells with ANPs loaded with both the drugs (Cur/Dox@ANPs). We found that the simultaneous drug co-administration led to a greater intra-cellular accumulation of Dox and cell killing with respect to the sequential drug co-administration. However, the simultaneous drug co-administration led to a lower intracellular accumulation of Cur with respect to the sequential drug co-administration. We showed that this result was due to the aggregation and entrapment of Cur in the lysosomes as soon as it was released from Cur@ANPs, a phenomenon called lysosomotropism. In contrast, the simultaneous release of Dox and Cur from Cur/Dox@ANPs into the lysosomes led to lysosomal pH elevation, which, in turn, avoided Cur aggregation, led to lysosome swelling and drug release in the cytosol, and finally provoked efficient cell killing. Our study shed the light on the molecular processes driving the therapeutic effects of anti-cancer drugs co-administered to cancer cells in different manners.
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  • Abbasi S, Paul A, Shao W, Prakash S (2012) Cationic albumin nanoparticles for enhanced drug delivery to treat breast cancer:preparation and in vitro assessment. J Drug Deliv 2012:686108
    Azizi M, Ghourchian H, Yazdian F, Bagherifam S, Bekhradnia S, Nyström B (2017) Anti-cancerous effect of albumin coated silver nanoparticles on MDA-MB 231 human breast cancer cell line. Sci Rep 7:5178
    Bronze-Uhle ES, Costa BC, Ximenes VF, Lisboa-Filho PN (2017) Synthetic nanoparticles of bovine serum albumin with entrapped salicylic acid. Nanotechnol Sci Appl 10:11-21
    Burger H, den Dekker AT, Segeletz S, Boersma AW, de Bruijn P, Debiec-Rychter M, Taguchi T, Sleijfer S, Sparreboom A, Mathijssen RH, Wiemer EA (2015) Lysosomal sequestration determines intracellular imatinib levels. Mol Pharmacol 88:477-487
    Carvalho FS, Burgeiro A, Garcia R, Moreno AJ, Carvalho RA, Oliveira PJ (2014) Doxorubicin-induced cardiotoxicity:from bioenergetic failure and cell death to cardiomyopathy. Med Res Rev 34:106-135
    Céspedes MV, Unzueta U, Tatkiewicz W, Sánchez-Chardi A, Conchillo-Solé O, Álamo P, Xu Z, Casanova I, Corchero JL, Pesarrodona M, Cedano J, Daura X, Ratera I, Veciana J, FerrerMiralles N, Vazquez E, Villaverde A, Mangues R (2014) In vivo architectonic stability of fully de novo designed protein-only nanoparticles. ACS Nano 8:4166-4176
    Cheema MA, Taboada P, Barbosa S, Juárez J, Gutiérrez-Pichel M, Siddiq M, Mosquera V (2009) Human serum albumin unfolding pathway upon drug binding:a thermodynamic and spectroscopic description. J Chem Thermodyn 41:439-447
    Chen Q, Liu X, Chen J, Zeng J, Cheng Z, Liu Z (2015) A selfassembled albumin-based nanoprobe for in vivo ratiometric photoacoustic pH imaging. Adv Mater 27:6820-6827
    Darandale SS, Vavia PR (2013) Cyclodextrin-based nanosponges of curcumin:formulation and physicochemical characterization. J Incl Phenom Macrocycl Chem 75:315-322
    Deepa K, Singha S, Panda T (2014) Doxorubicin nanoconjugates. J Nanosci Nanotechnol 14:892-904
    Dreis S, Rothweiler F, Michaelis M, Cinatl J Jr, Kreuter J, Langer K (2007) Preparation, characterisation and maintenance of drug efficacy of doxorubicin-loaded human serum albumin (HSA) nanoparticles. Int J Pharm 341:207-214
    Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O, Fédération Francophone de Cancérologie Digestive (FFCD) 2000-05 Collaborative Group (2011) Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05):an openlabel, randomised, phase 3 trial. Lancet Oncol 12:1032-1044
    Gong Z, Liu Z, Dong X, Ding YH, Dong MQ, Tang C (2017) Protocol for analyzing protein ensemble structures from chemical cross-links using DynaXL. Biophys Rep 3:100-108
    Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S (2014) Drug resistance in cancer:an overview. Cancers 6:1769-1792
    Hsieh YW, Huang CY, Yang SY, Peng YH, Yu CP, Chao PD, Hou YC (2014) Oral intake of curcumin markedly activated CYP 3A4:in vivo and ex vivo studies. Sci Rep 4:6587
    Huang P, Li Z, Hu H, Cui D (2010) Synthesis and characterization of bovine serum albumin-conjugated copper sulfide nanocomposites. J Nanomater 2010:1-6 Jayakumar R, Nair A, Rejinold NS, Maya S, Nair SV (2012) Doxorubicin-loaded pH-responsive chitin nanogels for drug delivery to cancer cells. Carbohydr Polym 87:2352-2356
    Jenita JL, Chocalingam V, Wilson B (2014) Albumin nanoparticles coated with polysorbate 80 as a novel drug carrier for the delivery of antiretroviral drug-Efavirenz. Int J Pharm Investig 4:142-148
    Kratz F (2008) Albumin as a drug carrier:design of prodrugs, drug conjugates and nanoparticles. J Control Release 132:171-183
    Kuzu OF, Toprak M, Noory MA, Robertson GP (2017) Effect of lysosomotropic molecules on cellular homeostasis. Pharmacol Res 117:177-184 Lee MJ, Ye AS, Gardino AK, Heijink AM, Sorger PK, MacBeath G, Yaffe MB (2012) Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 149:780-794
    Li F-Q, Su H, Wang J, Liu JY, Zhu QG, Fei YB, Pan YH, Hu JH (2008) Preparation and characterization of sodium ferulate entrapped bovine serum albumin nanoparticles for liver targeting. Int J Pharm 349:274-282
    Li H, Yan K, Shang Y, Shrestha L, Liao R, Liu F, Li P, Xu H, Xu Z, Chu PK (2015) Folate-bovine serum albumin functionalized polymeric micelles loaded with superparamagnetic iron oxide nanoparticles for tumor targeting and magnetic resonance imaging. Acta Biomater 15:117-126
    Li DL, Wang ZV, Ding G, Tan W, Luo X, Criollo A, Xie M, Jiang N, May H, Kyrychenko V, Schneider JW, Gillette TG, Hill JA (2016) Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133:1668-1687
    Lin X, Xie J, Niu G, Zhang F, Gao H, Yang M, Quan Q, Aronova MA, Zhang G, Lee S, Leapman R, Chen X (2011) Chimeric ferritin nanocages for multiple function loading and multimodal imaging. Nano Lett 11:814-819
    Lin G, Zhu W, Yang L, Wu J, Lin B, Xu Y, Cheng Z, Xia C, Gong Q, Song B, Ai H (2014) Delivery of siRNA by MRI-visible nanovehicles to overcome drug resistance in MCF-7/ADR human breast cancer cells. Biomaterials 35:9495-9507
    Logan R, Kong AC, Krise JP (2014) Time-dependent effects of hydrophobic amine-containing drugs on lysosome structure and biogenesis in cultured human fibroblasts. J Pharm Sci 103:3287-3296
    Lohcharoenkal W, Wang L, Chen YC, Rojanasakul Y (2014) Protein nanoparticles as drug delivery carriers for cancer therapy. Biomed Res Int 2014:1-12
    Lv MM, Zhu XY, Chen WX, Zhong SL, Hu Q, Ma TF, Zhang J, Chen L, Tang JH, Zhao JH (2014) Exosomes mediate drug resistance transfer in MCF-7 breast cancer cells and a probable mechanism is delivery of P-glycoprotein. Tumor Biol 35:10773-10779
    Ma X, Sun X, Hargrove D, Chen J, Song D, Dong Q, Lu X, Fan TH, Fu Y, Lei Y (2016) A biocompatible and biodegradable protein hydrogel with green and red autofluorescence:preparation, characterization and in vivo biodegradation tracking and modeling. Sci Rep 6:19370
    Ma W, Guo Q, Li Y, Wang X, Wang J, Tu P (2017) Co-assembly of doxorubicin and curcumin targeted micelles for synergistic delivery and improving anti-tumor efficacy. Eur J Pharm Biopharm 112:209-223
    Mohanty C, Sahoo SK (2010) The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation. Biomaterials 31:6597-6611
    Neek M, Tucker JA, Il Kim T, Molino NM, Nelson EL, Wang SW (2018) Co-delivery of human cancer-testis antigens with adjuvant in protein nanoparticles induces higher cellmediated immune responses. Biomaterials 156:194-203
    Neerati P, Sudhakar YA, Kanwar JR (2013) Curcumin regulates colon cancer by inhibiting P-glycoprotein in in situ cancerous colon perfusion rat model. J Cancer Sci Ther 5:313
    Neville-Webbe HL, Rostami-Hodjegan A, Evans CA, Coleman RE, Holen I (2005) Sequence-and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer 113:364-371
    Peng Y, Zhao S, Wu Y, Cao H, Xu Y, Liu X, Shui W, Cheng J, Zhao S, Shen L, Ma J, Quinn RJ, Stevens RC, Zhong G, Liu ZJ (2018) Identification of natural products as novel ligands for the human 5-HT2C receptor. Biophys Rep 4:50-61
    Sahu BP, Hazarika H, Bharadwaj R, Loying P, Baishya R, Dash S, Das MK (2016) Curcumin-docetaxel co-loaded nanosuspension for enhanced anti-breast cancer activity. Expert Opin Drug Deliv 13(8):1065-1074
    She W, Luo K, Zhang C, Wang G, Geng Y, Li L, He B, Gu Z (2013) The potential of self-assembled, pH-responsive nanoparticles of mPEGylated peptide dendron-doxorubicin conjugates for cancer therapy. Biomaterials 34:1613-1623
    Tarragó-Trani MT, Storrie B (2007) Alternate routes for drug delivery to the cell interior:pathways to the Golgi apparatus and endoplasmic reticulum. Adv Drug Deliv Rev 59:782-797
    Umsumarng S, Pitchakarn P, Sastraruji K, Yodkeeree S, Ung AT, Pyne SG, Limtrakul P (2015) Reversal of human multi-drug resistance leukaemic cells by stemofoline derivatives via inhibition of p-glycoprotein function. Basic Clin Pharmacol Toxicol 116:390-397
    Unsoy G, Khodadust R, Yalcin S, Mutlu P, Gunduz U (2014) Synthesis of doxorubicin loaded magnetic chitosan nanoparticles for pH responsive targeted drug delivery. Eur J Pharm Sci 62:243-250
    Vinod BS, Antony J, Nair HH, Puliyappadamba VT, Saikia M, Narayanan SS, Bevin A, Anto RJ (2013) Mechanistic evaluation of the signaling events regulating curcumin-mediated chemosensitization of breast cancer cells to 5-fluorouracil. Cell Death Dis 4:e505
    Wang C, Xu H, Liang C, Liu Y, Li Z, Yang G, Cheng L, Li Y, Liu Z (2013a) Iron oxide@polypyrrole nanoparticles as a multifunctional drug carrier for remotely controlled cancer therapy with synergistic antitumor effect. ACS Nano 7:6782-6795
    Wang P, Zhang L, Peng H, Li Y, Xiong J, Xu Z (2013b) The formulation and delivery of curcumin with solid lipid nanoparticles for the treatment of on non-small cell lung cancer both in vitro and in vivo. Mater Sci Eng C 33:4802-4808
    Wang J, Wang F, Li F, Zhang W, Shen Y, Zhou D, Guo S (2016) A multifunctional poly (curcumin) nanomedicine for dualmodal targeted delivery, intracellular responsive release, dual-drug treatment and imaging of multidrug resistant cancer cells. J Mater Chem B 4:2954-2962
    Yallapu MM, Jaggi M, Chauhan SC (2010) b-Cyclodextrin-curcumin self-assembly enhances curcumin delivery in prostate cancer cells. Colloids Surf B 79:113-125
    Yan T, Li D, Li J, Cheng F, Cheng J, Huang Y, He J (2016) Effective codelivery of doxorubicin and curcumin using a glycyrrhetinic acid-modified chitosan-cystamine-poly (e-caprolactone) copolymer micelle for combination cancer chemotherapy. Colloids Surfaces B 145:526-538
    Zhang Y, Yang C, Wang W, Liu J, Liu Q, Huang F, Chu L, Gao H, Li C, Kong D, Liu Q, Liu J (2016) Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer. Sci Rep 6:21225
    Zhao X, Chen Q, Liu W, Li Y, Tang H, Liu X, Yang X (2015) Codelivery of doxorubicin and curcumin with lipid nanoparticles results in improved efficacy of chemotherapy in liver cancer. Int J Nanomed 10:257-270
    Zhitomirsky B, Assaraf YG (2016) Lysosomes as mediators of drug resistance in cancer. Drug Resist Updat 24:23-33
    Zhou T, Du Y, Wei T (2015) Transcriptomic analysis of human breast cancer cells reveals differentially expressed genes and related cellular functions and pathways in response to gold nanorods. Biophys Rep 1:106-114
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