Folate-chitosan Coated Quercetin Liposomes for Targeted Cancer
Therapy

Chun-hui      Chang; De-en      Han; Yu-ying      Ji; Meng-yan      Wang; Dong-hong      Li; Zhi-ling      Xu; Jia-hao      Li; Sheng-nan      Huang; Xia-li      Zhu; Yong-yan      Jia

doi:10.2174/0113892010264479231006045014

Abstract

Background: Although quercetin exhibits promising anti-tumor properties, its clinical application is limited due to inherent defects and a lack of tumor targeting.

Objectives: This study aimed to prepare and characterize active targeting folate-chitosan modified quercetin liposomes (FA-CS-QUE-Lip), and its antitumor activity in vitro and in vivo was also studied.

Materials and Methods: Box-Behnken Design (BBD) response surface method was used to select the optimal formulation of quercetin liposomes (QUE-LP). On this basis, FA-CS-QUE-LP was obtained by connecting folic acid chitosan complex (FA-CS) and QUE-LP. The release characteristics in vitro of QUE-LP and FA-CS-QUE-LP were studied. Its inhibitory effects on HepG2 cells were studied by the MTT method. The pharmacokinetics and pharmacodynamics in vivo were studied in healthy Wistar mice and S180 tumor-bearing mice, respectively.

Results: The average particle size, zeta potential and encapsulation efficiency of FA-CS-QUELP were 261.6 ± 8.5 nm, 22.3 ± 1.7 mV, and 98.63 ± 1.28 %, respectively. FA-CS-QUE-LP had a sustained release effect and conformed to the Maloid-Banakar release model (R2=0.9967). The results showed that FA-CS-QUE-LP had higher inhibition rates on HepG2 cells than QUE-Sol (P < 0.01). There was a significant difference in AUC, t_1/2, CL and other pharmacokinetic parameters among QUE-LP, FA-CS-QUE-LP, and QUE-Sol (P < 0.05). In in vivo antitumor activity study, the weight inhibition rate and volume inhibition rate of FA-CS-QUE-LP were 30.26% and 37.35%, respectively.

Conclusion: FA-CS-QUE-LP exhibited a significant inhibitory effect on HepG2 cells, influenced the pharmacokinetics of quercetin in mice, and demonstrated a certain inhibitory effect on S180 tumor-bearing mice, thus offering novel avenues for cancer treatment.

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[1]
Shen, S.; Du, M.; Liu, Q.; Gao, P.; Wang, J.; Liu, S.; Gu, L. Development of GLUT1-targeting alkyl glucoside-modified dihydroartemisinin liposomes for cancer therapy. Nanoscale,  2020, 12(42), 21901-21912.
 [http://dx.doi.org/10.1039/D0NR05138A] [PMID:  33108431]

[2]
Wang, G.; Wang, J.J.; Chen, X.L.; Du, L.; Li, F. Quercetin-loaded freeze-dried nanomicelles: Improving absorption and anti-glioma efficiency in vitro and in vivo. J. Control. Release,  2016, 235, 276-290.
 [http://dx.doi.org/10.1016/j.jconrel.2016.05.045] [PMID:  27242199]

[3]
Wang, X.; Chen, Y.; Dahmani, F.Z.; Yin, L.; Zhou, J.; Yao, J. Amphiphilic carboxymethyl chitosan-quercetin conjugate with P-gp inhibitory properties for oral delivery of paclitaxel. Biomaterials,  2014, 35(26), 7654-7665.
 [http://dx.doi.org/10.1016/j.biomaterials.2014.05.053] [PMID:  24927684]

[4]
Zhang, Z.; Xu, S.; Wang, Y.; Yu, Y.; Li, F.; Zhu, H.; Shen, Y.; Huang, S.; Guo, S. Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells. J. Colloid Interface Sci.,  2018, 509, 47-57.
 [http://dx.doi.org/10.1016/j.jcis.2017.08.097] [PMID:  28881205]

[5]
Wu, Q.; Deng, S.; Li, L.; Sun, L.; Yang, X.; Liu, X.; Liu, L.; Qian, Z.; Wei, Y.; Gong, C. Biodegradable polymeric micelle-encapsulated quercetin suppresses tumor growth and metastasis in both transgenic zebrafish and mouse models. Nanoscale,  2013, 5(24), 12480-12493.
 [http://dx.doi.org/10.1039/c3nr04651f] [PMID:  24165931]

[6]
Zhao, J.; Liu, J.; Wei, T.; Ma, X.; Cheng, Q.; Huo, S.; Zhang, C.; Zhang, Y.; Duan, X.; Liang, X.J. Quercetin-loaded nanomicelles to circumvent human castration-resistant prostate cancer in vitro and in vivo. Nanoscale,  2016, 8(9), 5126-5138.
 [http://dx.doi.org/10.1039/C5NR08966B] [PMID:  26875690]

[7]
Pham, T.N.D.; Stempel, S.; Shields, M.A.; Spaulding, C.; Kumar, K.; Bentrem, D.J.; Matsangou, M.; Munshi, H.G. Quercetin enhances the anti-tumor effects of BET inhibitors by suppressing hnRNPA1. Int. J. Mol. Sci.,  2019, 20(17), 4293.
 [http://dx.doi.org/10.3390/ijms20174293] [PMID:  31480735]

[8]
Wu, T.C.; Chan, S.T.; Chang, C.N.; Yu, P.S.; Chuang, C.H.; Yeh, S.L. Quercetin and chrysin inhibit nickel-induced invasion and migration by downregulation of TLR4/NF-κB signaling in A549 cells. Chem. Biol. Interact.,  2018, 292, 101-109.
 [http://dx.doi.org/10.1016/j.cbi.2018.07.010] [PMID:  30016632]

[9]
Zhao, H.; Li, L.; Zhang, J.; Zheng, C.; Ding, K.; Xiao, H.; Wang, L.; Zhang, Z. C-C Chemokine Ligand 2 (CCL2) Recruits macrophage-membrane-camouflaged hollow bismuth selenide nanoparticles to facilitate photothermal sensitivity and inhibit lung metastasis of breast cancer. ACS Appl. Mater. Interfaces,  2018, 10(37), 31124-31135.
 [http://dx.doi.org/10.1021/acsami.8b11645] [PMID:  30141614]

[10]
Maurya, A.K.; Vinayak, M. Anticarcinogenic action of quercetin by downregulation of phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) via induction of p53 in hepatocellular carcinoma (HepG2) cell line. Mol. Biol. Rep.,  2015, 42(9), 1419-1429.
 [http://dx.doi.org/10.1007/s11033-015-3921-7] [PMID:  26311153]

[11]
Wang, Y.; Han, A.; Chen, E.; Singh, R.K.; Chichester, C.O.; Moore, R.G.; Singh, A.P.; Vorsa, N. The cranberry flavonoids PAC DP-9 and quercetin aglycone induce cytotoxicity and cell cycle arrest and increase cisplatin sensitivity in ovarian cancer cells. Int. J. Oncol.,  2015, 46(5), 1924-1934.
 [http://dx.doi.org/10.3892/ijo.2015.2931] [PMID:  25776829]

[12]
Dajas, F. Life or death: Neuroprotective and anticancer effects of quercetin. J. Ethnopharmacol.,  2012, 143(2), 383-396.
 [http://dx.doi.org/10.1016/j.jep.2012.07.005] [PMID:  22820241]

[13]
Granado-Serrano, A.B.; Martín, M.A.; Bravo, L.; Goya, L.; Ramos, S. Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: Involvement of p38. Chem. Biol. Interact.,  2012, 195(2), 154-164.
 [http://dx.doi.org/10.1016/j.cbi.2011.12.005] [PMID:  22197970]

[14]
Granado-Serrano, A.B.; Angeles Martín, M.; Bravo, L.; Goya, L.; Ramos, S. Time-course regulation of quercetin on cell survival/proliferation pathways in human hepatoma cells. Mol. Nutr. Food Res.,  2008, 52(4), 457-464.
 [http://dx.doi.org/10.1002/mnfr.200700203] [PMID:  18324708]

[15]
Tian, F.; Dahmani, F.Z.; Qiao, J.; Ni, J.; Xiong, H.; Liu, T.; Zhou, J.; Yao, J. A targeted nanoplatform co-delivering chemotherapeutic and antiangiogenic drugs as a tool to reverse multidrug resistance in breast cancer. Acta Biomater.,  2018, 75, 398-412.
 [http://dx.doi.org/10.1016/j.actbio.2018.05.050] [PMID:  29874597]

[16]
Mu, Y.; Fu, Y.; Li, J.; Yu, X.; Li, Y.; Wang, Y.; Wu, X.; Zhang, K.; Kong, M.; Feng, C.; Chen, X. Multifunctional quercetin conjugated chitosan nano-micelles with P-gp inhibition and permeation enhancement of anticancer drug. Carbohydr. Polym.,  2019, 203, 10-18.
 [http://dx.doi.org/10.1016/j.carbpol.2018.09.020] [PMID:  30318192]

[17]
Samadi, A.; Pourmadadi, M.; Yazdian, F.; Rashedi, H.; Navaei-Nigjeh, M.; Eufrasio-da-silva, T. Ameliorating quercetin constraints in cancer therapy with pH-responsive agarose-polyvinylpyrrolidone-hydroxyapatite nanocomposite encapsulated in double nanoemulsion. Int. J. Biol. Macromol.,  2021, 182, 11-25.
 [http://dx.doi.org/10.1016/j.ijbiomac.2021.03.146] [PMID:  33775763]

[18]
Xu, G.; Shi, H.; Ren, L.; Gou, H.; Gong, D.; Gao, X.; Huang, N. Enhancing the anti-colon cancer activity of quercetin by self-assembled micelles. Int. J. Nanomedicine,  2015, 10, 2051-2063.
 [PMID:  25844036]

[19]
Qian, J.; Liu, S.; Yang, T.; Xiao, Y.; Sun, J.; Zhao, J.; Zhang, Z.; Xie, Y. Polyethyleneimine-tocopherol hydrogen succinate/hyaluronic acid-quercetin (PEI-TOS/HA-QU) core-shell micelles delivering paclitaxel for combinatorial treatment of MDR breast cancer. J. Biomed. Nanotechnol.,  2021, 17(3), 382-398.
 [http://dx.doi.org/10.1166/jbn.2021.3032] [PMID:  33875073]

[20]
Abbaszadeh, S.; Rashidipour, M.; Khosravi, P.; Shahryarhesami, S.; Ashrafi, B.; Kaviani, M.; Moradi Sarabi, M. Biocompatibility, cytotoxicity, antimicrobial and epigenetic effects of novel chitosan-based quercetin nanohydrogel in human cancer cells. Int. J. Nanomedicine,  2020, 15, 5963-5975.
 [http://dx.doi.org/10.2147/IJN.S263013] [PMID:  32884259]

[21]
Sadalage, P.S.; Patil, R.V.; Havaldar, D.V.; Gavade, S.S.; Santos, A.C.; Pawar, K.D. Optimally biosynthesized, PEGylated gold nanoparticles functionalized with quercetin and camptothecin enhance potential anti-inflammatory, anti-cancer and anti-angiogenic activities. J. Nanobiotechnology,  2021, 19(1), 84.
 [http://dx.doi.org/10.1186/s12951-021-00836-1] [PMID:  33766058]

[22]
Mutlu Gençkal, H.; Erkisa, M.; Alper, P.; Sahin, S.; Ulukaya, E.; Ari, F. Mixed ligand complexes of Co(II), Ni(II) and Cu(II) with quercetin and diimine ligands: synthesis, characterization, anti-cancer and anti-oxidant activity. J. Biol. Inorg. Chem.,  2020, 25(1), 161-177.
 [http://dx.doi.org/10.1007/s00775-019-01749-z] [PMID:  31832781]

[23]
Du, Y.; He, W.; Xia, Q.; Zhou, W.; Yao, C.; Li, X. Thioether phosphatidylcholine liposomes: A novel ros-responsive platform for drug delivery. ACS Appl. Mater. Interfaces,  2019, 11(41), 37411-37420.
 [http://dx.doi.org/10.1021/acsami.9b08901] [PMID:  31556583]

[24]
Hu, Q.; Luo, Y. Polyphenol-chitosan conjugates: Synthesis, characterization, and applications. Carbohydr. Polym.,  2016, 151, 624-639.
 [http://dx.doi.org/10.1016/j.carbpol.2016.05.109] [PMID:  27474608]

[25]
Souza, M.P.C.; Sábio, R.M.; Ribeiro, T.C.; Santos, A.M.; Meneguin, A.B.; Chorilli, M. Highlighting the impact of chitosan on the development of gastroretentive drug delivery systems. Int. J. Biol. Macromol.,  2020, 159, 804-822.
 [http://dx.doi.org/10.1016/j.ijbiomac.2020.05.104] [PMID:  32425271]

[26]
Yadollahi, M.; Farhoudian, S.; Barkhordari, S.; Gholamali, I.; Farhadnejad, H.; Motasadizadeh, H. Facile synthesis of chitosan/ZnO bio-nanocomposite hydrogel beads as drug delivery systems. Int. J. Biol. Macromol.,  2016, 82, 273-278.
 [http://dx.doi.org/10.1016/j.ijbiomac.2015.09.064] [PMID:  26433177]

[27]
Keawchaoon, L.; Yoksan, R. Preparation, characterization and in vitro release study of carvacrol-loaded chitosan nanoparticles. Colloids Surf. B Biointerfaces,  2011, 84(1), 163-171.
 [http://dx.doi.org/10.1016/j.colsurfb.2010.12.031] [PMID:  21296562]

[28]
Rashidipour, M.; Maleki, A.; Kordi, S.; Birjandi, M.; Pajouhi, N.; Mohammadi, E.; Heydari, R.; Rezaee, R.; Rasoulian, B.; Davari, B. Pectin/chitosan/tripolyphosphate nanoparticles: efficient carriers for reducing soil sorption, cytotoxicity, and mutagenicity of paraquat and enhancing its herbicide activity. J. Agric. Food Chem.,  2019, 67(20), 5736-5745.
 [http://dx.doi.org/10.1021/acs.jafc.9b01106] [PMID:  31042035]

[29]
Cresswell, G.M.; Wang, B.; Kischuk, E.M.; Broman, M.M.; Alfar, R.A.; Vickman, R.E.; Dimitrov, D.S.; Kularatne, S.A.; Sundaram, C.P.; Singhal, S.; Eruslanov, E.B.; Crist, S.A.; Elzey, B.D.; Ratliff, T.L.; Low, P.S. Folate receptor beta designates immunosuppressive tumor-associated myeloid cells that can be reprogrammed with folate-targeted drugs. Cancer Res.,  2021, 81(3), 671-684.
 [http://dx.doi.org/10.1158/0008-5472.CAN-20-1414] [PMID:  33203700]

[30]
Unnikrishnan, B.S.; Sen, A.; Preethi, G.U.; Joseph, M.M.; Maya, S.; Shiji, R.; Anusree, K.S.; Sreelekha, T.T. Folic acid-appended galactoxyloglucan-capped iron oxide nanoparticles as a biocompatible nanotheranostic agent for tumor-targeted delivery of doxorubicin. Int. J. Biol. Macromol.,  2021, 168, 130-142.
 [http://dx.doi.org/10.1016/j.ijbiomac.2020.11.205] [PMID:  33278441]

[31]
Yassemi, A.; Kashanian, S.; Zhaleh, H. Folic acid receptor-targeted solid lipid nanoparticles to enhance cytotoxicity of letrozole through induction of caspase-3 dependent-apoptosis for breast cancer treatment. Pharm. Dev. Technol.,  2020, 25(4), 397-407.
 [http://dx.doi.org/10.1080/10837450.2019.1703739] [PMID:  31893979]

[32]
Mortezazadeh, T.; Gholibegloo, E.; Khoobi, M.; Alam, N.R.; Haghgoo, S.; Mesbahi, A. In vitro and in vivo characteristics of doxorubicin-loaded cyclodextrine-based polyester modified gadolinium oxide nanoparticles: a versatile targeted theranostic system for tumour chemotherapy and molecular resonance imaging. J. Drug Target.,  2020, 28(5), 533-546.
 [http://dx.doi.org/10.1080/1061186X.2019.1703188] [PMID:  31842616]

[33]
Angelopoulou, A.; Kolokithas-Ntoukas, A.; Fytas, C.; Avgoustakis, K. Folic acid-functionalized, condensed magnetic nanoparticles for targeted delivery of doxorubicin to tumor cancer cells over expressing the folate receptor. ACS Omega,  2019, 4(26), 22214-22227.
 [http://dx.doi.org/10.1021/acsomega.9b03594] [PMID:  31891105]

[34]
de Oliveira Silva, J.; Fernandes, R.S.; Ramos Oda, C.M.; Ferreira, T.H.; Machado Botelho, A.F.; Martins Melo, M.; de Miranda, M.C.; Assis Gomes, D.; Dantas Cassali, G.; Townsend, D.M.; Rubello, D.; Oliveira, M.C.; de Barros, A.L.B. Folate-coated, long-circulating and pH-sensitive liposomes enhance doxorubicin antitumor effect in a breast cancer animal model. Biomed. Pharmacother.,  2019, 118, 109323.
 [http://dx.doi.org/10.1016/j.biopha.2019.109323] [PMID:  31400669]

[35]
Zhang, B.; Pan, W.; Deng, Y.; He, H.; Gou, J.; Wang, Y.; Zhang, Y.; Yin, T.; Liu, D.; Tang, X. Panax quinquefolium saponin liposomes prepared by passive drug loading for improving intestinal absorption. Drug Dev. Ind. Pharm.,  2020, 46(10), 1684-1694.
 [http://dx.doi.org/10.1080/03639045.2020.1820036] [PMID:  32996345]

[36]
Huang, Y.; Nan, L.; Xiao, C.; Ji, Q.; Li, K.; Wei, Q.; Liu, Y.; Bao, G. Optimum preparation method for self-assembled PEG ylation nano-adjuvant based on rehmannia glutinosa polysaccharide and its immunological effect on macrophages. Int. J. Nanomedicine,  2019, 14, 9361-9375.
 [http://dx.doi.org/10.2147/IJN.S221398] [PMID:  31819437]

[37]
Blazaki, S.; Pachis, K.; Tzatzarakis, M.; Tsilimbaris, M.; Antimisiaris, S.G. Novel Liposome Aggregate Platform (LAP) system for sustained retention of drugs in the posterior ocular segment following intravitreal injection. Int. J. Pharm.,  2020, 576, 118987.
 [http://dx.doi.org/10.1016/j.ijpharm.2019.118987] [PMID:  31870961]

[38]
Xu, H; Zhang, CH; Guan, X Study on the therapeutic effect of quercetin PLGA-TPGS nanoparticles on ectopic solid tumor of hepatocellular carcinoma in mice. J. China Med. Univ.,  2017, 46(09), 791-795.

[39]
T S, A.; Lu, Y.J.; Chen, J.P. Optimization of the preparation of magnetic liposomes for the combined use of magnetic hyperthermia and photothermia in dual magneto-photothermal cancer therapy. Int. J. Mol. Sci.,  2020, 21(15), 23.
 [http://dx.doi.org/10.3390/ijms21155187] [PMID:  32707876]

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DOI https://dx.doi.org/10.2174/0113892010264479231006045014	Print ISSN 1389-2010
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Folate-chitosan Coated Quercetin Liposomes for Targeted Cancer Therapy

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