Resistance to common chemotherapeutic agents is a frequent phenomenon in late-stage breast cancers. An ideal system capable of the co-delivery of hydrophobic and hydrophilic chemotherapeutic agents can regulate the dosage and co-localization of pharmaceutical compounds and thereby improve the anticancer efficacy. Here, for the first time, we have intercalated curcumin (Cur) into a double-layered membrane of cisplatin (Cis) liposomes to obtain a dosage controlled co-delivery formulation, capable of inducing apoptosis in breast cancer cells. The concentrations of Cur and Cis in nanoliposome (Cur-Cis@NLP) were optimized by response surface methodology (RSM); RSM optimization showed 99.81 and 23.86% entrapment efficiency for Cur and Cis, respectively. TEM analysis demonstrated the fabrication of nanoparticles with average diameter of 100 nm. The anticancer and apoptotic effects of Cur-Cis@NLPs were also evaluated using MTT assay, fluorescent staining and flow cytometry assays. Cytotoxicity assessments of various Cur-Cis@NLPs concentrations demonstrated a concentration-dependent manner. In comparison to free and liposomal Cis, Cur-Cis@NLP reduced breast cancer cells’ viability (82.5%) in a significant manner at a final concentration of 32 μg.mL−1 and 20 μg.mL−1 of Cur and Cis, respectively. Combination index values calculation of Cur-Cis@NLP showed an overall CI value <1, indicating synergetic effect of the designed co-delivery system. Additionally, flow cytometry assay demonstrated Cur-Cis@NLPs triggered apoptosis about 10-folds higher than liposomal Cis. This co-drug delivery system has a potential for the encapsulation and release of both hydrophobic and hydrophilic drugs, while taking the advantages of the reduced cytotoxic effect along with achieving high potency.
PogribnyIPFilkowskiJNTryndyakVP, et al.
Alterations of microRNAs and their targets are associated with acquired resistance of MCF‐7 breast cancer cells to cisplatin. Int J Cancer2010;
127: 1785–1794.
7.
HeSZhongYShuaiC, et al.
Tumor suppressor NGX6 inhibits the growth and metastasis of multiple cancers. Tumour Biol2016;
37: 5751–5760.
8.
HammackJEMichalakJCLoprinziCL, et al.
Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain2002;
98: 195–203.
9.
ChoiY-MKimH-KShimW, et al.
Mechanism of cisplatin-induced cytotoxicity is correlated to impaired metabolism due to mitochondrial ROS generation. PloS One2015;
10: e0135083.
10.
ChavoshiHVahedianVSaghaeiS, et al.
Adjuvant therapy with silibinin improves the efficacy of paclitaxel and cisplatin in MCF-7 breast cancer cells. Asian Pacific J Cancer Prevent2017;
18: 2243.
11.
O'DonnellJLJoyceMRShannonAM, et al.
Oncological implications of hypoxia inducible factor-1α (HIF-1α) expression. Cancer Treat Rev2006;
32: 407–416.
SemenzaG.HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr Pharm Des2009;
15: 3839–3843.
14.
NiedernhoferLJOdijkHBudzowskaM, et al.
The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Mol Cell Biol2004;
24: 5776–5787.
15.
MenonVPSudheerAR.Antioxidant and anti-inflammatory properties of curcumin. The molecular targets and therapeutic uses of curcumin in health and disease.
Berlin:
Springer, 2007, pp.105–125.
16.
López and LázaroM.Anticancer and carcinogenic properties of curcumin: considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent. Mol Nutr Food Res2008;
52: S103.
17.
AbeYHashimotoSHorieT.Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res1999;
39: 41–47.
18.
OdotJAlbertPCarlierA, et al.
In vitro and in vivo anti‐tumoral effect of curcumin against melanoma cells. Int J Cancer2004;
111: 381–387.
19.
de AlmeidaMda RochaBAFranciscoCRL, et al.
Evaluation of the in vivo acute antiinflammatory response of curcumin-loaded nanoparticles. Food Funct2018;
9: 440–449.
20.
TsaiM-SWengS-HKuoY-H, et al.
Synergistic effect of curcumin and cisplatin via down-regulation of thymidine phosphorylase and excision repair cross-complementary 1 (ERCC1). Mol Pharmacol2011;
80: 136–146.
21.
YeM-XZhaoY-LLiY, et al.
Curcumin reverses cis-platin resistance and promotes human lung adenocarcinoma A549/DDP cell apoptosis through HIF-1α and caspase-3 mechanisms. Phytomedicine2012;
19: 779–787.
22.
GrecoFVicentMJ.Combination therapy: opportunities and challenges for polymer–drug conjugates as anticancer nanomedicines. Adv Drug Deliv Rev2009;
61: 1203–1213.
23.
MisraRAcharyaSSahooS.Cancer nanotechnology: application of nanotechnology in cancer therapy. Drug Discov Today2010;
15: 842–850.
24.
RuttalaHBChitrapriyaNKalirajK, et al.
Facile construction of bioreducible crosslinked polypeptide micelles for enhanced cancer combination therapy. Acta Biomater2017;
63: 135–149.
25.
RamasamyTRuttalaHBGuptaB, et al.
Smart chemistry-based nanosized drug delivery systems for systemic applications: a comprehensive review. J Control Release2017;
258: 226–253.
26.
RamasamyTRuttalaHBChitrapriyaN, et al.
Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors. Acta Biomater2017;
48: 131–143.
27.
RamasamyTHaidarZSTranTH, et al.
Layer-by-layer assembly of liposomal nanoparticles with PEGylated polyelectrolytes enhances systemic delivery of multiple anticancer drugs. Acta Biomater2014;
10: 5116–5127.
28.
MousavizadehAJabbariAAkramiM, et al.
Cell targeting peptides as smart ligands for targeting of therapeutic or diagnostic agents: a systematic review. Colloids Surf B Biointerfaces2017;
158: 507–517.
29.
SchwendenerRA.Liposomes in biology and medicine. Bio-applications of nanoparticles.
Berlin:
Springer, 2007, pp.117–128.
SahooSKLabhasetwarV.Nanotech approaches to drug delivery and imaging. Drug Discov Today2003;
8: 1112–1120.
32.
KimJ-S.Liposomal drug delivery system. J Pharma Investig2016;
46: 387–392.
33.
NarayananNKNargiDRandolphC, et al.
Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice. Int J Cancer2009;
125: 1–8.
34.
EloyJOPetrilliRChescaDL, et al.
Anti-HER2 immunoliposomes for co-delivery of paclitaxel and rapamycin for breast cancer therapy. Eur J Pharm Biopharm2017;
115: 159–167.
35.
WuJLuYLeeA, et al.
Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. J Pharm Pharm Sci2007;
10: 350–357.
36.
ChengYZhaoPWuS, et al.
Cisplatin and curcumin co-loaded nano-liposomes for the treatment of hepatocellular carcinoma. Int J Pharm2018;
545: 261–273.
37.
BardaniaHShojaosadatiSAKobarfardF, et al.
Optimization of RGD-modified nano-liposomes encapsulating eptifibatide. Iran J Biotechnol2016;
14: 33–40.
38.
BardaniaHShojaosadatiSAKobarfardF, et al.
Encapsulation of eptifibatide in RGD-modified nanoliposomes improves platelet aggregation inhibitory activity. J Thromb Thrombolysis2017;
43: 184–193.
39.
KhodayarSBardaniaHShojaosadatiSA, et al.
Optimization and characterization of aspirin encapsulated nano-Liposomes. Iran J Pharm Res2018;
17: 11–22.
40.
MyersRHMontgomeryDC.Response surface methodology.
New York:
John Wiley & Sons, 2002.
41.
RavarFSaadatEKelishadiPD, et al.
Liposomal formulation for co-delivery of paclitaxel and lapatinib, preparation, characterization and optimization. J Liposome Res2016;
26: 175–187.
42.
HashemiSHMontazerMNaghdiN, et al.
Formulation and characterization of alprazolam-loaded nanoliposomes: screening of process variables and optimizing characteristics using RSM. Drug Dev Ind Pharm2018;
44: 296–305.
43.
JosephJB NVHDRD.Experimental optimization of lornoxicam liposomes for sustained topical delivery. Eur J Pharm Sci2018;
112: 38–51.
44.
AydinRPulatM.5-Fluorouracil encapsulated chitosan nanoparticles for pH-stimulated drug delivery: evaluation of controlled release kinetics. J Nanomaterials2012;
2012: 42.
45.
RamtekeKDighePKharatA, et al.
Mathematical models of drug dissolution: a review. Sch Acad J Pharm2014;
3: 388–396.
46.
Mohammad-BeigiHShojaosadatiSAMorshediD, et al.
Preparation and in vitro characterization of gallic acid-loaded human serum albumin nanoparticles. J Nanoparticle Res2015;
17: 1–16.
47.
MosmannT.Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods1983;
65: 55–63.
48.
TaloreteTPBouazizMSayadiS, et al.
Influence of medium type and serum on MTT reduction by flavonoids in the absence of cells. Cytotechnology2007;
52: 189–198.
49.
ChouT-C.Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev2006;
58: 621–681.
50.
VermesIHaanenCSteffens-NakkenH, et al.
A novel assay for apoptosis flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled annexin V. J Immunol Methods1995;
184: 39–51.
51.
QasimMAsgharKDharmapuriG, et al.
Investigation of novel superparamagnetic Ni0. 5Zn0. 5Fe2O4@ albumen nanoparticles for controlled delivery of anticancer drug. Nanotechnology2017;
28: 365101.
52.
BaneshiMDadfarniaSShabaniAMH, et al.
A novel theranostic system of AS1411 aptamer-functionalized albumin nanoparticles loaded on iron oxide and gold nanoparticles for doxorubicin delivery. Int J Pharm2019;
564: 145–152.
53.
BozzutoGMolinariA.Liposomes as nanomedical devices. Int J Nanomedicine2015;
10: 975–999.
54.
TorchilinVP.Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov2005;
4: 145–160.
55.
MujokoroBAdabiMSadroddinyE, et al.
Nano-structures mediated co-delivery of therapeutic agents for glioblastoma treatment: a review. Mater Sci Eng C Mater Biol Appl2016;
69: 1092–1102.
56.
KulkarniSBBetageriGVSinghM.Factors affecting microencapsulation of drugs in liposomes. J Microencapsul1995;
12: 229–246.
57.
AliakbariFShabaniAABardaniaH, et al.
Formulation and anti-neurotoxic activity of baicalein-incorporating neutral nanoliposome. Colloids Surf B Biointerfaces2018;
161: 578–587.
58.
MahiraSKommineniNHusainGM, et al.
Cabazitaxel and silibinin co-encapsulated cationic liposomes for CD44 targeted delivery: a new insight into nanomedicine based combinational chemotherapy for prostate cancer. Biomed Pharmacother2019;
110: 803–817.
59.
PanJRostamizadehKFilipczakN, et al.
Polymeric co-delivery systems in cancer treatment: an overview on component drugs’ dosage ratio effect. Molecules2019;
24: 1035.
NgouneRPetersAvon ElverfeldtD, et al.
Accumulating nanoparticles by EPR: a route of no return. J Control Release2016;
238: 58–70.
62.
LiLAhmedBMehtaK, et al.
Liposomal curcumin with and without oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in colorectal cancer. Mol Cancer Therapeut2007;
6: 1276–1282.
63.
LiCGeXWangL.Construction and comparison of different nanocarriers for co-delivery of cisplatin and curcumin: a synergistic combination nanotherapy for cervical cancer. Biomed Pharmacother2017;
86: 628–636.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
