A Novel Long-circulating DOX Liposome: Formulation and Pharmacokinetics Studies

Author(s): Peihong Xiao, Juan Zhao, Yi Huang, Rongrong Jin, Zhonglan Tang, Ping Wang, Xu Song*, Hongfei Zhu*, Zibin Yang, Nie Yu

Journal Name: Pharmaceutical Nanotechnology

Volume 8 , Issue 5 , 2020


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Graphical Abstract:


Abstract:

Background: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDA-approved PEG-liposomes of DOX for the treatment of over 600,000 cancer patients, and it can overcome doxorubicin-induced cardiomyopathy and other side effects and prolong life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment.

Objective: We intended to prepare a novel DOX liposome that was prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical application.

Methods: DOX liposomes were prepared using the combination of thin-film dispersion ultrasonic method and ammonium sulfate gradient method and the factors that influenced formulation quality were optimized. After formulation, particle size, entrapment efficiency, drug loading, stability, and pharmacokinetics were determined.

Results: DOX liposomes were near-spherical morphology with the average size of 90 nm and polydispersity index (PDI) of less than 0.30. The drug loading was up to 7.5%, and the entrapment efficiency was over 80%. The pharmacokinetic studies showed that free DOX could be easily removed and the blood concentration of free DOX group was significantly lower than that of DOX liposomes, which indicated that the novel DOX liposome had a certain sustainedrelease effect.

Conclusion: In summary, DOX liposome is economical and easy-prepared with prolonged circulation time.

Lay Summary: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDAapproved PEG-liposomes of DOX to treat over 600.000 cancer patients, overcoming doxorubicin- induced cardiomyopathy and other side effects and prolonging life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. We intend to prepare a novel DOX liposome prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical use. The novel DOX liposome is economical and easy-prepared with prolonged circulation time.

Keywords: DOX liposome, drug loading, entrapment efficiency, Kolliphor HS15, particle size, pharmacokinetics.

[1]
Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 1965; 13(1): 238-52.
[http://dx.doi.org/10.1016/S0022-2836(65)80093-6] [PMID: 5859039]
[2]
Zahednezhad F, Saadat M, Valizadeh H, Zakeri-Milani P, Baradaran B. Liposome and immune system interplay: challenges and potentials. J Control Release 2019; 305: 194-209.
[http://dx.doi.org/10.1016/j.jconrel.2019.05.030 ] [PMID: 31121278]
[3]
Bardania H, Tarvirdipour S, Dorkoosh F. Liposome-targeted delivery for highly potent drugs. Artif Cells Nanomed Biotechnol 2017; 45(8): 1478-89.
[http://dx.doi.org/10.1080/21691401.2017.1290647] [PMID: 28278584]
[4]
Bulbake U, Doppalapudi S, Kommineni N, Khan W. Liposomal formulations in clinical use: an updated review. Pharmaceutics 2017; 9(2): 12.
[http://dx.doi.org/10.3390/pharmaceutics9020012] [PMID: 28346375]
[5]
Valizadeh H, Ghanbarzadeh S, Zakeri-Milani P. Fusogenic liposomal formulation of sirolimus: improvement of drug anti-proliferative effect on human T-cells. Drug Dev Ind Pharm 2015; 41(9): 1558-65.
[http://dx.doi.org/10.3109/03639045.2014.971032] [PMID: 25311425]
[6]
Alavi M, Karimi N, Safaei M. Application of various types of liposomes in drug delivery systems. Adv Pharm Bull 2017; 7(1): 3-9.
[http://dx.doi.org/10.15171/apb.2017.002 ] [PMID: 28507932]
[7]
Kao YJ, Juliano RL. Interactions of liposomes with the reticuloendothelial system. Effects of reticuloendothelial blockade on the clearance of large unilamellar vesicles. Biochim Biophys Acta 1981; 677(3-4): 453-61.
[http://dx.doi.org/10.1016/0304-4165(81)90259-2] [PMID: 6895332]
[8]
Moghimi SM, Szebeni J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res 2003; 42(6): 463-78.
[http://dx.doi.org/10.1016/S0163-7827(03)00033-X] [PMID: 14559067]
[9]
Kapoor M, Lee SL, Tyner KM. Liposomal drug product development and quality: current US experience and perspective. AAPS J 2017; 19(3): 632-41.
[http://dx.doi.org/10.1208/s12248-017-0049-9] [PMID: 28160164]
[10]
Zhou C, Guo C, Li W, et al. A novel honokiol liposome: formulation, pharmacokinetics, and antitumor studies. Drug Dev Ind Pharm 2018; 44(12): 2005-12.
[http://dx.doi.org/10.1080/03639045.2018.1506475] [PMID: 30058387]
[11]
Illum L, Jordan F, Lewis AL. CriticalSorb: a novel efficient nasal delivery system for human growth hormone based on Solutol HS15. J Control Release 2012; 162(1): 194-200.
[http://dx.doi.org/10.1016/j.jconrel.2012.06.014 ] [PMID: 22709592]
[12]
Ta HT, Dass CR, Larson I, Choong PF, Dunstan DE. A chitosan-dipotassium orthophosphate hydrogel for the delivery of Doxorubicin in the treatment of osteosarcoma. Biomaterials 2009; 30(21): 3605-13.
[http://dx.doi.org/10.1016/j.biomaterials.2009.03.022] [PMID: 19345993]
[13]
Bavli Y, Winkler I, Chen BM, et al. Doxebo (doxorubicin-free Doxil-like liposomes) is safe to use as a pre-treatment to prevent infusion reactions to PEGylated nanodrugs. J Control Release 2019; 306: 138-48.
[http://dx.doi.org/10.1016/j.jconrel.2019.06.007 ] [PMID: 31176656]
[14]
Gabizon AA, Lyass O, Berry GJ, Wildgust M. Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies. Cancer Invest 2004; 22(5): 663-9.
[http://dx.doi.org/10.1081/CNV-200032899] [PMID: 15581046]
[15]
Zhao T, Zhou H, Lei L, et al. A new tandem peptide modified liposomal doxorubicin for tumor “ecological therapy”. Nanoscale 2020; 12(5): 3359-69.
[http://dx.doi.org/10.1039/C9NR09585C ] [PMID: 31984408]
[16]
Song X, Wan Z, Chen T, et al. Development of a multi-target peptide for potentiating chemotherapy by modulating tumor microenvironment. Biomaterials 2016; 108: 44-56.
[http://dx.doi.org/10.1016/j.biomaterials.2016.09.001] [PMID: 27619239]
[17]
Jiang K, Song X, Yang L, et al. Enhanced antitumor and anti-metastasis efficacy against aggressive breast cancer with a fibronectin-targeting liposomal doxorubicin. J Control Release 2018; 271: 21-30.
[http://dx.doi.org/10.1016/j.jconrel.2017.12.026 ] [PMID: 29277681]
[18]
Ran C, Chen D, Xu M, Du C, Li Q, Jiang Y. A study on characteristic of different sample pretreatment methods to evaluate the entrapment efficiency of liposomes. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1028: 56-62.
[http://dx.doi.org/10.1016/j.jchromb.2016.06.008] [PMID: 27322630]
[19]
Jung SH, Kim SK, Jung SH, et al. Increased stability in plasma and enhanced cellular uptake of thermally denatured albumin-coated liposomes. Colloids Surf B Biointerfaces 2010; 76(2): 434-40.
[http://dx.doi.org/10.1016/j.colsurfb.2009.12.002] [PMID: 20036109]
[20]
Charrois GJ, Allen TM. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. Biochim Biophys Acta 2004; 1663(1-2): 167-77.
[http://dx.doi.org/10.1016/j.bbamem.2004.03.006] [PMID: 15157619]
[21]
Wu W, Chen H, Shan F, et al. A novel doxorubicin-loaded in situ forming gel based high concentration of phospholipid for intratumoral drug delivery. Mol Pharm 2014; 11(10): 3378-85.
[http://dx.doi.org/10.1021/mp500019p ] [PMID: 24735404]
[22]
Cao X, Luo J, Gong T, Zhang ZR, Sun X, Fu Y. Coencapsulated doxorubicin and bromotetrandrine lipid nanoemulsions in reversing multidrug resistance in breast cancer in vitro and in vivo. Mol Pharm 2015; 12(1): 274-86.
[http://dx.doi.org/10.1021/mp500637b ] [PMID: 25469833]
[23]
Charrois GJ, Allen TM. Rate of biodistribution of STEALTH liposomes to tumor and skin: influence of liposome diameter and implications for toxicity and therapeutic activity. Biochim Biophys Acta 2003; 1609(1): 102-8.
[http://dx.doi.org/10.1016/S0005-2736(02)00661-2] [PMID: 12507764]


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Article Details

VOLUME: 8
ISSUE: 5
Year: 2020
Published on: 13 August, 2020
Page: [391 - 398]
Pages: 8
DOI: 10.2174/2211738508666200813141454
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