Antitumor Effects of Docetaxel in Truncated Basic Fibroblast Growth Factor- Functionalized Liposomes Delivered by d-α-tocopheryl Polyethylene Glycol 2000 Succinate

Author(s): Jiaolin Wen, Zhoufeng Wang, Neng Qiu, Huili Liu, Xiaoming Shu, Zejiang Zhu, Peng Bai, Li Yang, Lijuan Chen*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 34 , 2020

Become EABM
Become Reviewer
Call for Editor


Background: PEGylation of stealth liposomes elevates their stability and prolongs plasma half-life. Stealth liposomes modified with targeting ligands are expected to be ideal drug delivery carriers.

Objective: To encapsulate docetaxel in tbFGF (truncated basic fibroblast growth factor)-functionalized liposomes with mPEG2000-VE (d-α-tocopheryl polyethylene glycol succinate, TPGS2K) and measure their antitumor effects in vitro and in vivo.

Methods: TPGS2K and COOH-PEG2000-VE were synthesized, and tbFGF was conjugated to COOH-PEG2000-VE to prepare tbFGF-PEG2000-VE. Then, tbFGF-functionalized liposomes (DTX-tbFGF-LPs) were prepared by inserting tbFGF-PEG2000-VE into docetaxel liposomes comprising TPGS2K (DTX-PEG-LPs). The stabilities and drug release profiles of the formulation were evaluated. P-glycoprotein (P-gp) inhibition was measured by ATPase assay. MTT and cell uptake were measured with B16 cells. A B16 C57BL/6 mouse model was used to evaluate in vivo antitumor efficacy.

Results: Both DTX-PEG-LPs and DTX-tbFGF-LPs exhibited good stability and sustained drug release. MTT, flow cytometry, and fluorescence microscopy of B16 cells revealed higher antitumor activity and more efficient cell uptake for DTX-tbFGF-LPs compared with DTX-PEG-LPs and DTX-LPs. The P-gp ATPase assay showed that both PEG-LP and tbFGF-PEG-LP formulations inhibited P-gp pump activity in vitro. DTX-tbFGF-LPs had the highest antitumor efficacy and lowest toxicity in vivo.

Conclusion: Truncated basic fibroblast growth factor-functionalized liposomes with TPGS2K as drug delivery nanocarriers were effective chemotherapy agents targeting FGFR-overexpressing tumors.

Keywords: Truncated basic human fibroblast growth factor, d-α-tocopheryl polyethylene 2000 glycol succinate, docetaxel, liposome, antitumor, P-gp pump.

Iwamoto T. Clinical application of drug delivery systems in cancer chemotherapy: Review of the efficacy and side effects of approved drugs. Biol Pharm Bull 2013; 36(5): 715-8.
[] [PMID: 23649331]
Zamboni WC. Liposomal, nanoparticle, and conjugated formulations of anticancer agents. Clin Cancer Res 2005; 11(23): 8230-4.
[] [PMID: 16322279]
Nishiyama N, Kataoka K. Current state, achievements, and future prospects of polymeric micelles as nanocarriers for drug and gene delivery. Pharmacol Ther 2006; 112(3): 630-48.
[] [PMID: 16815554]
Lee JS, Feijen J. Polymersomes for drug delivery: design, formation and characterization. J Control Release 2012; 161(2): 473-83.
[] [PMID: 22020381]
Manjappa AS, Chaudhari KR, Venkataraju MP, et al. Antibody derivatization and conjugation strategies: application in preparation of stealth immunoliposome to target chemotherapeutics to tumor. J Control Release 2011; 150(1): 2-22.
[] [PMID: 21095210]
La-Beck NM, Gabizon AA. Nanoparticle interactions with the immune system: Clinical implications for liposome-based cancer chemotherapy. Front Immunol 2017; 8: 416.
[] [PMID: 28428790]
Li L, ten Hagen TL, Schipper D, et al. Triggered content release from optimized stealth thermosensitive liposomes using mild hyperthermia. J Control Release 2010; 143(2): 274-9.
[] [PMID: 20074595]
Gabizon A, Goren D, Horowitz A, Tzemach D, Lossos A, Siegal T. Long-circulating liposomes for drug delivery in cancer therapy: a review of biodistribution studies in tumor-bearing animals. Adv Drug Deliv Rev 1997; 24: 337-44.
Hadinoto K, Sundaresan A, Cheow WS. Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform: a review. Eur J Pharm Biopharm 2013; 85(3 Pt A): 427-43.
[] [PMID: 23872180]
Che J, Okeke CI, Hu ZB, Xu J. DSPE-PEG: a distinctive component in drug delivery system. Curr Pharm Des 2015; 21(12): 1598-605.
[] [PMID: 25594410]
Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release 2010; 148(2): 135-46.
[] [PMID: 20797419]
Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005; 4(2): 145-60.
[] [PMID: 15688077]
Zhang Z, Tan S, Feng SS. Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomaterials 2012; 33(19): 4889-906.
[] [PMID: 22498300]
Mi Y, Liu Y, Feng SS. Formulation of Docetaxel by folic acid-conjugated d-α-tocopheryl polyethylene glycol succinate 2000 (Vitamin E TPGS(2k)) micelles for targeted and synergistic chemotherapy. Biomaterials 2011; 32(16): 4058-66.
[] [PMID: 21396707]
Zhang XP, Yang L, Shi HS, et al. An N-, C-terminally truncated basic fibroblast growth factor and LPD (liposome-polycation-DNA) complexes elicits a protective immune response against murine colon carcinoma. Cancer Biol Ther 2010; 10(3): 276-81.
[] [PMID: 20543584]
Terada T, Mizobata M, Kawakami S, Yamashita F, Hashida M. Optimization of tumor-selective targeting by basic fibroblast growth factor-binding peptide grafted PEGylated liposomes. J Control Release 2007; 119(3): 262-70.
[] [PMID: 17467100]
Terada T, Mizobata M, Kawakami S, Yabe Y, Yamashita F, Hashida M. Basic fibroblast growth factor-binding peptide as a novel targeting ligand of drug carrier to tumor cells. J Drug Target 2006; 14(8): 536-45.
[] [PMID: 17050120]
Brannon-Peppas L, Blanchette J. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 2012; 64: 206-12.
[] [PMID: 15350294]
He QM, Wei YQ, Tian L, et al. Inhibition of tumor growth with a vaccine based on xenogeneic homologous fibroblast growth factor receptor-1 in mice. J Biol Chem 2003; 278(24): 21831-6.
[] [PMID: 12651849]
Chen X, Wang XH, Wang Y, et al. Improved tumor-targeting drug delivery and therapeutic efficacy by cationic liposome modified with truncated bFGF peptide. J Control Release 2010; 145(1): 17-25.
[] [PMID: 20307599]
Xiao WJ, Chen X, Yang L, et al. Co-delivery of doxorubicin and plasmid by a novel FGFR-mediated cationic liposome. Int J Pharm 2010; 393(1-2): 119-26.
[] [PMID: 20416367]
Cai L, Wang X, Wang W, et al. Peptide ligand and PEG-mediated long-circulating liposome targeted to FGFR overexpressing tumor in vivo. Int J Nanomedicine 2012; 7: 4499-510.
[] [PMID: 22923988]
Cai L, Qiu N, Li X, et al. A novel truncated basic fibroblast growth factor fragment-conjugated poly (ethylene glycol)-cholesterol amphiphilic polymeric drug delivery system for targeting to the FGFR-overexpressing tumor cells. Int J Pharm 2011; 408(1-2): 173-82.
[] [PMID: 21277964]
Qiu N, Cai LL, Xie D, et al. Synthesis, structural and in vitro studies of well-dispersed monomethoxy-poly(ethylene glycol)-honokiol conjugate micelles. Biomed Mater 2010; 5(6): 065006.
[] [PMID: 20966535]
Yang DB, Zhu JB, Huang ZJ, Ren HX, Zheng ZJ. Synthesis and application of poly(ethylene glycol)-cholesterol (Chol-PEGm) conjugates in physicochemical characterization of nonionic surfactant vesicles. Colloids Surf B Biointerfaces 2008; 63(2): 192-9.
[] [PMID: 18295461]
Wu Y, Ma Q, Song X, et al. Biocompatible poly (ethylene glycol)-poly(c-Cholesterol-L-Glutamate) copolymers: synthesis, characterization, and in vitro studies. J Polymer Sci 2012; 50: 4532-7.
Savva M, Duda E, Huang L. A genetically modified recombinant tumor necrosis factor-alpha conjugated to the distal terminals of liposomal surface grafted polyethyleneglycol chains. Int J Pharm 1999; 184(1): 45-51.
[] [PMID: 10425350]
Immordino ML, Brusa P, Arpicco S, Stella B, Dosio F, Cattel L. Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing docetaxel. J Control Release 2003; 91(3): 417-29.
[] [PMID: 12932719]
Wang XH, Deng L, Cai L, et al. Preparation, characterization, pharmacokinetics, and bioactivity of honokiol-in-hydroxypropyl-β-cyclodextrin-in-liposome. J Pharm Sci 2011; 100(8): 3357-64.
[] [PMID: 21387317]
Zhu H, Chen H, Zeng X, et al. Co-delivery of chemotherapeutic drugs with vitamin E TPGS by porous PLGA nanoparticles for enhanced chemotherapy against multi-drug resistance. Biomaterials 2014; 35(7): 2391-400.
[] [PMID: 24360574]
Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65(1-2): 55-63.
[] [PMID: 6606682]
Zheng D, Li X, Xu H, Lu X, Hu Y, Fan W. Study on docetaxel-loaded nanoparticles with high antitumor efficacy against malignant melanoma. Acta Biochim Biophys Sin (Shanghai) 2009; 41(7): 578-87.
[] [PMID: 19578721]
Muthu MS, Kulkarni SA, Xiong J, Feng SS, Vitamin E. Vitamin E TPGS coated liposomes enhanced cellular uptake and cytotoxicity of docetaxel in brain cancer cells. Int J Pharm 2011; 421(2): 332-40.
[] [PMID: 22001537]
Panyam J, Sahoo SK, Prabha S, Bargar T, Labhasetwar V. Fluorescence and electron microscopy probes for cellular and tissue uptake of poly(D,L-lactide-co-glycolide) nanoparticles. Int J Pharm 2003; 262(1-2): 1-11.
[] [PMID: 12927382]
Liu BY, Wu C, He XY, Zhuo RX, Cheng SX. Multi-drug loaded vitamin E-TPGS nanoparticles for synergistic drug delivery to overcome drug resistance in tumor treatment. Sci Bulletin 2016; 61(7): 552-60.
Zhao J, Feng SS. Effects of PEG tethering chain length of vitamin E TPGS with a Herceptin-functionalized nanoparticle formulation for targeted delivery of anticancer drugs. Biomaterials 2014; 35(10): 3340-7.
[] [PMID: 24461325]
Acharya S, Dilnawaz F, Sahoo SK. Targeted epidermal growth factor receptor nanoparticle bioconjugates for breast cancer therapy. Biomaterials 2009; 30(29): 5737-50.
[] [PMID: 19631377]
Ma M, Hao Y, Liu N, et al. A novel lipid-based nanomicelle of docetaxel: evaluation of antitumor activity and biodistribution. Int J Nanomedicine 2012; 7: 3389-98.
[] [PMID: 22848167]
Sanchez-Perez L, Kottke T, Diaz RM, et al. Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo. Cancer Res 2005; 65(5): 2009-17.
[] [PMID: 15753401]
Ren Z, Ye X, Fang C, et al. Intratumor injection of oncolytic adenovirus expressing HSP70 prolonged survival in melanoma B16 bearing mice by enhanced immune response. Cancer Biol Ther 2008; 7(2): 191-5.
[] [PMID: 18073525]
Riaz MK, Riaz MA, Zhang X, et al. Surface functionalization and targeting strategies of liposomes in solid tumor therapy: A review. Int J Mol Sci 2018; 19(1): 195.
[] [PMID: 29315231]
Ahani E, Montazer M, Toliyat T, Mahmoudi Rad M, Harifi T. Preparation of nano cationic liposome as carrier membrane for polyhexamethylene biguanide chloride through various methods utilizing higher antibacterial activities with low cell toxicity. J Microencapsul 2017; 34(2): 121-31.
[] [PMID: 28609225]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 12 October, 2020
Page: [4338 - 4348]
Pages: 11
DOI: 10.2174/1381612826666200423093357
Price: $65

Article Metrics

PDF: 14