Characterization of 9-nitrocamptothecin Liposomes: Anticancer Properties and Mechanisms on Hepatocellular Carcinoma in Vitro and in Vivo

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Jun 23

PMID 21695227

Citations 7

Authors

Shunzhen Zheng

Shuang Chang

Jinli Lu

Zhihui Chen

Li Xie

Yu Nie

Bin He

Shengquan Zou

Zhongwei Gu

Affiliations

Soon will be listed here.

Abstract

Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. 9-Nitrocamptothecin (9NC) is a potent topoisomerase-I inhibitor with strong anticancer effect. To increase the solubility and stability, we synthesized a novel 9NC loaded liposomes (9NC-LP) via incorporating 9NC into liposomes. In the present study, we determined the effects of 9NC and 9NC-LP on in vitro and in vivo, and the underlying mechanisms.

Methodology/principal Findings: We first analyzed the characteristics of 9NC-LP. Then we compared the effects of 9NC and 9NC-LP on the proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro. We also investigated their anticancer properties in nude mice bearing HCC xenograft in vivo. 9NC-LP has a uniform size (around 190 nm) and zeta potential (∼-11 mV), and exhibited a steady sustained-release pattern profile in vitro. Both 9NC and 9NC-LP could cause cell cycle arrest and apoptosis in a dose-dependent and p53-dependent manner. However, this effect was not ubiquitous in all cell lines. Exposure to 9NC-LP led to increased expression of p53, p21, p27, Bax, caspase-3, caspase-8, caspase-9 and apoptosis-inducing factor, mitochondrion-associated 1 and decreased expression of Bcl-2, cyclin E, cyclin A, Cdk2 and cyclin D1. Furthermore, 9NC-LP exhibited a more potent antiproliferative effect and less side effects in vivo. Western blot analysis of the xenograft tumors in nude mice showed similar changes in protein expression in vivo.

Conclusions/significance: In conclusion, 9NC and 9NC-LP can inhibit HCC growth via cell cycle arrest and induction of apoptosis. 9NC-LP has a more potent anti-tumor effect and fewer side effects in vivo, which means it is a promising reagent for cancer therapy via intravenous administration.

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References

Alexis F, Pridgen E, Langer R, Farokhzad O . Nanoparticle technologies for cancer therapy. Handb Exp Pharmacol. 2010; (197):55-86. DOI: 10.1007/978-3-642-00477-3_2. View

Soussi T . The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann N Y Acad Sci. 2000; 910:121-37; discussion 137-9. DOI: 10.1111/j.1749-6632.2000.tb06705.x. View

Malam Y, Loizidou M, Seifalian A . Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci. 2009; 30(11):592-9. DOI: 10.1016/j.tips.2009.08.004. View

Owens 3rd D, Peppas N . Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2005; 307(1):93-102. DOI: 10.1016/j.ijpharm.2005.10.010. View

Meeran S, Katiyar S . Cell cycle control as a basis for cancer chemoprevention through dietary agents. Front Biosci. 2007; 13:2191-202. PMC: 2387048. DOI: 10.2741/2834. View

Hochegger H, Takeda S, Hunt T . Cyclin-dependent kinases and cell-cycle transitions: does one fit all?. Nat Rev Mol Cell Biol. 2008; 9(11):910-6. DOI: 10.1038/nrm2510. View

Strieth S, Eichhorn M, Werner A, Sauer B, Teifel M, Michaelis U . Paclitaxel encapsulated in cationic liposomes increases tumor microvessel leakiness and improves therapeutic efficacy in combination with Cisplatin. Clin Cancer Res. 2008; 14(14):4603-11. DOI: 10.1158/1078-0432.CCR-07-4738. View

Vousden K . p53: death star. Cell. 2000; 103(5):691-4. DOI: 10.1016/s0092-8674(00)00171-9. View

Maeda H, Sawa T, Konno T . Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. J Control Release. 2001; 74(1-3):47-61. DOI: 10.1016/s0168-3659(01)00309-1. View

10.

STAHLER F, Roemer K . Mutant p53 can provoke apoptosis in p53-deficient Hep3B cells with delayed kinetics relative to wild-type p53. Oncogene. 1999; 17(26):3507-12. DOI: 10.1038/sj.onc.1202245. View

11.

Chan K, Meng F, Li Q, Ho C, Lam T, To Y . Cucurbitacin B induces apoptosis and S phase cell cycle arrest in BEL-7402 human hepatocellular carcinoma cells and is effective via oral administration. Cancer Lett. 2010; 294(1):118-24. DOI: 10.1016/j.canlet.2010.01.029. View

12.

Cha C, Saif M, Yamane B, Weber S . Hepatocellular carcinoma: current management. Curr Probl Surg. 2009; 47(1):10-67. DOI: 10.1067/j.cpsurg.2009.09.003. View

13.

Wang J, Ki S . Choosing between growth arrest and apoptosis through the retinoblastoma tumour suppressor protein, Abl and p73. Biochem Soc Trans. 2001; 29(Pt 6):666-73. DOI: 10.1042/0300-5127:0290666. View

14.

Aagaard L, Rossi J . RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev. 2007; 59(2-3):75-86. PMC: 1978219. DOI: 10.1016/j.addr.2007.03.005. View

15.

Padma S, Martinie J, Iannitti D . Liver tumor ablation: percutaneous and open approaches. J Surg Oncol. 2009; 100(8):619-34. DOI: 10.1002/jso.21364. View

16.

Maeda H, Wu J, Sawa T, Matsumura Y, Hori K . Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000; 65(1-2):271-84. DOI: 10.1016/s0168-3659(99)00248-5. View

17.

Koo O, Rubinstein I, Onyuksel H . Camptothecin in sterically stabilized phospholipid micelles: a novel nanomedicine. Nanomedicine. 2007; 1(1):77-84. DOI: 10.1016/j.nano.2004.11.002. View

18.

Anand S, Honari G, Hasan T, Elson P, Maytin E . Low-dose methotrexate enhances aminolevulinate-based photodynamic therapy in skin carcinoma cells in vitro and in vivo. Clin Cancer Res. 2009; 15(10):3333-43. PMC: 2744072. DOI: 10.1158/1078-0432.CCR-08-3054. View

19.

Rivera E . Liposomal anthracyclines in metastatic breast cancer: clinical update. Oncologist. 2003; 8 Suppl 2:3-9. DOI: 10.1634/theoncologist.8-suppl_2-3. View

20.

Khan D, Rezler E, Lauer-Fields J, Fields G . Effects of drug hydrophobicity on liposomal stability. Chem Biol Drug Des. 2007; 71(1):3-7. DOI: 10.1111/j.1747-0285.2007.00610.x. View