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Spatiotemporally Controlled Co-delivery of Anti-vasculature Agent and Cytotoxic Drug by Octreotide-Modified Stealth Liposomes

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ABSTRACT

Purpose

Both combretastatin A-4 (CA-4) and doxorubicin (DOX) was loaded in different form in a targeted nanomedicine in order to achieve the active delivery of these two drugs followed by sequentially suppressing tumor vasculature and tumor cells.

Methods

Octreotide-modified stealth liposomes loaded with CA-4 and DOX (Oct-L[CD]) were prepared and characterized. Then in vitro release, cellular uptake, in vitro antitumor effect, pharmacokinetics, in vivo sequential killing effect, in vivo antitumor efficacy against somatostatin receptor (SSTR) positive cells, as well as the action mechanism of such system, were studied.

Results

A rapid release of CA-4 followed by a slow release of DOX was observed in vitro. The active targeted liposomes Oct-L[CD] showed a specific cellular uptake through ligand-receptor interaction and a higher antitumor effect in vitro against SSTR-positive cell line. The in vivo sequential killing effect of such system was found as evidenced by the fast inhibition of blood vessels and slow apoptosis-inducing of tumor cells. Oct-L[CD] also exhibited the strongest antitumor effect in MCF-7 subcutaneous xenograft models.

Conclusions

Oct-modified co-delivery system may have great potential as an effective carrier for cancer therapy.

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Abbreviations

AUC:

area under the plasma concentration-time curve

CA-4:

combretastatin A-4

CA-4P:

combretastatin A-4 phosphate

DDS:

drug delivery system

DOX:

doxorubicin

DSPE-PEG (PEG Mw 2000):

1.2-distearoyl-sn-glycero-3-phosphoethanola mine-N-[poly(ethylene-glycol)]

DSPE-PEG-Oct:

conjugate of octreotide with DSPE-PEG

EPC:

egg phosphatidylcholine

FBS:

fetal bovine serum

IC50 :

50% inhibitory concentration

K :

elimination rate constant

L[C]:

liposomes encapsulating CA-4

L[CD]:

liposomes encapsulating both CA-4 and DOX

L[D]:

liposomes encapsulating DOX

Oct:

octreotide

Oct-L[CD]:

octreotide-targeted liposomes encapsulating both CA-4 and DOX

PBS:

phosphate buffered saline

PD:

pharmacodynamics

PDI:

polydispersity index

PK:

pharmacokinetics

SRB:

sulforhodamine B

SSTR2:

somatostatin receptor subtype 2

SSTRs:

somatostatin receptors

T1/2 :

plasma half-life

TEM:

transmission electron microscope

VDAs:

vascular disrupting agents

VEGF:

vascular endothelial growth factor

REFERENCES

  1. Lisa BP, James OB. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev. 2004;56:1649–59.

    Article  Google Scholar 

  2. Zhang L, Radovic-Moreno AF, Alexis F, Gu FX, Basto PA, Bagalkot V, Jon S, Langer RS, Farokhzad OC. Co-delivery of hydrophobic and hydrophilic drugs from nanoparticle-aptamer bioconjugates. Chem Med Chem. 2007;2:1268–71.

    PubMed  CAS  Google Scholar 

  3. Mitragotris S. Synergistic effect of enhancers for transdermal drug delivery. Pharm Res. 2000;17:1354–59.

    Article  Google Scholar 

  4. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29:15–8.

    PubMed  CAS  Google Scholar 

  5. Siemann DW, Chaplin DJ, Horsman MR. Vascular-targeting therapies for treatment of malignant disease. Cancer. 2004;100:2491–97.

    Article  PubMed  CAS  Google Scholar 

  6. Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004;10:415–27.

    Article  PubMed  Google Scholar 

  7. Dziba JM, Marcinek R, Venkataraman G, Robinson JA, Ain KB. Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors. Thyroid. 2002;12:1063–70.

    Article  PubMed  CAS  Google Scholar 

  8. Nelkin BD, Ball DW. Combretastatin A-4 and doxorubicin combination treatment is effective in a preclinical model of human medullary thyroid carcinoma. Oncol Rep. 2001;8:157–60.

    PubMed  CAS  Google Scholar 

  9. Yeung SC, She M, Yang H, Pan J, Sun L, Chaplin D. Combination chemotherapy including combretastatin A4 phosphate and paclitaxel is effective against anaplastic thyroid cancer in a nude mouse xenograft model. J Clin Endocrinol Metab. 2007;92:2902–09.

    Article  PubMed  CAS  Google Scholar 

  10. Verheul HMW, Voest EE, Schlingemann RO. Are tumours angiogenesis-depent? J Pathol. 2004;202:5–13.

    Article  PubMed  CAS  Google Scholar 

  11. Lee SM, Woll PJ, Rudd R, Ferry D, O’Brien M, Middleton G, Spiro S, James L, Ali K, Jitlal M, Hackshaw A. Anti-angiogenic therapy using thalidomide combined with chemotherapy in small cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst. 2009;101:1049–57.

    Article  PubMed  CAS  Google Scholar 

  12. Sapra P, Tyagi P, Allen TM. Ligand-targeted liposomes for cancer treatment. Curr Drug Deliv. 2005;2:368–81.

    Article  Google Scholar 

  13. Bauer W, Briner U, Doepfner W, Haller R, Huguenin R, Marbach P, Petcher TJ, Pless J. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 1982;31:1133–40.

    Article  PubMed  CAS  Google Scholar 

  14. Reubi JC, Kvols L, Krenning E, Lamberts SW. Distribution of somatotatin receptors in normal and tumor tissue. Metabolism. 1990;39:78–81.

    Article  PubMed  CAS  Google Scholar 

  15. Volante M, Rosas R, Allia E, Granata R, Baragli A, Muccioli G, Papotti M. Somatostatin, cortistatin and their receptors in tumours. Mol Cell Endocrinol. 2008;286:219–29.

    Article  PubMed  CAS  Google Scholar 

  16. Wild D, Schmitt JS, Ginj M, Mäcke HR, Bernard BF, Krenning E, De Jong M, Wenger S, Reubi JC. DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals. Eur J Nucl Med Mol Imaging. 2003;30:1338–47.

    Article  PubMed  CAS  Google Scholar 

  17. Ginj M, Schmitt JS, Chen J, Waser B, Reubi JC, de Jong M, Schulz S, Maecke HR. Design, synthesis, and biological evaluation of somatostatin-based radiopeptides. Chem Biol. 2006;13:1081–90.

    Article  PubMed  CAS  Google Scholar 

  18. Shen H, Hu D, Du J, Wang X, Liu Y, Wang Y, Wei JM, Ma D, Wang P, Li L. Paclitaxel–octreotide conjugates in tumor growth inhibition of A549 human non-small cell lung cancer xenografted into nude mice. Eur J Pharmacol. 2008;601:23–9.

    Article  PubMed  CAS  Google Scholar 

  19. Lasfer M, Vadrot N, Schally AV, Nagy A, Halmos G, Pessayre D, Feldmann G, Reyl-Desmars FJ. Potent induction of apoptosis in human hepatoma cell lines by targeted cytotoxic somatostatin analogue AN-238. J Hepatol. 2005;42:230–37.

    Article  PubMed  CAS  Google Scholar 

  20. Moody TW, Fuselier J, Coy DH, Mantey S, Pradhan T, Nakagawa T, Jensen RT. Camptothecin-somatostatin conjugates inhibit the growth of small cell lung cancer cells. Peptides. 2005;26:1560–66.

    Article  PubMed  CAS  Google Scholar 

  21. Zhang YF, Wang JC, Bian DY, Zhang X, Zhang Q. Targeted delivery of RGD-modified liposomes encapsulating both combretastatin A-4 and doxorubicin for tumor therapy: In vitro and in vivo studies. Eur J Pharm Biopharm. 2010;74:467–73.

    Article  PubMed  CAS  Google Scholar 

  22. Sengupta S, Eavarone D, Capila I, Zhao G, Watson N, Kiziltepe T, Sasisekharan R. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature. 2005;436:568–72.

    Article  PubMed  CAS  Google Scholar 

  23. Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;1:1112–16.

    Article  PubMed  CAS  Google Scholar 

  24. Zhang J, ** W, Wang X, Wang J, Zhang X, Zhang Q. A novel octreotide modified lipid vesicle improved the anticancer efficacy of doxorubicin in somatostatin receptor 2 positive tumor models. Mol Pharm. 2010;7:1159–68.

    Article  PubMed  Google Scholar 

  25. Zhang Y, Wang X, Wang J, Zhang X, Zhang Q. Octreotide-modified polymeric micelles as potential carriers for targeted docetaxel delivery to somatostatin receptor overexpressing tumor cells. Pharm Res. 2011;28:1167–78.

    Article  PubMed  CAS  Google Scholar 

  26. Sun M, Wang Y, Shen J, **ao Y, Su Z, ** Q. Octreotide-modification enhances the delivery and targeting of doxorubicin-loaded liposomes to somatostatin receptors expressing tumor in vitro and in vivo. Nanotechnology. 2010;21:475101–12.

    Article  PubMed  Google Scholar 

  27. Fritze A, Hens F, Kimpfler A, Schubert R, Peschka-Süss R. Remote loading of doxorubicin into nanoliposomes driven by a transmembrane phosphate gradient. Biochim Biophys Acta. 2006;1758:1633–40.

    Article  PubMed  CAS  Google Scholar 

  28. Gu F, Zhang L, Teply BA, Mann N, Wang A, Radovic-Moreno AF, Langer R, Farokhzad OC. Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc Natl Acad Sci USA. 2008;105:2586–91.

    Article  PubMed  CAS  Google Scholar 

  29. Cairo CW, Gestwicki JE, Kanai M, Kiessling LL. Control of multivalent interactions by binding epitope density. J Am Chem Soc. 2002;124:1615–19.

    Article  PubMed  CAS  Google Scholar 

  30. Jule E, Nagasaki Y, Kataoka K. Lactose-installed poly(ethylene glycol)-poly(d, l-lactide) block copolymer micelles exhibit fast-rate binding and high affinity toward a protein bed simulating a cell surface. A surface plasmon resonance study. Bioconjug Chem. 2003;14:177–86.

    Article  PubMed  CAS  Google Scholar 

  31. Emanuel N, Kedar E, Bolotin E, Smorodinsky NI, Barenholz Y. Targeted delivery of doxorubicin via sterically stabilized immunoliposomes: pharmacokinetics and biodistribution in tumor-bearing mice. Pharm Res. 1996;13:861–68.

    Article  PubMed  CAS  Google Scholar 

  32. Turka MJ, Watersb DJ, Low PS. Folate-conjugated liposomes preferentially target macrophages associated with ovarian carcinoma. Cancer Lett. 2004;213:165–72.

    Article  Google Scholar 

  33. Linuma H, Maruyama K, Okinaga K. Intracellular targeting therapy of cisplatin-encapsulated transferrin-polyethylene glycol liposomes on peritoneal dissemination of gastric cancer. Int J Cancer. 2002;299:130–37.

    Google Scholar 

  34. Mayer LD, Bally MB, Cullis PR, Wilson SL, Emerman JT. Comparison of free and liposome encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SC115 murine. Cancer Lett. 1990;53(2–3):183–90.

    Article  PubMed  CAS  Google Scholar 

  35. Lu WL, Qi XR, Zhang Q, Li RY, Wang GL, Zhang RJ, Wei SL. A pegylated liposomal platform: pharmacokinetics, pharmacodynamics, and toxicity in mice using doxorubicin as a model drug. J Pharmacol Sci. 2004;95(3):381–9.

    Article  PubMed  CAS  Google Scholar 

  36. Gabizon AA. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest. 2001;19(4):424–36.

    Article  PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by the National Nature Science Foundation (No.81130059), National Basic Research Program of China (No. 2009CB930300).

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Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences, Peking University, Bei**g, 100191, People’s Republic of China

    Wenbing Dai, Wu **, Junlin Zhang, Xueqing Wang, Jiancheng Wang, Xuan Zhang & Qiang Zhang

  2. Neuroscience Research Institute, Department of Neurobiology School of Basic Medical Sciences, Peking University, Bei**g, 100191, People’s Republic of China

    Wenbing Dai & You Wan

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  1. Wenbing Dai
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  2. Wu **
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  3. Junlin Zhang
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Correspondence to Qiang Zhang.

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Dai, W., **, W., Zhang, J. et al. Spatiotemporally Controlled Co-delivery of Anti-vasculature Agent and Cytotoxic Drug by Octreotide-Modified Stealth Liposomes. Pharm Res 29, 2902–2911 (2012). https://doi.org/10.1007/s11095-012-0797-2

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  • DOI: https://doi.org/10.1007/s11095-012-0797-2

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