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Nano-Encapsulation of Plitidepsin: In Vivo Pharmacokinetics, Biodistribution, and Efficacy in a Renal Xenograft Tumor Model

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Abstract

Purpose

Plitidepsin is an antineoplasic currently in clinical evaluation in a phase III trial in multiple myeloma (ADMYRE). Presently, the hydrophobic drug plitidepsin is formulated using Cremophor®, an adjuvant associated with unwanted hypersensitivity reactions. In search of alternatives, we developed and tested two nanoparticle-based formulations of plitidepsin, aiming to modify/improve drug biodistribution and efficacy.

Methods

Using nanoprecipitation, plitidepsin was loaded in polymer nanoparticles made of amphiphilic block copolymers (i.e. PEG-b-PBLG or PTMC-b-PGA). The pharmacokinetics, biodistribution and therapeutic efficacy was assessed using a xenograft renal cancer mouse model (MRI-H-121 xenograft) upon administration of the different plitidepsin formulations at maximum tolerated multiple doses (0.20 and 0.25 mg/kg for Cremophor® and copolymer formulations, respectively).

Results

High plitidepsin loading efficiencies were obtained for both copolymer formulations. Considering pharmacokinetics, PEG-b-PBLG formulation showed lower plasma clearance, associated with higher AUC and Cmax than Cremophor® or PTMC-b-PGA formulations. Additionally, the PEG-b-PBLG formulation presented lower liver and kidney accumulation compared with the other two formulations, associated with an equivalent tumor distribution. Regarding the anticancer activity, all formulations elicited similar efficacy profiles, as compared to the Cremophor® formulation, successfully reducing tumor growth rate.

Conclusions

Although the nanoparticle formulations present equivalent anticancer activity, compared to the Cremophor® formulation, they show improved biodistribution profiles, presenting novel tools for future plitidepsin-based therapies.

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Abbreviations

CEW:

Cremophor®:Ethanol:Water (15:15:70 v/v%)

CLp:

Clearance

Cmax:

Maximum concentration

CRE:

Cremophor®

FWR:

Feed Weight Ratio

HPLC:

High performance liquid chromatography

iv.:

Intravenous

LC:

Loading content

LE:

Loading efficiency

MTD:

Maximum tolerated dose

PEG-b-PBLG:

Poly(ethylene glycol)-block-poly(γ-benzyl-L-glutamate)

PTMC-b-PGA:

Poly(trimethylene carbonate)-block-poly(glutamic acid)

SD:

Standard deviation

t1/2:

Terminal half-life time

Vdss:

Apparent volume of distribution at steady state

References

  1. Davis ME, Chen ZG, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 2008;7:771–82.

    Article  CAS  PubMed  Google Scholar 

  2. Alexis F, Pridgen EM, Langer R, Farokhzad OC. Nanoparticle technologies for cancer therapy. Handb Exp Pharmacol. 2010;197:55–86.

    Google Scholar 

  3. De Oliveira H, Thevenot J, Lecommandoux S. Smart polymersomes for therapy and diagnosis: fast progress toward multifunctional biomimetic nanomedicines. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012;4:525–46.

    Article  PubMed  Google Scholar 

  4. Rinehart K, Lithgow-Berelloni AM. Novel antiviral and cytotoxic agent. PCT Int. Pat. Appl. WO 91.04985, Apr. 18, 1991K; GB Appl. 89/22,026, Sept, 515 29, 1989; International patent number:115:248086q.

  5. Mitsiades CS, Ocio EM, Pandiella A, Maiso P, Gajate C, Garayoa M, et al. Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo. Cancer Res. 2008;68:5216–25.

    Article  CAS  PubMed  Google Scholar 

  6. Caers J, Menu E, De Raeve H, Lepage D, Van Valckenborgh E, Van Camp B, et al. Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic models of multiple myeloma. Br J Cancer. 2008;98:1966–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Straight AM, Oakley K, Moores R, Bauer AJ, Patel A, Tuttle RM, et al. Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes. Cancer Chemother Pharmacol. 2006;57:7–14.

    Article  CAS  PubMed  Google Scholar 

  8. Gonzalez-Santiago L, Suarez Y, Zarich N, Munoz-Alonso MJ, Cuadrado A, Martinez T, et al. Aplidin induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation. Cell Death Differ. 2006;13:1968–81.

    Article  CAS  PubMed  Google Scholar 

  9. Garcia-Fernandez LF, Losada A, Alcaide V, Alvarez AM, Cuadrado A, Gonzalez L, et al. Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C delta. Oncogene. 2002;21:7533–44.

    Article  CAS  PubMed  Google Scholar 

  10. Cuadrado A, Gonzalez L, Suarez Y, Martinez T, Munoz A. JNK activation is critical for Aplidin-induced apoptosis. Oncogene. 2004;23:4673–80.

    Article  CAS  PubMed  Google Scholar 

  11. Faivre S, Chieze S, Delbaldo C, Ady-Vago N, Guzman C, Lopez-Lazaro L, et al. Phase I and pharmacokinetic study of aplidine, a new marine cyclodepsipeptide in patients with advanced malignancies. J Clin Oncol. 2005;23:7871–80.

    Article  CAS  PubMed  Google Scholar 

  12. Maroun JA, Belanger K, Seymour L, Matthews S, Roach J, Dionne J, et al. Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115. Ann Oncol. 2006;17:1371–8.

    Article  CAS  PubMed  Google Scholar 

  13. Izquierdo MA, Bowman A, Garcia M, Jodrell D, Martinez M, Pardo B, et al. Phase I clinical and pharmacokinetic study of plitidepsin as a 1-hour weekly intravenous infusion in patients with advanced solid tumors. Clin Cancer Res. 2008;14:3105–12.

    Article  CAS  PubMed  Google Scholar 

  14. Schoffski P, Guillem V, Garcia M, Rivera F, Tabernero J, Cullell M, et al. Phase II randomized study of Plitidepsin (Aplidin), alone or in association with L-carnitine, in patients with unresectable advanced renal cell carcinoma. Mar Drugs. 2009;7:57–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Eisen T, Thatcher N, Leyvraz S, Miller Jr WH, Couture F, Lorigan P, et al. Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer. Lung Cancer. 2009;64:60–5.

    Article  PubMed  Google Scholar 

  16. Eisen T, Thomas J, Miller Jr WH, Gore M, Wolter P, Kavan P, et al. Phase II study of biweekly plitidepsin as second-line therapy in patients with advanced malignant melanoma. Melanoma Res. 2009;19:185–92.

    Article  CAS  PubMed  Google Scholar 

  17. Dumez H, Gallardo E, Culine S, Galceran JC, Schoffski P, Droz JP, et al. Phase II study of biweekly plitidepsin as second-line therapy for advanced or metastatic transitional cell carcinoma of the urothelium. Mar Drugs. 2009;7:451–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Baudin E, Droz JP, Paz-Ares L, van Oosterom AT, Cullell-Young M, Schlumberger M. Phase II study of plitidepsin 3-hour infusion every 2 weeks in patients with unresectable advanced medullary thyroid carcinoma. Am J Clin Oncol. 2010;33:83–8.

    Article  CAS  PubMed  Google Scholar 

  19. Peschel C, Hartmann JT, Schmittel A, Bokemeyer C, Schneller F, Keilholz U, et al. Phase II study of plitidepsin in pretreated patients with locally advanced or metastatic non-small cell lung cancer. Lung Cancer. 2008;60:374–80.

    Article  PubMed  Google Scholar 

  20. Mateos MV, Cibeira MT, Richardson PG, Prosper F, Oriol A, de la Rubia J, et al. Phase II clinical and pharmacokinetic study of plitidepsin 3-hour infusion every two weeks alone or with dexamethasone in relapsed and refractory multiple myeloma. Clin Cancer Res. 2010;16:3260–9.

    Article  CAS  PubMed  Google Scholar 

  21. Ribrag V, Caballero D, Ferme C, Zucca E, Arranz R, Briones J, et al. Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin’s lymphoma. Haematologica. 2013;98(3):357–63.

    Google Scholar 

  22. Weiss RB, Donehower RC, Wiernik PH, Ohnuma T, Gralla RJ, Trump DL, et al. Hypersensitivity reactions from taxol. J Clin Oncol. 1990;8:1263–8.

    CAS  PubMed  Google Scholar 

  23. Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37:1590–8.

    Article  CAS  PubMed  Google Scholar 

  24. Bristol-Myers Squibb Co. Princeton. Taxol® (paclitaxel) Injection. March 2003. Available from: http://www.acessdata.fda.

  25. Bazile D, Prud’homme C, Bassoullet MT, Marlard M, Spenlehauer G, Veillard M. Stealth Me.PEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system. J Pharm Sci. 1995;84:493–8.

    Article  CAS  PubMed  Google Scholar 

  26. Nuijen B, Bouma M, Henrar RE, Manada C, Bult A, Beijnen JH. Compatibility and stability of aplidine, a novel marine-derived depsipeptide antitumor agent, in infusion devices, and its hemolytic and precipitation potential upon i.v. administration. Anticancer Drugs. 1999;10:879–87.

    Article  CAS  PubMed  Google Scholar 

  27. Barbosa MEM, Montembault V, Cammas-Marion S, Ponchel G, Fontaine L. Synthesis and characterization of novel poly(γ-benzyl-L-glutamate) derivatives tailored for the preparation of nanoparticles of pharmaceutical interest. Polym Int. 2007;56:317–24.

    Article  CAS  Google Scholar 

  28. Sanson C, Schatz C, Le Meins J-FO, Brûlet A, Soum A, Lecommandoux SB. Biocompatible and Biodegradable Poly(trimethylene carbonate)-b-Poly(l-glutamic acid) Polymersomes: Size Control and Stability. Langmuir. 2009;26:2751–60.

    Article  Google Scholar 

  29. 3rd Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307:93–102.

    Article  CAS  PubMed  Google Scholar 

  30. Gonzalo T, Lollo G, Garcia-Fuentes M, Torres D, Correa J, Riguera R, et al. A new potential nano-oncological therapy based on polyamino acid nanocapsules. J Control Release. 2013;169:10–6.

    Article  CAS  PubMed  Google Scholar 

  31. Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, et al. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci U S A. 1991;88:11460–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R. Biodegradable long-circulating polymeric nanospheres. Science. 1994;263:1600–3.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments AND DISCLOSURES

This work was supported by funding from the European Commission under the seventh framework within the frame of the NanoTher project (Integration of novel NANOparticle based technology for THERapeutics and diagnosis of different types of cancer CP-IP 213631–2).

Author information

Author notes

  1. Hugo Oliveira

    Present address: BIOTIS, Inserm U1026, Zone Nord, Bât. 4a, 2ème étage, 146 rue Léo Saignat, 33076, Bordeaux Cedex, France

Authors and Affiliations

  1. Pharma Mar S.A., Sociedad Unipersonal, Colmenar Viejo, Madrid, Spain

    Pilar Calvo, Pablo Aviles & Maria Jose Guillen

  2. Université de Bordeaux/IPB, ENSCBP, 16 avenue Pey Berland, 33607, Pessac Cedex, France

    Hugo Oliveira, Julie Thevenot, Elisabeth Garanger, Emmanuel Ibarboure & Sébastien Lecommandoux

  3. CNRS, Laboratoire de Chimie des Polymères Organiques (UMR5629), 16 Avenue Pey Berland, 33607, Pessac Cedex, France

    Hugo Oliveira, Julie Thevenot, Elisabeth Garanger, Emmanuel Ibarboure & Sébastien Lecommandoux

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  1. Hugo Oliveira
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Correspondence to Hugo Oliveira or Sébastien Lecommandoux.

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Oliveira, H., Thevenot, J., Garanger, E. et al. Nano-Encapsulation of Plitidepsin: In Vivo Pharmacokinetics, Biodistribution, and Efficacy in a Renal Xenograft Tumor Model. Pharm Res 31, 983–991 (2014). https://doi.org/10.1007/s11095-013-1220-3

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  • DOI: https://doi.org/10.1007/s11095-013-1220-3

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