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Pharmaceutical Research

, Volume 31, Issue 4, pp 983–991 | Cite as

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

  • Hugo OliveiraEmail author
  • Julie Thevenot
  • Elisabeth Garanger
  • Emmanuel Ibarboure
  • Pilar Calvo
  • Pablo Aviles
  • Maria Jose Guillen
  • Sébastien LecommandouxEmail author
Research Paper

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.

Key words

cancer therapy drug delivery nanomedicine plitidepsin polymersomes 

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

Notes

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).

Supplementary material

11095_2013_1220_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1286 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Hugo Oliveira
    • 2
    • 3
    • 4
    Email author
  • Julie Thevenot
    • 2
    • 3
  • Elisabeth Garanger
    • 2
    • 3
  • Emmanuel Ibarboure
    • 2
    • 3
  • Pilar Calvo
    • 1
  • Pablo Aviles
    • 1
  • Maria Jose Guillen
    • 1
  • Sébastien Lecommandoux
    • 2
    • 3
    Email author
  1. 1.Pharma Mar S.A., Sociedad UnipersonalMadridSpain
  2. 2.Université de Bordeaux/IPB, ENSCBPPessac CedexFrance
  3. 3.CNRS, Laboratoire de Chimie des Polymères Organiques (UMR5629)Pessac CedexFrance
  4. 4.BIOTIS, Inserm U1026Bordeaux CedexFrance

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