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Pharmaceutical Research

, Volume 32, Issue 5, pp 1794–1803 | Cite as

Osteotropic Polypeptide Nanoparticles with Dual hydroxyapatite Binding Properties and Controlled Cisplatin Delivery

  • Laura de Miguel
  • Iuliana Popa
  • Magali Noiray
  • Eric Caudron
  • Ludovica Arpinati
  • Didier Desmaele
  • Gerardo Cebrián-Torrejón
  • Antonio Doménech-Carbó
  • Gilles Ponchel
Research Paper

Abstract

Purpose

Nanoparticles with prolonged residence time in bone constitute a valuable strategy for bone disease treatments. The aim of this work was to synthesise a simple nanoparticulate system exhibiting both anticancer and hydroxyapatite binding properties for potential bone cancer applications.

Methods

The amphiphilic copolymer poly(γ-benzyl-glutamate)-block-poly(glutamic acid) (PBLG-b-PGlu) was synthetised by ring opening polymerization and nanoparticles were obtained by a simple nanoprecipitation method. Nanoparticles were characterized in terms of cisplatin interaction, association, and release as well as interaction with hydroxyapatite and their cytoxicity was studied in three prostate cancer cell lines.

Results

PBLG-b-PGlu nanoparticles of ~50 nm in size were successfully prepared. They could display for the first time dual hydroxyapatite binding and anticancer properties mediated by the PGlu moiety. They could complex cisplatin at a drug loading content of 6.2% (w/w). Cisplatin release was triggered by physiological concentrations of chloride ions according to an almost zero order kinetics during 14 days. Simultaneously, these nanoparticles showed in vitro hydroxyapatite binding. Finally, they were shown to exert a cytotoxic effect in three prostate cancer cell lines that potentially metastasize to bone.

Conclusions

These properties suggest the potential utility of cisplatin-loaded PBLG-b-PGlu nanoparticles as carrier systems for the treatment of bone metastases.

KEY WORDS

cisplatin hydroxyapatite nanoparticles poly(benzylglutamate) poly(glutamic acid) 

ABBREVIATIONS

AAS

Atomic absorption spectroscopy

BLG-NCA

γ-benzyl-L-glutamate-N-carboxylic anhydride

CDCl3

Deuterated chloroform

CDDP

Cisplatin

DLS

Dynamic light scattering

DMF

Dimethylformamide

DPn

Degree of polymerization

FTIR

Fourier transform infrared spectroscopy

H NMR

Proton nuclear magnetic resonance

HAP

Hydroxyapatite

ITC

Isothermal titration calorimetry

MTS

([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H tetrazolium, inner salt)

PBLG-b-PGlu

Poly(γ-benzyl-glutamate)-block-poly(glutamic acid)

PBS

Phosphate buffer saline

ROP

Ring opening polymerization

SEC

Size exclusion chromatography

TEM

Transmission Electron Microscopy

TFA

Trifluoroacetic acid

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

We gratefully acknowledge the European postgraduate program from “Ibercaja Foundation” for the financial support of Laura de Miguel. This work has benefited from the facilities and expertise of the Platform for Transmission Electronic Microscopy of IMAGIF (Centre de Recherche de Gif - www.imagif.cnrs.fr) and we thank Miss Cynthia Gillet for her valuable help with the TEM image acquisitions. We thank Dr Silvia Mazzaferro and LCPO, Univ. Bordeaux, CNRS, UMR 5629 for the SEC analyses.

Supplementary material

11095_2014_1576_MOESM1_ESM.docx (25.7 mb)
ESM 1 (DOCX 25.7 Mb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Laura de Miguel
    • 1
  • Iuliana Popa
    • 1
  • Magali Noiray
    • 1
  • Eric Caudron
    • 2
    • 3
  • Ludovica Arpinati
    • 1
  • Didier Desmaele
    • 1
  • Gerardo Cebrián-Torrejón
    • 4
  • Antonio Doménech-Carbó
    • 4
  • Gilles Ponchel
    • 1
  1. 1.Institut Galien Paris-SudCNRS UMR 8612, Université Paris-SudChatenay-MalabryFrance
  2. 2.Hôpital Européen Georges Pompidou (AP-HP), Service de PharmacieParisFrance
  3. 3.Paris Sud Analytical Chemistry GroupSchool of Pharmacy, Université Paris-SudChâtenay-MalabryFrance
  4. 4.Departament de Química Analítica, Facultat de QuímicaUniversitat de ValènciaBurjassotSpain

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