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

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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.

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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

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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.

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Authors and Affiliations

  1. Institut Galien Paris-Sud, CNRS UMR 8612, Université Paris-Sud, 5 rue Jean Baptiste Clément, 92296, Chatenay-Malabry, France

    Laura de Miguel, Iuliana Popa, Magali Noiray, Ludovica Arpinati, Didier Desmaele & Gilles Ponchel

  2. Hôpital Européen Georges Pompidou (AP-HP), Service de Pharmacie, Paris, France

    Eric Caudron

  3. Paris Sud Analytical Chemistry Group, School of Pharmacy, Université Paris-Sud, 5 rue Jean Baptiste Clément, Châtenay-Malabry, France

    Eric Caudron

  4. Departament de Química Analítica, Facultat de Química, Universitat de València, Dr. Moliner 50, 46100, Burjassot, Valencia, Spain

    Gerardo Cebrián-Torrejón & Antonio Doménech-Carbó

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  1. Laura de Miguel
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Correspondence to Laura de Miguel.

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de Miguel, L., Popa, I., Noiray, M. et al. Osteotropic Polypeptide Nanoparticles with Dual hydroxyapatite Binding Properties and Controlled Cisplatin Delivery. Pharm Res 32, 1794–1803 (2015). https://doi.org/10.1007/s11095-014-1576-z

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  • DOI: https://doi.org/10.1007/s11095-014-1576-z

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