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A method to Quantify the Affinity of Cabazitaxel for PLA-PEG Nanoparticles and Investigate the Influence of the Nano-Assembly Structure on the Drug/Particle Association

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Abstract

Purpose

To study the impact of the size and the structure of the nano-assembly on the drug/particle association, determining the intrinsic partition coefficient, in order to better master the encapsulation and release properties of the carrier.

Methods

An experimental methodology is proposed to characterize the drug/nanoparticle association by mean of a partition coefficient between the PLA-PEG nanoparticles and the suspending aqueous medium, referred to as Kp. The determination was made from apparent values (referred to as Kp ap) measured in the presence of solubilizing agents (albumin and hydroxypropyl-βcyclodextrin) and extrapolation to zero concentration. The structure of nanoparticles was investigated by Transmission Electron Microscopy and static light scattering.

Results

Depending on the manufacturing process and the PEG length of the copolymer, the nanoparticles structured either as aggregates of copolymer chains or micelles exhibiting significantly different Kp values.

Conclusion

The methodological tool described here showed that the difference in cabazitaxel/nanoparticle association between aggregates and micelles could be attributed to the difference in PLA-PEG chains packing.

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Abbreviations

a:

Length of the lactide monomer repeat unit nm

a2 :

Excluded volume of the particle nm3

C BSA susp :

Concentration of albumin in the external phase mol/L

C drug bound :

Concentration of drug bound to the solubilizing agent mg/mL

C drug diss :

Concentration of drug solubilized in water and associated to the solubilizing agent mg/mL

C drug free :

Concentration of free drug in the external phase mg/mL

C drug tot :

Total concentration of drug mg/mL

C HPβCD susp :

Concentration of HPβCD in the external phase mol/L

CNaDoc :

Concentration of sodium deoxycholate mg/mL

C PLA − PEG susp :

Concentration of PLA-PEG in the suspension mg/mL

C PLA ‐ PEG Acetone :

Concentration of PLA-PEG in acetone mg/mL

C PLA ‐ PEG CH2Cl2 :

Concentration of PLA-PEG in methylene chloride mg/mL

C solub susp :

Concentration of solubilizing agent in the suspension mol/L

D:

Coefficient of diffusion of nanoparticle nm2/s

dH :

Hydrodynamic diameternm

dn/dc:

Specific refractive index increment of the PLA-PEG nanoparticles mL/g

dPLA-PEG :

Bulk density of solid PLA-PEG g/cm3

η:

Viscosity of the dispersed medium of nanoparticles Pa.s

g:

Correlation function of diffusion

Itol :

Intensity of light scattered from a toluene solution, used as a reference

INP :

Intensity of light scattered from the dispersion

K′:

Optical constant mol.cm3/g2

Kd :

Dissolution constant mol/L

Kp :

Partition coefficient between nanoparticle and water

Kp ap :

Partition coefficient between nanoparticle and aqueous phase, containing the solubilizing agent

MA2 :

Second Virial coefficient cm3/g

m drug encaps :

Mass of encapsulated cabazitaxel mg

Mn PLA-PEG :

Average molecular weight of PLA-PEG g/mol

Mw NP :

Average molecular weight of nanoparticles g/mol

NA :

Avogadro’s number mol−1

Nagg :

Aggregation number of nanoparticle

NPEG :

Number of monomer units on PEG

NPLA :

Number of monomer units on PLA

ntol :

Refractive index of toluene

PDI:

Polydispersity index

q:

Scattering vector nm−1

Rcore :

Core radius of PLA-PEG micelle nm

Rg :

Radius of gyration of PLA-PEG nanoparticles nm

RH :

Hydrodynamic radius of PLA-PEG nanoparticles nm

Rtol :

Rayleigh ratio of toluene cm−1

S caba in solub :

Maximal solubility of cabazitaxel in solubilizing agent μg/mL

Vext :

Volume of the external phase mL

Vint :

Total volume of nanoparticles mL

V PLA − PEG :

Volume occupied by one PLA-PEG chain inside the nanoparticle nm3/molec

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ACKNOWLEDGMENTS AND DISCLOSURES

The post-doctorate fellowship of Odile Diou was financed by Sanofi. The authors would like to thank Guillaume Louit (Sanofi, Vitry sur Seine) for fruitful advices about partition experiments, Jean Alie (Sanofi, Montpellier) for TEM observations and Eric Didier (Sanofi, Vitry sur Seine) for synthesizing PLA-PEG copolymers. The authors acknowledge Thierry Verrecchia who did pioneering experiments on partition coefficient during his Pharm D thesis in 1998.

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Authors and Affiliations

  1. Sanofi Research and Development, Lead Generation to Candidate Realization Platform, 13 Quai Jules Guesde, 94403, Vitry-sur-Seine, France

    O. Diou, S. Greco, T. Beltran, J.-R. Authelin & D. Bazile

  2. Laboratoire Léon Brillouin, CEA Saclay, Gif-sur-Yvette Cedex, 91191, France

    D. Lairez

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  1. O. Diou
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  2. S. Greco
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  5. J.-R. Authelin
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  6. D. Bazile
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Correspondence to D. Bazile.

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Diou, O., Greco, S., Beltran, T. et al. A method to Quantify the Affinity of Cabazitaxel for PLA-PEG Nanoparticles and Investigate the Influence of the Nano-Assembly Structure on the Drug/Particle Association. Pharm Res 32, 3188–3200 (2015). https://doi.org/10.1007/s11095-015-1696-0

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