Colloidal stability of Pluronic F68-coated PLGA nanoparticles: A variety of stabilisation mechanisms

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Abstract

Poloxamers are a family of polypropylene oxide (PPO) and polyethylene oxide (PEO) tri-block copolymers that are usually employed in the micro- and nanoparticulate engineering for drug delivery systems. The aim of this work is to study the electrophoretic mobility (μe) and colloidal stability of complexes formed by adsorbing a poloxamer (Pluronic F68) onto poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles. A variety of stabilisation mechanisms have been observed for the Pluronic-coated PLGA nanoparticles, where DLVO interactions, solvent–polymer segment interactions and hydration forces play different roles as a function of the adsorbed amount of Pluronic. In addition, the μe and stability data of these complexes have been compared to those obtained previously using a PLGA–Pluronic F68 blend formulation. As both the μe and the stability data are identical between the two systems, a phase separation of both components in the PLGA–Pluronic blend formulation is suggested, being the PLGA located in the core of the particles and the Pluronic in an adsorbed shell.

Introduction

The use of adsorbing macromolecules to modify the aggregation state, sedimentation behaviour, and rheological properties of colloidal dispersions represents an industrially significant, although largely empirical, technology [1]. The pharmaceutical industry also develops and works with colloidal systems for drug delivery purposes. In this case, any successful pharmaceutical application requires adjustment of the surface properties of the polymeric drug delivery system to be compatible with the biological environment. Thus, the use of biocompatible macromolecules adsorbed onto biodegradable nanoparticles is necessary, not only to avoid spontaneous particle aggregation under certain physico-chemical conditions of pH, ionic strength and temperature, but also to prevent the rapid uptake of intravenously injected particulate drug carriers by the cells of the reticuloendothelial system [2]. It has been proven that surface modification of the carriers by adsorption of non-ionic amphiphilic macromolecules (i.e., poloxamers, poloxamines or PEG derivatives) helps to overcome such a drawback [3]. In addition, the presence of these macromolecules in the drug carrier composition may also help to improve the release of the encapsulated materials (drugs, proteins, DNA, and so on) and even protects the proteins encapsulated into the carriers against partial or total denaturation [4], [5]. This protective action can be explained as follows. The PLGA degradation is governed by hydrolytic processes and leads to the formation of acidic oligo- and monomers that cause an acidic microclimate. The use of protective excipients (i.e., polaxamers and poloxamines) could possibly prevent unwanted interactions between the drug and the PLGA as well as neutralise the acidity generated in the course of polymer degradation.

Although adsorption of this kind of surfactants is the most wide known procedure to modify the surface characteristics of the primitive carriers, the incorporation of these copolymers into the particles during the manufacturing process has become an alternative strategy. Successful incorporation of polypropylene oxide–polyethylene oxide (PPO–PEO) copolymers into poly(d,l-lactic-co-glycolic acid) (PLGA) particles has been recently reported [5], [6]. The extent of incorporation depends strongly on both the hydrophobic/hydrophilic degree of the carrier matrix and the hydrophilia–lipophilia balance (HLB) values of the PPO–PEO-derivatives. Therefore, whereas the incorporation of surfactants with high hydrophilicity (high HLB values) into hydrophobic nanoparticle matrixes is probably limited, an effective mixture and homogeneous distribution would be expected for surfactants with large hydrophobic and short hydrophilic moieties (low HLB values). This statement have been recently confirmed by Kiss et al. [7], [8] who have studied the distribution of different poloxamers (Pluronics) into poly(lactic acid) (PLA) and PLGA blend films.

In the present work, the adsorption of Pluronic F68 on PLGA nanoparticles has been studied and, subsequently, the electrophoretic mobility (μe) and colloidal stability of these complexes have been analysed. As will be shown, different stability mechanisms have been observed as a function of the surfactant coverage, which suggests different spatial conformations of the poloxamer molecules in the adsorbed layer. In addition, a comparison between the μe and stability of our complexes with those of other particles obtained in another work [9] (where they were manufactured by simultaneously mixing PLGA and Pluronic F68 during the formulation of the particles) is presented. As electrophoretic mobility and colloidal stability are exclusively dependent on the surface characteristics, the comparison may help us to gain an insight into the exact location of the polyoxide copolymers in the blend formulations. That is, if pure PLGA particles covered by Pluronic and blended PLGA–Pluronic particles present similar mobility and stability properties, it could be inferred that, in the blend formulation, a large part of the poloxamer must be located on the particle surface.

Section snippets

Materials

The polymer poly(d,l-lactic acid/glycolic acid) 50/50 (PLGA) was purchased from Boehringer–Ingelheim, under the commercial name of Resomer RG 503. Its average molecular weight was 35,000 Da. The poloxamer Pluronic F68 was obtained from Sigma Aldrich. It is a polyoxyethylene–polyoxypropylene–polyoxyethylene type polymer (see Fig. 1) with a molecular weight equal to 8500 Da. All other solvents and chemicals used were of the highest grade commercially available. Buffered solutions presented a

Results and discussion

Four sets of experiments were performed to determine different properties of our Pluronic-coated PLGA particles: adsorption isotherm, Pluronic adlayer thickness, electrokinetic behaviour of the complexes versus the pH, and colloidal stability as a function of the electrolyte concentration.

Adsorption isotherm results are shown in Fig. 2. As expected from the work of Kayes and Rawlins [12], the specific adsorption values for Pluronic F68 reach a clear plateau value at bulk polymer concentrations

Conclusions

In this work has been demonstrated that both the electrophoretic mobility and the colloidal stability results of PLGA nanoparticles fully coated by Pluronic F68 practically coincide those obtained with PLGA–Pluronic blend formulations. This would suggest a two phase separation of both components in PLGA–Pluronic (50:50 w/w) mixtures, which has also been predicted theoretically analysing the miscibility of these polymers at a molecular scale, where PLGA would form the core and the poloxamer

Acknowledgements

Financial support from ‘Comisión Interministerial de Ciencia y Tecnología’ Projects MAT2003-01257 and AGL2004-01531/ALI (European FEDER support included) is gratefully acknowledged.

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