Long-term stability of PBCA nanoparticle suspensions suggests clinical usefulness

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Abstract

The stability of polybutylcyanoacrylate (PBCA) nanoparticle suspensions was examined by measuring particle sizes and size distributions over a period of 2 months in different solutions (hydrochloric acid, phosphate buffered saline). When stored in acidic medium, nanoparticles were found to be stable for at least 2 months. In this case, degradation of the polymer is decelerated and particle agglomeration is reduced. When added to human blood serum, nanoparticles were found not to agglomerate, remaining stable in size for at least five days. Previous stabilization protocols required lyophilization and resuspension by ultrasonification; however, the technique presented here using acidic storage solutions proves to be superior for clinical applications.

Introduction

Polybutylcyanoacrylate (PBCA) nanoparticles are used in a variety of approaches for drug targeting. Depending on their chemical characteristics drugs, can be incorporated into the nanoparticle core (Beck et al., 1993, Beck et al., 1994) or they can be adsorbed onto the nanoparticle surface (Losa et al., 1991; Beck et al., 1993, Schroeder and Sabel, 1996). The benefits of binding drugs to nanoparticles are, for example, a changed body distribution after administration (Grislain et al., 1983, Verdun et al., 1986, Beck et al., 1994, Kreuter et al., 1995, Schroeder and Sabel, 1996), lower toxicity (Couvreur et al., 1982, Couvreur et al., 1986, Verdun et al., 1986), and protection of the drug against enzymatic degradation (Lowe and Temple, 1994, Nakada et al., 1996). Concerning a changed body distribution, especially a higher concentration of drugs in the brain is of clinical interest, and nanoparticles are now developed as a carrier system to deliver drugs across the blood-brain barrier (Kreuter et al., 1995, Schroeder and Sabel, 1996).

The preparation of nanoparticles is not complicated (Kreuter, 1994) and storage in a lyophilized form normally ensures long durability (Verdun et al., 1986). However, the resuspension of these lyophilized nanoparticles is an unpractical and unreliable step when intravenous administration of the nanoparticle suspension is desired (Beck et al., 1990). Due to the danger of particle agglomeration, insufficient resuspension could result in microembolisms (Beck et al., 1993) which have to be avoided. Consequently, resuspension usually requires a powerful ultrasonification bath and, to be certain of sufficient resuspension, it is necessary to determine particle size. These circumstances severely limit the clinical use of nanoparticles by creating instrumental problems for the clinician. To overcome these difficulties, we have now developed new non-perishable forms of PBCA nanoparticles with long-term stability which may be adequate for the clinical setting.

Section snippets

Materials

n-Butylcyanoacrylate (BCA) was obtained from Sichelwerke (Hannover, Germany), dextran 70 000 from Sigma-Aldrich Chemie (Deisenhofen, Germany) and mannitol from J. Baker (Deventer, Netherlands). Filter paper was obtained from Schleicher and Schuell (Dassel, Germany): No. 595 (used for filtering the suspensions), and No. 402106 (0.05 μm; used for filtering the water before particle size determination). Human blood serum was kindly supplied by the Institute of Clinical Chemistry at the

Preparation and purification

As depicted in Table 1 the particle size of the PBCA nanoparticles varied from 164 to 326 nm immediately after preparation. This size differences resulted from the slightly variable preparation conditions such as type of reaction vessel, amount of solution, stirring speed and quality, velocity and place of adding the monomer BCA. That the particles tend to agglomerate after the purification steps by centrifugation and after lyophilization as mentioned in the literature (for example by Kreuter

Conclusions

The results of this study indicate that an acidic medium protects PBCA nanoparticles against decomposition in agreement with earlier observations (Stein and Hamacher, 1992, Scherer et al., 1994), and under these conditions there is only negligible agglomeration for many months. A small temperature dependence was observable; higher temperature seems to promote the degradation of the nanoparticles (Stein and Hamacher, 1992). It is not yet known if this degradation is triggered by esterhydrolysis

Acknowledgements

This work was supported by a grant from the Ministry of Culture, State of Sachsen-Anhalt (AZ 1880 A/0025).

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