From Preparation to Real Applications as Drug Delivery Systems

CHRISTINE VAUTHIER, PATRICK COUVREUR, and CATHERINE DUBERNET Universite de Paris Sud, Chatenay-Malabry, France

I. INTRODUCTION

Poly(alkylcyanoacrylates) (PACA) have not been much employed as polymers. On the contrary, their corresponding monomers, alkylcyanoacrylates, have received increased interest since their synthesis in 1947 [1] because of their remarkable polymerization ability and strong reactivity. Indeed, cyanoacrylate monomers can polymerize extremely rapidly in the presence of moisture or basic component traces. Their excellent adhesive properties result from bonds of high strength they are able to form with most polar substrates. Therefore, they were extensively used as adhesives [2].

A very active field of investigation for poly(alkylcyanoacrylate)-based materials is biomedical research. Alkylcyanoacrylates have been used as surgical glue because of their excellent adhesion to living tissues, including skin. They were also developed as tissue adhesive for the closure of skin wounds [3] and as embolitic material for endovascular surgery [4]. At the moment, an exciting application is the use of poly(alkylcyanoacrylates) as drug particulate carriers. This is an area of research that emerged in the 1980s [5-7] for cancer treatments, which generally involve highly toxic molecules on healthy tissue. Other molecules of interest consist of poorly stable compounds like peptides and nucleic acids [8-10].

Today, PACA nanoparticles are considered to be the most promising polymer colloidal drug delivery system in clinical development for cancer therapy [1115]. As described in this chapter, PACA nanoparticles can be prepared by emulsion and interfacial polymerization of alkylcyanoacrylates and also from copoly-

mers of poly(alkylcyanoacrylate)-co-poly(ethylene glycol cyanoacrylate). The main developments pertaining to use of PACA nanoparticles as drug carriers for cancer treatments will be described and discussed in another section of this chapter.

II. PREPARATION OF

POLY(ALKYLCYANOACRYLATE) NANOPARTICLES

Poly(alkylcyanoacrylate) nanoparticles can be prepared either by polymerization of alkylcyanoacrylates or directly from the polymer. In this case, nanoparticles can be prepared by nanoprecipitation and emulsification-solvent evaporation methods.

A. Preparation of Nanoparticles by Polymerization

For polymerization, monomers are mainly prepared by a method based on a Knoevenagel condensation of formaldehyde with the corresponding alkylcya-noacetate synthesized in turn by Fisher esterification of cyanoacetic acid with the glycolate ester. This method provides a high yield of monomer (>80%) [1] and a purity grade over 99% [16-18]. Monomers generally occurring as clear and colorless liquid with a low viscosity are highly reactive compounds and extremely difficult to handle in the pure form [1,16,19-21]. Inhibitors are essential to maintain their stability. The most common anionic inhibitors used are acidic gases (sulfur dioxide) and strong acids (aliphatic and aromatic sulfonic acids, mineral acids). Free-radical polymerization inhibitors are usually added to a level of 100 to several thousand ppm (hydroquinone, other quinones, methyl ether of hydroquinone, methoxyhydroquinone) [18,19,21].

The polymerization of alkylcyanoacrylates can theoretically occur according to three different mechanisms: free-radical, anionic, and zwitterionic mechanisms (Fig. 1). In practice, the anionic and zwitterionic routes are strongly favored because they are rapidly initiated at ambient temperature. Classical initiators of the anionic polymerization are anions (i.e. I-, CH3COO-, Br-, OH-, etc.), weak bases such as alcohols, water, and amino acids encountered in living tissues [16]. Tertiary bases such as phosphine and pyridine derivatives were described to initiate zwitterionic polymerization [19,22]. In both cases, the growing end is a carbanion and the reaction is difficult to control. Indeed, in the case of the anionic polymerization carried out in an organic solvent, the polymer chain growth could only be interrupted by the addition of a very strong mineral acid [20].

In contrast to anionic and zwitterionic polymerization processes, radical polymerization is slower and requires much higher activation energy (125 kJ/mol).

Rope And Pulley Systems
FIG. 1 Different routes of the polymerization initiation of alkylcyanoacrylates. (A) Anionic polymerization; (B) zwitterionic polymerization; (C) radical polymerization.

In addition, the reaction rate greatly depends on temperature and quantity of radicals. This polymerization has been described in bulk in such a condition that the anionic polymerization was mainly under control [23-27].

1. Preparation of Matricial Poly(alkylcyanoacrylate) Nanoparticles (i.e., Nanospheres) by Emulsion Polymerization

Emulsion polymerization of alkylcyanoacrylates was introduced by Couvreur et al. in 1979 [5] to design biodegradable polymer particles suitable for in vivo delivery of drugs. Polymerization media formulated to prepare poly(alkylcya-noacrylate) nanoparticles to be used as drug carriers are usually very complex. For example, the monomer (100 pL) is dispersed in acidified water containing a surfactant or a stabilizing agent (10 mL of a 0.5-1% solution of Pluronic F68 or dextran 70 at pH 2.5 with HCl) and let polymerization occur spontaneously for a few hours (3-4 h). This unusual mode of polymerization for such reactive monomers leads to the formation of colloidal polymer particles with a diameter ranging of 50-300 nm. These particles presenting a matricial structure were named "nanospheres" [5]. At pH higher than 3, the polymerization is too fast and polymer aggregates are formed. It is noteworthy that the polymerization can even be initiated in the presence of acids normally capable of its inhibition in organic solvents at pH lower than 1 because of the presence of additives, including surfactants or stabilizing agents dissolved in the reaction medium [28-31].

The molecular weight of the polymers forming the nanoparticles is usually low as evaluated by size exclusion chromatography. It is affected by the pH of the polymerization medium, by the presence or the absence of surface-active agents, and by the presence or the absence of a drug [32-35]. Recently, Nehan et al. [36] investigated in detail the polymerization of alkylcyanoacrylates at different pH in the presence of 0.1% dextran. They suggested a rather complex mechanism for the formation of the polymer nanoparticles involving first oligomers that are allowed to polymerize further through a reinitiation, repolymeriza-tion process. This complex mechanism was based on the assumption that only the hydroxyl groups from water were responsible for the polymerization initiation. It totally omitted the fact that hydroxyl groups from dextran could also initiate the polymerization of alkylcyanoacrylate under the same conditions, as previously demonstrated by Douglas et al. [29].

The size of the nanoparticle formed can be controlled by the amount of surface-active agent or by the molecular weight of colloidal stabilizer like dex-tran [29,37,38]. Another important parameter to consider for controlling particle size is the concentration of sulfur dioxide dissolved in the monomer as the inhibitor of anionic polymerization. Contradictory results have been reported considering either the effect of the pH or the effect of the monomer sulfur dioxyde concentration [32,39]. Since the pH of the polymerization medium controls the partition and ionization of sulfur dioxide in water, it affects in turn the sulfur dioxide concentration in the monomer once it is dispersed in the aqueous polymerization medium. Thus, both the pH and the sulfur dioxide concentration are affecting the polymerization process and controlling the size of the nanopar-ticles that form [40].

Many drugs were entrapped with success in polyalkylcyanoacrylate nano-particles [41]. However, in rare cases, drugs were shown to initiate the polymerization reaction and lost their biological activity [33-35]. For certain drugs, cyclodextrins can be added to the polymerization medium to promote their association with the carrier [42,43]. Side reactions occurring during polymerization can advantageously be used to associate compounds by covalent binding with nanoparticles. This has been applied to naphthalocyanines, photo-sensitizers used in phototherapy of tumors [44], and a series of molecules containing dieth-yltriaminepentaacetic acid (DTPA) capable of complexing radioactive metals for radiolabeling of nanoparticles in medical imaging [45]. These reactions were also used to produce nanoparticles with modified surface properties, allowing the covalent coupling of macromolecules on the nanoparticle surface [29-31, 46,47].

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