Iii Stability And Toxicity Of Polyalkylcyanoacrylate Nanoparticles
Degradation and toxicity of poly(alkylcyanoacrylates) is often discussed in the literature especially for the in vivo applications of nanoparticles as drug delivery systems.
Concerning the stability of the nanoparticles, different pathways for their degradation have been described. The predominent mechanism greatly depends on the experimental conditions. Among the known degradation pathways, the most likely to occur in vivo are of two kinds. One mechanism consists of hydrolysis of the ester bond of the alkyl side chain of the polymer [32,65] (Fig. 2A). Degradation products consist of an alkylalcohol and poly(cyanoacrylic acid), which can dissolve in water and be eliminated in vivo through kidney filtration. This degradation has been shown to be catalyzed by esterases from serum, lyso-somes, and pancreatic juice [66,67] and is believed to occur as the major degradation pathway in vivo. According to this mechanisms, nanoparticles are usually degraded within in a couple of hours depending on the alkyl side chain length of the poly(alkylcyanoacrylates).
The other mechanism that may occur in biological systems consists of an unzipping depolymerization of the parent polymer with immediate repolymeri-zation to give a new polymer of much lower molecular weight. The whole phenomenom occurs within a few seconds and is generally induced by a base (Fig. 2B) [21].
The well-known inverse Knoevenagel reaction resulting from water hydrolysis reaches an equilibrium of formaldehyde and cyanoacetic ester production that is limited at physiological pH to only 5% after 24 h. This degradation pathway is much slower to compete with the other mechanisms occurring much faster in vivo and being further catalyzed by enzymes [68-70].
Toxicity of poly(alkylcyanoacrylates) is still a subject of debate. However, as applied in various biomedical applications, poly(alkylcyanoacrylates) did not reveal major problems of toxicity [17,71-75]. This is in agreement with the suspected in vivo degradation mechanism leading to the release of alcohol and poly(cyanoacrylic acid) as major metabolization products. The transitory minor
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FIG. 2 More probable degradation routes of poly(alkylcyanoacrylate) encountered in vivo. (A) Hydrolysis of the ester bond of the alkyl side chain [32,65]; (B) unzipping depolymerization-repolymerization mechanism [21].
toxic effects or inflammatory responses that may be observed with these polymers were a function of the rate of the polymer degradation [17,73-75]. Polymers expected to degrade slowly showed the best compatibility with living tissues. Regarding the toxicity, the LD50 values found for poly(isobutylcynoacry-late) and poly(isohexylcyanoacrylate) nanospheres given intravenously to mice were 200 mg/kg and 700 mg/kg, respectively [71,72]. The low toxicity found with PACA nanoparticles has inspired clinical trials for human cancer [11,72]. A phase I trial confirmed the good tolerance of the drug carrier because only secondary effects due to the associated drug could be highlighted.
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