Acute and Subchronic Toxicity Evaluation of Poly(ɛ-Caprolactone) Lipid-Core Nanocapsules in Rats

Abstract

Owing to concerns over the effects of the physicochemical properties of nanoparticles and their interaction with biological systems, further investigation is required. We investigated, for the first time, the toxicity of lipid-core nanocapsules (LNCs) containing a polymeric wall of poly(ε-caprolactone) and a coating of polysorbate 80 used as drug delivery devices (~245nm) in Wistar rats after single- and repeated-dose treatments. The suspensions were prepared by interfacial deposition of the polymer and were physicochemically characterized. Toxicological effects were determined after single doses of 18.03, 36.06, and 72.12 × 10(12) LNC/kg and repeated doses of 6.01, 12.02, and 18.03 × 10(12) LNC/kg for 28 days by ip administration. The results for both the treatments showed no mortality or permanent body weight changes during the experiments. A granulomatous foreign body reaction was observed in the liver and spleen of higher dose groups in acute and subchronic treatments. Most of the hepatotoxicity and nephrotoxicity markers were within the reference values and/or were similar to the control group. However, a slight alteration in the hematologic parameters was observed in both the studies. Thus, to verify a possible methodological influence, we performed an in vitro test to confirm such influence. These findings are in agreement with earlier reports regarding no appreciable toxicity of biodegradable polymeric nanoparticles, indicating that LNC might be a safe candidate for drug delivery system. Furthermore, the results presented in this study are important for health risk assessment and to implement strategies for testing biodegradable polymeric nanoparticles.

Caenorhabditis elegans as an alternative in vivo model to determine oral uptake, nanotoxicity, and efficacy of melatonin-loaded lipid-core nanocapsules on paraquat damage

“…20,54 In vitro and in vivo studies reported that the large surface area of NPs results in a high reactivity, which could lead to cytotoxicity. 16,[20][21][22]54 The NPs' properties such as chemical composition, shape, size, surface chemistry, and large surface reactivity are mainly responsible for the possible toxicological effects caused by NPs. 16,21,22 Thus, although the present work did not explore different physical and chemical characteristics of nanocapsules, this alternative model is recommended for toxicological screening because it allows a systematic evaluation of many particularities of nanomaterials, yielding rapid and accurate results.…”

“…Previous studies from our research group have evaluated acute and subchronic LNC toxicity in rats after intraperitoneal and intradermal administration, whose results showed the safety of this promising drug delivery system. [21][22][23] However, the great number of new nanomaterials requires the use of in vivo models to provide the toxicological screening, 24 and following the three Rs policy (to reduce, replace, and refine the animals used for this purpose) is important, 25 especially with alternative in vivo models.…”

Novel therapeutic mechanisms determine the effectiveness of lipid-core nanocapsules on melanoma models

“…Indeed, necropsy of the animals at the end of treatments showed agglomeration of LNC or AcE-LNC on the tissues of the abdominal cavity ( Figure S3B), which may contribute to the systemic toxic effects of ip injection. Indeed, Bulcão et al 67 showed similar peritoneal LNC accumulation in rats after local injection of LNC (72.12×10 12 LNC/kg). It may be surmised that the clearance systems in the peritoneal cavity, as lymph node draining and macrophages engulfment, are not sufficient to clear daily injections of LNCs.…”

Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model

“…Moreover, it is well demonstrated that the LNC formulation has no potential for either acute or sub-chronic toxicity in vivo. 32,33 The loading of MTX on LNC provides a stable pharmaceutical formulation with a high concentration in inflammatory sites.…”