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Based on the structure of polymeric nanocapsules containing a lipid-dispersed core composed of caprylic/capric trygliceride (CCT) and sorbitan monostearate (SM), we hypothesized that varying the core component concentrations the drug release kinetic could be modulated. Our objective was also to determine the parameters which were responsible for controlling the drug release kinetics. The nanocapsules were prepared by interfacial deposition of poly(epsilon-caprolactone). Interfacial hydrolysis of indomethacin ester (IndOEt) was used to simulate a sink condition of release. Mathematical modeling showed that the IndOEt half-lives increased (198 to 378 and 263 to 508 min) with the increase in the core lipid concentrations, and that the release mechanism was the anomalous transport. By increasing the SM concentration, the diameters were constant (around 250 nm) and the surface areas increased (from 1 06 × 10 4 to 1 51 × 10 4 cm 2 · ml −1 ), while by increasing the CCT concentration, the diameters increased (215 to 391 nm) and the surface areas reduced (1 46 × 10 4 to 1 06 × 10 4 cm 2 · ml −1 ). The presence of SM increased the viscosity of CCT and the IndOEt apparent permeability decreased from 4 26 × 10 −7 to 2 54 × 10 −7 cm · s −1 , while for CCT series, the apparent permeability was constant around 3 0 × 10 −7 cm · s −1 . A mathematical correlation was established and the IndOEt apparent permeability can be estimated by the SM concentration. In conclusion, varying the CCT and SM concentrations the IndOEt release was controlled by the nanocapsule surface area and by the viscosity of the core, respectively.

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Multimodal combinations of target agents with radiation and chemotherapy may enhance cancer treatment efficacy; however, despite these treatments, gliomas recur early due to their highly proliferative, infiltrative and invasive behaviors. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intensive interest in recent years since they may provide a sustained, controlled and targeted delivery. In the present study, we investigated the effect of indomethacin-loaded nanocapsules in an experimental glioma model. The rats treated with indomethacin-loaded nanocapsules demonstrated a significant reduction in tumor size and half of these animals presented just cells with characteristics of a residual tumor, as shown by immunostaining for nestin. Pathological analyses showed that the treated gliomas presented a significant reduction in the mitotic index and other histological characteristics that indicate a less invasive/proliferative tumor. An important finding of the present study is that indomethacin carried by polymeric nanocapsules achieved higher intracerebral drug concentrations than those of indomethacin in solution. Furthermore, indomethacin achieved a greater concentration in the hemisphere where the glioma was implanted, compared with the contralateral healthy hemisphere. Indomethacin-loaded nanocapsule treatment did not cause characteristics of toxicity and increased the survival of animals. Thus, our results show that polymeric nanocapsules are able to increase the intratumoral bioavailability of indomethacin and reduce the growth of implanted gliomas. Data suggest that indomethacin-loaded nanocapsules could offer new and potentially highly effective strategies for the treatment of malignant gliomas.

Background and purpose:The effects of systemic treatment with indomethacin-loaded nanocapsules (IndOH-NC) were compared with those of free indomethacin (IndOH) in rat models of acute and chronic oedema. Experimental approach: The following models of inflammation were employed: carrageenan-induced acute oedema (measured between 30 min and 4 h), sub-chronic oedema induced by complete Freund's adjuvant (CFA) (determined between 2 h and 72 h), and CFA-induced arthritis (oedema measured between 14 and 21 days). Key results: IndOH or IndOH-NC produced equal inhibition of carrageenan-elicited oedema. However, IndOH-NC was more effective in both the sub-chronic (33 Ϯ 4% inhibition) and the arthritis (35 Ϯ 2% inhibition) model of oedema evoked by CFA, when compared with IndOH (21 Ϯ 2% and 14 Ϯ 3% inhibition respectively) (P < 0.01). In the CFA arthritis model, treatment with IndOH-NC markedly inhibited the serum levels of the pro-inflammatory cytokines tumour necrosis factor a and IL-6 (by 83 Ϯ 8% and 84 Ϯ 11% respectively), while the levels of the anti-inflammatory cytokine IL-10 were significantly increased (196 Ϯ 55%). The indices of gastrointestinal damage in IndOH-NC-treated animals were significantly less that those after IndOH treatment (58 Ϯ 16%, 72 Ϯ 6% and 69 Ϯ 2%, for duodenum, jejunum and ileum respectively). Conclusions and implications: IndOH-NC produced an increased anti-inflammatory efficacy in long-term models of inflammation, allied to an improved gastrointestinal safety. This formulation might represent a promising alternative for treating chronic inflammatory diseases, with reduced undesirable effects.

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