Design and statistical modeling of mannose-decorated dapsone-containing nanoparticles as a strategy of targeting intestinal M-cells

Abstract

The aim of the present work was to develop and optimize surface-functionalized solid lipid nanoparticles (SLNs) for improvement of the therapeutic index of dapsone (DAP), with the application of a design of experiments. The formulation was designed to target intestinal microfold (M-cells) as a strategy to increase internalization of the drug by the infected macrophages. DAP-loaded SLNs and mannosylated SLNs (M-SLNs) were successfully developed by hot ultrasonication method employing a three-level, three-factor Box–Behnken design, after the preformulation study was carried out with different lipids. All the formulations were systematically characterized regarding their diameter, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, and loading capacity. They were also subjected to morphological studies using transmission electron microscopy, in vitro release study, infrared analysis (Fourier transform infrared spectroscopy), calorimetry studies (differential scanning calorimetry), and stability studies. The diameter of SLNs, SLN-DAP, M-SLNs, and M-SLN-DAP was approximately 300 nm and the obtained PDI was <0.2, confirming uniform populations. Entrapment efficiency and loading capacity were approximately 50% and 12%, respectively. Transmission electron microscopy showed spherical shape and nonaggregated nanoparticles. Fourier transform infrared spectroscopy was used to confirm the success of mannose coating process though Schiff’s base formation. The variation of the ZP between uncoated (approximately −30 mV) and mannosylated formulations (approximately +60 mV) also confirmed the successful coating process. A decrease in the enthalpy and broadening of the lipid melting peaks of the differential scanning calorimetry thermograms are consistent with the nanostructure of the SLNs. Moreover, the drug release was pH-sensitive, with a faster drug release at acidic pH than at neutral pH. Storage stability for the formulations for at least 8 weeks is expected, since they maintain the original characteristics of diameter, PDI, and ZP. These results pose a strong argument that the developed formulations can be explored as a promising carrier for treating leprosy with an innovative approach to target DAP directly to M-cells.

Keywords:

• Box-Behnken design
• leprosy
• drug delivery
• targeting
• oral route
• solid lipid nanoparticle

Acknowledgments

Alexandre Vieira thanks the CNPq, Ministry of Education of Brazil for the fellowship 246514/2012-4. Luíse Chaves thanks the CAPES Foundation, Ministry of Education of Brazil for the Doctoral fellowship 0831-12-3. Marina Pinheiro is thankful to Fundação para a Ciência e Tecnologia (FCT) for the Post-Doc Grant (SFRH/BPD/99124/2013). Additionally, this work was possible with financial support from FCT/MEC through National Funds and co-financed by FEDER, under the partnership agreement PT2020 – UID/MULTI/04378/2013 -POCI/01/0145/FERDER/007728.

Disclosure

The authors report no conflicts of interest in this work.