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Gelsolin Amyloidogenesis Is Effectively Modulated by Curcumin and Emetine Conjugated PLGA Nanoparticles.

Srivastava A, Arya P, Goel S, Kundu B, Mishra P, Fnu A - PLoS ONE (2015)

Bottom Line: These two types of aggregates differed in their morphologies, surface hydrophobicity and secondary structural signatures, confirming that they followed distinct pathways.In spite of differences, both these aggregates displayed reduced toxicity against SH-SY5Y human neuroblastoma cells as compared to control gelsolin amyloids.We conclude that the cytotoxicity of gelsolin amyloids can be reduced by either stalling or accelerating its fibrillation process.

View Article: PubMed Central - PubMed

Affiliation: Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India.

ABSTRACT
Small molecule based therapeutic intervention of amyloids has been limited by their low solubility and poor pharmacokinetic characteristics. We report here, the use of water soluble poly lactic-co-glycolic acid (PLGA)-encapsulated curcumin and emetine nanoparticles (Cm-NPs and Em-NPs, respectively), as potential modulators of gelsolin amyloidogenesis. Using the amyloid-specific dye Thioflavin T (ThT) as an indicator along with electron microscopic imaging we show that the presence of Cm-NPs augmented amyloid formation in gelsolin by skipping the pre-fibrillar assemblies, while Em-NPs induced non-fibrillar aggregates. These two types of aggregates differed in their morphologies, surface hydrophobicity and secondary structural signatures, confirming that they followed distinct pathways. In spite of differences, both these aggregates displayed reduced toxicity against SH-SY5Y human neuroblastoma cells as compared to control gelsolin amyloids. We conclude that the cytotoxicity of gelsolin amyloids can be reduced by either stalling or accelerating its fibrillation process. In addition, Cm-NPs increased the fibrillar bulk while Em-NPs defibrillated the pre-formed gelsolin amyloids. Moreover, amyloid modulation happened at a much lower concentration and at a faster rate by the PLGA encapsulated compounds as compared to their free forms. Thus, besides improving pharmacokinetic and biocompatible properties of curcumin and emetine, PLGA conjugation elevates the therapeutic potential of both small molecules against amyloid fibrillation and toxicity.

No MeSH data available.


Related in: MedlinePlus

Chemical and morphological characteristics of nanoparticles.The chemical structure of curcumin (A) and emetine (B), SEM (C) and AFM (D) images of Cm-NPs, SEM (E) and AFM (F) images of Em-NPs. The scale bar in SEM images represents 1 μm.
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pone.0127011.g002: Chemical and morphological characteristics of nanoparticles.The chemical structure of curcumin (A) and emetine (B), SEM (C) and AFM (D) images of Cm-NPs, SEM (E) and AFM (F) images of Em-NPs. The scale bar in SEM images represents 1 μm.

Mentions: The biological activity of both the compounds depend on their specific functional groups viz. phenol rings in curcumin and isoquinoline ring in emetine (Fig 2A and 2B). PLGA polymer was used for encapsulation of curcumin or emetine by oil in water and water in oil in water solvent evaporation method, respectively. The corresponding SEM and AFM analysis showed roughly spherical morphology of both the NPs (Fig 2C & 2D; 2E & 2F). The physico-chemical properties of the NPs are presented in Table 1. The nanoparticles showed narrow size distribution with an average diameter of 261.5±8 nm. To assess the surface charge, their average zeta potential was determined and was found as -30.8 mV, -37.6 mV and -35.9 mV for the Em-NPs, Cm-NPs the control PLGA NPs, respectively (S1 Fig). The FTIR spectra of NPs are shown in Fig 3. A characteristic C = O absorption band at 1750 cm-1 of PLGA was observed in all the three cases. In the Cm-NPs, additional peak of curcumin at 3379 cm-1 characteristic of O-H stretching was observed. For the Em-NPs, very sharp peak of isoquinoline at 3395 cm-1 characteristic of N-H stretching was observed. The aromatic signatures of C-C were found overlapping in all the samples. Based on actual loading of compounds, entrapment efficiency (EE) of Cm-NPs and Em-NPs was found ~19% and ~27%, respectively (Table 1).


Gelsolin Amyloidogenesis Is Effectively Modulated by Curcumin and Emetine Conjugated PLGA Nanoparticles.

Srivastava A, Arya P, Goel S, Kundu B, Mishra P, Fnu A - PLoS ONE (2015)

Chemical and morphological characteristics of nanoparticles.The chemical structure of curcumin (A) and emetine (B), SEM (C) and AFM (D) images of Cm-NPs, SEM (E) and AFM (F) images of Em-NPs. The scale bar in SEM images represents 1 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440822&req=5

pone.0127011.g002: Chemical and morphological characteristics of nanoparticles.The chemical structure of curcumin (A) and emetine (B), SEM (C) and AFM (D) images of Cm-NPs, SEM (E) and AFM (F) images of Em-NPs. The scale bar in SEM images represents 1 μm.
Mentions: The biological activity of both the compounds depend on their specific functional groups viz. phenol rings in curcumin and isoquinoline ring in emetine (Fig 2A and 2B). PLGA polymer was used for encapsulation of curcumin or emetine by oil in water and water in oil in water solvent evaporation method, respectively. The corresponding SEM and AFM analysis showed roughly spherical morphology of both the NPs (Fig 2C & 2D; 2E & 2F). The physico-chemical properties of the NPs are presented in Table 1. The nanoparticles showed narrow size distribution with an average diameter of 261.5±8 nm. To assess the surface charge, their average zeta potential was determined and was found as -30.8 mV, -37.6 mV and -35.9 mV for the Em-NPs, Cm-NPs the control PLGA NPs, respectively (S1 Fig). The FTIR spectra of NPs are shown in Fig 3. A characteristic C = O absorption band at 1750 cm-1 of PLGA was observed in all the three cases. In the Cm-NPs, additional peak of curcumin at 3379 cm-1 characteristic of O-H stretching was observed. For the Em-NPs, very sharp peak of isoquinoline at 3395 cm-1 characteristic of N-H stretching was observed. The aromatic signatures of C-C were found overlapping in all the samples. Based on actual loading of compounds, entrapment efficiency (EE) of Cm-NPs and Em-NPs was found ~19% and ~27%, respectively (Table 1).

Bottom Line: These two types of aggregates differed in their morphologies, surface hydrophobicity and secondary structural signatures, confirming that they followed distinct pathways.In spite of differences, both these aggregates displayed reduced toxicity against SH-SY5Y human neuroblastoma cells as compared to control gelsolin amyloids.We conclude that the cytotoxicity of gelsolin amyloids can be reduced by either stalling or accelerating its fibrillation process.

View Article: PubMed Central - PubMed

Affiliation: Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India.

ABSTRACT
Small molecule based therapeutic intervention of amyloids has been limited by their low solubility and poor pharmacokinetic characteristics. We report here, the use of water soluble poly lactic-co-glycolic acid (PLGA)-encapsulated curcumin and emetine nanoparticles (Cm-NPs and Em-NPs, respectively), as potential modulators of gelsolin amyloidogenesis. Using the amyloid-specific dye Thioflavin T (ThT) as an indicator along with electron microscopic imaging we show that the presence of Cm-NPs augmented amyloid formation in gelsolin by skipping the pre-fibrillar assemblies, while Em-NPs induced non-fibrillar aggregates. These two types of aggregates differed in their morphologies, surface hydrophobicity and secondary structural signatures, confirming that they followed distinct pathways. In spite of differences, both these aggregates displayed reduced toxicity against SH-SY5Y human neuroblastoma cells as compared to control gelsolin amyloids. We conclude that the cytotoxicity of gelsolin amyloids can be reduced by either stalling or accelerating its fibrillation process. In addition, Cm-NPs increased the fibrillar bulk while Em-NPs defibrillated the pre-formed gelsolin amyloids. Moreover, amyloid modulation happened at a much lower concentration and at a faster rate by the PLGA encapsulated compounds as compared to their free forms. Thus, besides improving pharmacokinetic and biocompatible properties of curcumin and emetine, PLGA conjugation elevates the therapeutic potential of both small molecules against amyloid fibrillation and toxicity.

No MeSH data available.


Related in: MedlinePlus