title: Gelsolin Amyloidogenesis Is Effectively Modulated by Curcumin and Emetine Conjugated PLGA Nanoparticles.
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.
authors.affiliation: Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India.
authors.forename: Ankit
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Department of Biochemical Engineering and Biotechnology, IIT Delhi, New Delhi, India.
authors.forename: Prabha
authors.initials: P
authors.lastname: Arya
authors.affiliation: Department of Biochemical Engineering and Biotechnology, IIT Delhi, New Delhi, India.
authors.forename: Surbhi
authors.initials: S
authors.lastname: Goel
authors.affiliation: Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India.
authors.forename: Bishwajit
authors.initials: B
authors.lastname: Kundu
authors.affiliation: Department of Biochemical Engineering and Biotechnology, IIT Delhi, New Delhi, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Mishra
authors.affiliation: CSIR Institute of Microbial Technology, Chandigarh 160036, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Fnu
mesh_terms: D000595:Amino Acid Sequence; D058227:Amyloidogenic Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D003474:Curcumin / Q000008:administration & dosage* / Q000737:chemistry; D004640:Emetine / Q000008:administration & dosage* / Q000737:chemistry; D018260:Gelsolin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D066263:Protein Aggregation, Pathological; D011487:Protein Conformation
chemical_list: D058227:Amyloidogenic Proteins; D018260:Gelsolin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D003474:Curcumin; D004640:Emetine