Selegiline-functionalized, PEGylated poly(alkyl cyanoacrylate) nanoparticles: Investigation of interaction with amyloid-β peptide and surface reorganization.
ABSTRACT Alzheimer's disease (AD) is a neurodegenerative disorder for which the research of new treatments is highly challenging. Since the fibrillogenesis of amyloid-β peptide 1-42 (Aβ(1-42)) peptide is considered as a major cause of neuronal degeneration, specific interest has been focused on aromatic molecules for targeting this peptide. In this paper, the synthesis of selegiline-functionalized and fluorescent poly(alkyl cyanoacrylate) nanoparticles (NPs) and their evaluation for the targeting of the Aβ(1-42) peptide are reported. The synthetic strategy relied on the design of amphiphilic copolymers by tandem Knoevenagel-Michael addition of cyanoacetate derivatives, followed by their self-assembly in aqueous solutions to give the corresponding NPs. Different cyanoacetates were used: (i) hexadecyl cyanoacetate (HDCA) to form the hydrophobic core of the NPs; (ii) rhodamine B cyanoacetate (RCA) for fluorescent purposes; (iii) methoxypoly(ethylene glycol) cyanoacetate (MePEGCA) for stealth properties and (iv) selegiline-poly(ethylene glycol) cyanoacetate (SelPEGCA) to obtain the desired functionality. Two different amphiphilic copolymers were synthesized, a selegiline-containing copolymer, P(MePEGCA-co-SelPEGCA-co-HDCA), and a rhodamine-labelled counterpart, P(MePEGCA-co-RCA-co-HDCA), further blended at variable ratios to tune the amount of selegiline moieties displayed at the surface of the NPs. Optimal formulations involving the different amphiphilic copolymers were determined by the study of the NP colloidal characteristics. Interestingly, it was shown that the zeta potential value of the selegiline-functionalized nanoparticles dramatically decreased, thus emphasizing a significant modification in the surface charge of the nanoparticles. Capillary electrophoresis has then been used to test the ability of the selegiline-functionalized NPs to interact with the Aβ(1-42) peptide. In comparison with non functionalized NPs, no increase of the interaction between these functionalized NPs and the monomeric form of the Aβ(1-42) peptide was observed, thus highlighting the lack of availability of the ligand at the surface of the nanoparticles. A mechanism explaining this result has been proposed and was mainly based on the burial of the hydrophobic selegiline ligand within the nanoparticles core.
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ABSTRACT: We report herein a detailed study concerning the impact of different bioconjugation and nanoformulation strategies on the in vitro targeting ability of peptide-decorated squalenoyl gemcitabine (SQdFdC) nanoparticles (NPs). NPs have been functionalized with the CKAAKN peptide, previously identified as efficient homing device within the pancreatic pathological microenvironment. Two approaches have been followed: (i) either the CKAAKN peptide was directly conjugated at the surface of preformed SQdFdC nanoparticles (conjugation after NP formation) or (ii) it was first reacted with a maleimide squalenoyl derivative before the resulting bioconjugate was co-nanoprecipitated with SQdFdC to form the peptide-decorated NPs (conjugation before NP formation). NPs were characterized with respect to mean diameter, zeta potential and stability over time. Then, their specific interaction with the sFRP-4 protein was evaluated by surface plasmon resonance. Although both the synthetic strategies allowed to formulate NPs able to interact with the corresponding receptor, enhanced target binding and better specific avidity were observed with CKAAKN-NPs functionalized before NP formation. These NPs displayed the highest cell uptake and cytotoxicity in an in vitro model of human MIA Paca-2 pancreatic cancer cells.Bioconjugate Chemistry 10/2014; 25(11). DOI:10.1021/bc5003423 · 4.82 Impact Factor
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ABSTRACT: In recent decades, polysaccharides have come to play an important role in pharmaceutical science,among them in the domain of nanotechnology. As a result, there is an increased interest in their isolation, synthesis, modification, characterization, and application in this relevant new topic in nanotechnology. This has led to the use of modified polysaccharides in changing nanocomposite morphology and properties. Delivery of hydrophobic molecules, drugs, and proteins is difficult due to poor bioavailability following administration. Thus, modifications to natural polymeric carrier systems are being investigated to improve drug solubility, stability, and induced toxicity. Due to problems toxicity and immunogenicity, natural modified polysaccharides are being explored as substitutes for synthetic polymers in the development of new drug-delivery systems, such as coating or copolymer material. By conjugating different entities to the polysaccharide backbone, resultant materials can be used for preparing self-assembled micelles, coating polymeric microspheres, and self-reorganized nanostructures, improving drug release in tumoral areas.Polysaccharides, Edited by Kishan Gopal Ramawat, Jean-Michel Mérillon, 08/2014: chapter Modified Polysaccharides as Drug Delivery: pages 1-26; Springer International Publishing., ISBN: 978-3-319-03751-6
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ABSTRACT: The one-pot synthesis method was developed for the preparation of complex nanoparticles with a narrow size distribution and stable morphology. The vinyl monomers of (2-dimethylamino)ethyl methacrylate (DEMA) and diacetone acrylamide (DAA) were copolymerized in the presence of alginic acid in an aqueous solution without any organic solvents or surfactants, yielding stable complex nanoparticles in one-pot synthesis. The nanoparticle was composed of the complex of poly(DEMA-co-DAA) and alginic acid. The complex was formed via electrostatic interaction between polycations of DEMA and polyanions of alginate. The residual alginate segment around the core formed the shell of the nanoparticles. The average diameter of the nanoparticles varied from 120 to 213 nm when the molar percentage of DAA changed from 0.5 to 0 with respect to DEMA. The anti-cancer drug doxorubicin could be loaded onto the nanoparticles with a high-loading efficiency through the formation of polymer–drug conjugate. The drug release could be controlled by adjusting the pH value of the medium.Colloid and Polymer Science 12/2013; 291(12). DOI:10.1007/s00396-013-3031-9 · 2.41 Impact Factor