Selegiline-functionalized, PEGylated poly(alkyl cyanoacrylate) nanoparticles: Investigation of interaction with amyloid-β peptide and surface reorganization
Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, Univ. Paris-Sud 11, UMR CNRS 8612, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.International Journal of Pharmaceutics (Impact Factor: 3.65). 09/2011; 416(2):453-60. DOI: 10.1016/j.ijpharm.2011.01.015
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: Alzheimer's disease (AD) represents the most common form of dementia worldwide, affecting more than 35 million people. Advances in nanotechnology are beginning to exert a significant impact in neurology. These approaches, which are often based on the design and engineering of a plethora of nanoparticulate entities with high specificity for brain capillary endothelial cells, are currently being applied to early AD diagnosis and treatment. In addition, nanoparticles (NPs) with high affinity for the circulating amyloid-β (Aβ) forms may induce "sink effect" and improve the AD condition. There are also developments in relation to in vitro diagnostics for AD, including ultrasensitive NP-based bio-barcodes, immunosensors, as well as scanning tunneling microscopy procedures capable of detecting Aβ(1-40) and Aβ(1-42). However, there are concerns regarding the initiation of possible NP-mediated adverse events in AD, thus demanding the use of precisely assembled nanoconstructs from biocompatible materials. Key advances and safety issues are reviewed and discussed.Nanomedicine: nanotechnology, biology, and medicine 04/2011; 7(5):521-40. DOI:10.1016/j.nano.2011.03.008 · 6.16 Impact Factor
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ABSTRACT: Design and functionalization strategies for multifunctional nanocarriers (e.g., nanoparticles, micelles, polymersomes) based on biodegradable/biocompatible polymers intended to be employed for active targeting and drug delivery are reviewed. This review will focus on the nature of the polymers involved in the preparation of targeted nanocarriers, the synthesis methods to achieve the desired macromolecular architecture, the selected coupling strategy, the choice of the homing molecules (vitamins, hormones, peptides, proteins, etc.), as well as the various strategies to display them at the surface of nanocarriers. The resulting morphologies and the main colloidal features will be given as well as an overview of the biological activities, with a special focus on the main in vivo achievements.Chemical Society Reviews 12/2012; 42(3). DOI:10.1039/c2cs35265f · 33.38 Impact Factor
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ABSTRACT: The marriage of biodegradable polymer and fluorescent imaging has resulted in an important area of polymeric biomaterials: biodegradable fluorescent polymers. Researchers have put significant efforts on developing versatile fluorescent biomaterials due to their promising in biological/biomedical labeling, tracking, monitoring, imaging, and diagnostic applications, especially in drug delivery, tissue engineering, and cancer imaging applications. Biodegradable fluorescent polymers can function not only as implant biomaterials but also as imaging probes. Currently, there are two major classes of biodegradable polymers used as fluorescent materials. The first class is the combination of non-fluorescent biodegradable polymers and fluorescent agents such as organic dyes and quantum dots. Another class of polymers shows intrinsic photoluminescence as polymers by themselves carrying integral fluorescent chemical structures in or pendent to their polymer backbone, such as Green Fluorescent protein (GFP), and the recently developed biodegradable photoluminescent polymer (BPLP). Thus there is no need to conjugate or encapsulate additional fluorescent materials for the latter. In the present review, we will review the fluorescent biodegradable polymers with emphases on material fluorescence mechanism, design criteria for fluorescence, and their cutting-edge applications in biomedical engineering. We expect that this review will provide insightful discussion on the fluorescent biomaterial design and lead to innovations for the development of the next generation of fluorescent biomaterials and fluorescence-based biomedical technology.Journal of Materials Chemistry B 01/2013; 1(2):132-148. DOI:10.1039/C2TB00071G · 4.73 Impact Factor
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