Highly Functionalized Poly(alkyl cyanoacrylate) Nanoparticles Designed by Click Chemistry for Biological Applications in Alzheimer’s Disease
Benjamin Le Droumaguet, Julien Nicolas, Davide Brambilla, Karine Andrieux, Patrick Couvreur
Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, UMR CNRS 8612, Univ. Paris-Sud 11, Châtenay Malabry, France
Alzheimer’s disease (AD) is a very severe neurodegenerative disease leading to a progressive loss of cognitive functions. It is characterized at the phisiological level by two important features: an extracellular accumulation of aggregation plaques of amyloid β peptide (Aβ peptide) and an intracellular accumulation of the hyperphosphorylated θ protein (that lead to a microtubule disaggregation) in the brain; the first feature being admitted to be the major cause of AD. In this context, we have developped nanotechnologies and especially polymeric nanoparticles (NPs) for the treatment and diagnostic of AD for two specific reasons: they can be adressed to specific organs in the body such as the brain but they can also interact specifically with biomolecules (such as proteins/peptides) after suitable functionalization of the NP shell.
Copolymers constituted of poly(ethylene glycol) cyanoacrylate (PEGCA) and hexadecyl cyanoacrylate (HDCA) monomers, namely PEGylated PHDCA copolymers, have been widely studied in our laboratory as drug delivery nanocarriers due to their propensity to form stable, nanometer-sized particles, exhibiting several interresting properties1, 2: i) they are biocompatible and biodegradable ii) they present an increased plasma half-life due to their PEG shell, iii) they are even able to significantly overpass the blood-brain barrier, thus making them good candidates as therapeutical agents for neurodegenerative diseases.
The functionalization of these PEGylated PHDCA nanopartcles has already been investigated recently in our group and it was observed that nearly quantitative attachment of small model organic compounds was achieved at the surface of the PEGylated PHDCA NPs by copper-catalyzed click chemistry reaction (CuAAC).3 Following these interesting pioneer studies, we developed a slightly different strategy consisting in the attachment of ligands to PEG cyanoacetate, further involved in tandem Knoevenagel condensation-Michael addition reaction with hexadecyl cyanoacetate to yield the corresponding functionalized copolymer.
A number of different alkyne containing ligands (selegiline and curcumine for their Aβ peptide anti-aggregating properties as well as biotin and maleimide for protein binding properties) has been successfully synthesized and coupled to azido poly(ethylene glycol) by click chemistry, the other extremity being esterified with cyanoacetic acid for further copolymerization purposes with HDCA. After functional PEGCA-PHDCA copolymer synthesis and formation of the associated NPs, the properties of the resulting nanodevices towards either BBB overpassing or Aβ peptide interactions has been investigated.
1 Calvo, P.; Gouritin, B.; Chacun, H.; Desmaele, D.; D'Angelo, J.; Noel, J. P.; Georgin, D.; Fattal, E.; Andreux, J. P.; Couvreur, P. Pharm. Res. 2001, 18, 1157.
2 Nicolas, J.; Couvreur, P. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2009, 1, 111.
3 Nicolas, J.; Bensaid, F.; Desmaële, D.; Grogna, M.; Detrembleur, C.; Andrieux, K.; Couvreur, P. Macromolecules 2008, 41, 8418.
The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 212043.
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