Sébastien Cajot

Design of reversibly core cross-linked micelles sensitive to reductive environment

Azido-functional amphiphilic macromolecules based on a biodegradable aliphatic polyester (poly-ε-caprolactone, PCL) and a bioeliminable hydrophilic poly(ethylene oxide) (PEO) block have been used in order to build micellar drug delivery systems. Such azido groups being able to react by alkyne-azide 1,3 Huisgens cycloaddition (a click reaction) have been used further in order to cross-link the micelles via redox-sensitive disulfide bridges. This reversible cross-linking allows to prevent micelle dissociation at high dilution upon injection and to trigger their dissociation in more reductive environment, such as the cytosol. Copolymers having three different architectures, i.e. able to cross-link either the core or the shell of core-shell-corona system have been used to investigate their micellization, cross-linking and cross-linking reversibility. The stealthiness of these micelles cross-linked in the hydrophobic segment has also been studied in vitro.

Smart nanocarriers for pH-triggered targeting and release of hydrophobic drugs

The use of hybrid pH-sensitive micelles based mainly on the (PEO)(129)(P2VP)(43)(PCL)(17) ABC miktoarm star copolymer as potential triggered drug delivery systems was investigated. Co-micellization of this star copolymer with a second copolymer labeled by a targeting ligand, i.e. biotin, on the pH sensitive block (poly-2-vinylpyridine) is considered here in order to impart possible active targeting of the tumor cells. Two architectures were studied for these labeled copolymers, i.e. a miktoarm star or a linear ABC terpolymer, and the respective hybrid micelles are compared in terms of cytotoxicity (cells viability) and cellular uptake (using fluorescent dye loaded micelles). Finally, the triggered drug release in the cytosol of tumor cells was investigated by studying, on the one hand, the lysosomal integrity after internalization and, on the other hand, the release profile in function of the pH.

Novel functional degradable block copolymers for the building of reactive micelles

Amphiphilic biocompatible copolymers are promising materials for the elaboration of nanosystems for drug delivery applications. This paper aims at reporting on the synthesis of new functional amphiphilic copolymers based on biocompatible and bioeliminable blocks. Poly(ethylene oxide) was selected as the hydrophilic block, whereas an aliphatic polyester, i.e. poly(e-caprolactone), or a polycarbonate, i.e. poly(trimethylene carbonate), was chosen as the degradable hydrophobic block. In order to allow a post-functionalization of the micelles core, azide groups were introduced on the hydrophobic segment to provide reactivity towards functional alkyne derivatives by the copper azide–alkyne cycloaddition (CuAAC). For this purpose, a functional lactone, i.e. α-chloro-e-caprolactone, was introduced during the polymerization of the hydrophobic block before being converted into azide on the preformed copolymer. Such reactivity of the block copolymers and their self-assemblies is of prime interest for drugs or fluorescent dyes grafting, or for the crosslinking of the micelles core. The influence of the azides distribution along the degradable block on the micelles post-functionalization ability has been studied by using alkyne bearing fluorescent dyes as models for drugs. The hydrophilicity of the dye on the micelles post-functionalization efficiency has also been investigated.

In vitro investigations of smart drug delivery systems based on redox-sensitive cross-linked micelles.

Redox-sensitive micelles are designed by using block copolymers of different architectures composed of a hydrophilic block of poly(ethylene oxide), and hydrophobic blocks of poly(ϵ-caprolactone) and poly(α-azide-ϵ-caprolactone). Stability of these micelles is insured in diluted media by cross-linking their core via the addition of a bifunctional cross-linker, while redox sensitivity is provided to these micelles by inserting a disulfide bridge in the cross-linker. The potential of these responsive micelles to be used as nanocarriers is studied in terms of cytotoxicity and cellular internalization. The release profiles are also investigated by varying the environment reductive strength.

In vitro investigations of smart drug delivery systems based on redox-sensitive cross-linked micelles

Redox-sensitive micelles are designed by using block copolymers of different architectures composed of a hydrophilic block of poly(ethylene oxide), and hydrophobic blocks of poly(ϵ-caprolactone) and poly(α-azide-ϵ-caprolactone). Stability of these micelles is insured in diluted media by cross-linking their core via the addition of a bifunctional cross-linker, while redox sensitivity is provided to these micelles by inserting a disulfide bridge in the cross-linker. The potential of these responsive micelles to be used as nanocarriers is studied in terms of cytotoxicity and cellular internalization. The release profiles are also investigated by varying the environment reductive strength.

Tailor-made copolymers for responsive drug delivery nanosystems.

for the Symposium on Innovative Polymers for Controlled Delivery 1 TAILOR-MADE COPOLYMERS FOR RESPONSIVE DRUG DELIVERY NANOSYSTEMS Sébastien Cajot , Christine Jérôme 1 Center for Education and Research on Macromolecules (CERM), University of Liege, B6 Sart tilman, B-4000 Liege, Belgium. e-mail: s.cajot@ulg.ac.be Summary Amphiphilic macromolecules combining a biodegradabl e and a bioeliminable block have been synthesized in order to build micellar drug deliver y systems. Particularly, redox reversible disulfide linkages have been introduced in the structure to e nsure cross-linking of the micelles formed in water and prevent their dissociation at high dilution upo n injection. The synthesis of polymers and their micellization will be especially emphasized in this paper.