Tailor-made degradable copolymers for the design of advanced drug delivery systems

Doctoral thesis (2012)

Over the last decades, polymer micelles have attracted an increasing interest in drug pharmaceutical research because they could be used as efficient drug delivery systems. The goal of this thesis was ... [more ▼]

Over the last decades, polymer micelles have attracted an increasing interest in drug pharmaceutical research because they could be used as efficient drug delivery systems. The goal of this thesis was centered on the design of new smart nanocarriers and more particularly on the basis of reversibly redox-cross-linked polymer micelles. The first part of that work was dedicated to the synthesis of new macromolecular architectures associating biodegradable hydrophobic polymers such as polyester (e.g. PCL), polycarbonate (e.g. PTMC) or also polyphosphate (e.g. PBODOP) and the water soluble poly(ethylene oxide) (PEO) frequently used due to its biocompatible properties. Well-defined block copolymers have been synthesized by ring-opening polymerization. The second part of that work focused on the cross-linking of the hydrophobic block in order to obtain well stabilized micelles. The copolymerization of α-chloro-ε-caprolactone (αClεCL) allows to easy functionalize the hydrophobic block in order to reversibly cross-link the future micelle core by the addition of a disulfide bearing cross-linker. The self assembly of theses copolymers and redox-dependent micellization behaviours have been studied by diffusion light scattering and transmission electronic microscopy. Finally, the potential of these redox-sensitive micelles as active drug delivery system has been analysed by investigating their stealthy behaviours using the complement activation (CH50) test, their cytotoxicity, their cellular internalization and also the redox-sensitive profile of a hydrophobic dye. [less ▲]

Novel amphiphilic mikto-arm star-shaped copolymers for the preparation of PLA-based nanocarriers

in Macromolecular Symposia (2011), 309/310(1), 111-122

Three-arm (A2B) and four-arm (A2B2) star-shaped copolymers based on biocompatible and biodegradable hydrophobic poly(ε-caprolactone) (PCL) (A arms) and biocompatible and bioeliminable hydrophilic poly ... [more ▼]

Three-arm (A2B) and four-arm (A2B2) star-shaped copolymers based on biocompatible and biodegradable hydrophobic poly(ε-caprolactone) (PCL) (A arms) and biocompatible and bioeliminable hydrophilic poly(ethylene oxide) (PEO) (B arms) were synthesized by the coupling of an ω-azide terminated PEO chains with PCL chain bearing one (A2B) or two (A2B2) alkyne functions at the middle of the chain by the copper mediated azide-alkyne cycloaddition (CuAAC). The amphiphilic behavior of these different stars was confirmed by micellization experiments in water followed by dynamic light scattering and transmission electron microscopy analyses. The efficiency to stabilize PLA nanoparticles was investigated in function of the stars structure. [less ▲]

Disulfide bridges, new prospect in drug delivery systems?

Poster (2011, September 03)

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

in Journal of Controlled Release (2011), 152(1), 30-36

Azido-functional amphiphilic macromolecules based on a biodegradable aliphatic polyester (poly-epsilon-caprolactone, PCL) and a bioeliminable hydrophilic poly(ethylene oxide) (PEO) block have been used in ... [more ▼]

Azido-functional amphiphilic macromolecules based on a biodegradable aliphatic polyester (poly-epsilon-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 micelles 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 crosslink 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 crosslinked in the hydrophobic segment has also been studied in vitro. [less ▲]

Novel amphiphilic copolymers and design of smart nanoparticles for drug delivery systems

Poster (2011, April 29)

Tailor-made copolymers for responsive drug delivery nanosystems

Poster (2010, September 15)

Design of new pH-sensitive and cross-linked biomaterials for future medical applications

Poster (2010, March 18)

Novel Amphiphilic copolymers and design of smart nanoparticule for triggered drug delivery systems

Poster (2009, June 14)

Over the last decade, polymer micelles attracted an increasing interest in drug pharmaceutical research because they could be used as efficient drug delivery systems. Micelles of amphiphilic block ... [more ▼]

Over the last decade, polymer micelles attracted an increasing interest in drug pharmaceutical research because they could be used as efficient drug delivery systems. Micelles of amphiphilic block copolymers are supramolecular core-shell type assemblies of tens of nanometers in diameter. In principle, the micelles core is usually constructed with biodegradable hydrophobic polymers such as aliphatic polyesters, e.g. poly(epsilon-caprolactone) (PCL), which serves as a reservoir for the incorporation of various lipophilic drugs. Water soluble poly(ethylene oxide) (PEO) is most frequently used to build the micelle corona because it is very efficient in preventing protein adsorption at surfaces and in stabilizing the micelles in the blood compartment, giving rise to particles invisible to the body defence system (so-called stealthy or long circulating particles). Improvements of such simple systems however, rely on the development of novel chemistries and materials by advanced macromolecular engineering techniques. The tumour targeting of a cytotoxic agent refers to the passive accumulation of polymer nanocarriers to solid tumours (EPR effect) followed by active internalization in tumor cells. The internalization of the drug is required for cell death because most cytotoxic drugs act intracellularly. Accordingly, polymer micelles are usually modified by specific ligands. However, these ligands can decrease the micelles stealthiness and stability. No-specific ligands can be used if their exposition is modulated by the pH decrease typical of tumour tissues. Lipophilic drugs are generally incorporated in the hydrophobic core of the micelles. The release of the drug is ruled by diffusion and degradation of the biodegradable polymer used as reservoir. Even if micelles get a high stability in aqueous media thanks to their low critical micellar concentration, the dissociation of micelles is not always preserved when they are injected in the blood compartment. The cross-linking of the core of micelles by disulfide bridges will provide the stability of micelles after the administration and will release the drugs intracellularly by enzymatic breaking of disulfide bridges. This work consists in the development of new macromolecular architectures for the targeting of tumour cells. pH sensitive copolymers able to micellize so as non-specific ligand like biotin is exposed on their surface in response to pH decrease typical for tumour tissues will be synthesized by the incorporation of pH-sensitive linkers like hydrazone or imine benzoïc linkers. In addition, the core of these new micelles will be cross-linked by disulfide bridges to prevent dissociation around healthy cells and trigger the drug release inside tumour cells. [less ▲]

New pH-sensitive flower micelles for drug delivery systems

Poster (2008, June 23)

New pH-sensitive flower micelles for potential tumour targeting

Poster (2008, April 16)