Youssef Bakkour

From nanospheres to micelles: simple control of PCL-g-PEG copolymers’ amphiphilicity through thiol–yne photografting

A simple method for the synthesis of a family of poly(e-caprolactone)-g-polyethylene glycol (PCL-g-PEG) copolymers of controlled amphiphilicity and their use in generating nanospheres or micelles are reported. PCL-g-PEGs with various compositions are prepared from a single strategy relying on a combination of post-polymerization modification and subsequent thiol–yne photografting. Alkyne-functional PCL (PCL-yne) was first obtained by anionic activation and reaction with propargyl bromide to yield PCL-yne with 8% alkyne groups. PEG-thiol is then reacted on PCL-yne under UV activation to yield the targeted graft copolymer by thiol–yne photoaddition. The advantage of the approach is that control over the composition is easily achieved, yielding amphiphilic graft copolymers with ethylene glycol/caprolactone (EG/CL) ratios ranging from 0.1 to 1.3. Starting from this single strategy, it was therefore possible to obtain nanospheres (DH ∼ 55 nm) or micelles (DH ∼ 30 nm) by copolymer self-assembly depending on the EG/CL ratio. The potential of PCL-g-PEG micelles as drug carriers was finally evaluated with curcumin that was efficiently encapsulated, protected and released over 80 days. Interestingly it was found that drug encapsulation efficiency and drug loading were higher for PCL-g-PEG copolymers compared to block PCL-b-PEG.

PCL–PEG graft copolymers with tunable amphiphilicity as efficient drug delivery systems

The development of flexible drug delivery systems that can be tuned as a function of the drug to be delivered and of the target disease is crucial in modern medicine. For this aim, novel amphiphilic poly(ε-caprolactone)-g-poly(ethylene glycol) (PCL-g-PEG) copolymers with well-controlled design were synthesized by thiol-yne photochemistry. The grafting density and the copolymer amphiphilicity were easily controlled via the reaction parameters: concentration, reaction time, PEG length and the molar ratio between PCL and PEG or the photoinitiator in the reaction mixture. The self-assembling behavior of the copolymers was studied and a correlation between the composition of PCL-g-PEG and the nanoaggregate diameter sizes (28 to 73 nm) and critical aggregation concentrations (1.1 to 4.3 mg L-1) was found. The influence of copolymer amphiphilicity on the drug loading was evaluated with various drugs including anticancer drugs (paclitaxel, ABT-199), drugs to overcome multidrug resistance in cancer cells (curcumin, elacridar), an anti-inflammatory drug (dexamethasone) and an antibacterial drug (clofazimine). Finally, the influence of amphiphilicity on curcumin release and toxicity towards MCF-7 cancer cell lines was studied. The impact of the grafting density, PEG length and the overall EG/CL ratio is discussed in detail. Curcumin loaded PCL-g-PEG with lower EG/CL ratios and shorter PEG chains showed higher toxicity compared to their more hydrophilic counterparts.

Rapid and facile chemical actinometric protocol for photo-microfluidic systems using azobenzene and NMR spectroscopy

In this study, the photon flux inside a photomicroreactor was determined using chemical actinometry via the photoisomerization of azobenzene at 365 nm. For this purpose, a differential equation, in which the only external data are the tabulated absorption coefficient and the quantum yield of the E isomer, was derived enabling the use of concentrated solutions of azobenzene needed for simple NMR spectroscopy analysis. The developed protocol is shown to be efficient when working using different concentrations, light intensities and solvents.

Stabilization of poly(ethylene glycol)-poly(ε-caprolactone) star block copolymer micelles via aromatic groups for improved drug delivery properties

HYPOTHESIS The functionalization of poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) block copolymers with moieties allowing for core-crosslinking is expected to result in improved micellar stability and drug delivery properties. EXPERIMENTS PEG-(PCL)8 star block copolymers were functionalized with pendant benzylthioether (BTE) groups by applying an anionic post-polymerization modification technique followed by photoradical thiol-yne addition of benzyl mercaptan. The micellar properties of PEG-(PCL)8 and PEG-(PCL-BTE)8 were studied and compared in terms of critical micelle concentration (CMC), size, morphology, drug loading and release and in vitro cytotoxicity. FINDINGS In comparison with unmodified PEG-(PCL)8 micelles, PEG-(PCL-BTE)8 micelles exhibited a 15-fold lower CMC, a 15-fold smaller size and a 50% higher drug loading and encapsulation efficiency thanks to the presence of pendant benzyl groups which provide the possibility for micellar core-crosslinking via supramolecular π-π stacking and additional hydrophobic interactions. Whereas the PEG-(PCL)8 micelles showed significant aggregation during in vitro cytotoxicity experiments, the PEG-(PCL-BTE)8 micelles showed no signs of aggregation and were capable of solubilizing high concentrations of curcumin, resulting in a significant decrease in MCF-7 cell viability after 48 h. Their ease of synthesis combined with promising results regarding drug delivery make the PEG-(PCL-BTE)8 micelles appealing for application in the field of encapsulation.

MRI-visible polymer based on poly(methyl methacrylate) for imaging applications

Macromolecular contrast agents are very attractive to afford efficient magnetic resonance imaging (MRI) visualization of implantable medical devices. In this work, we report on the grafting of a Gd-based DTPA contrast agent onto a poly(methyl methacrylate) derivative backbone by combining free radical polymerization and copper-catalyzed azide-alkyne cycloaddition (CuAAC). Using free radical polymerization, poly(methyl methacrylate-co-propargyl methacrylate) copolymers were prepared with a control of the ratio in propargyl methacrylate monomer units. The synthesis of a new azido mono-functionalized DTPA ligand was also reported and characterized by 1H NMR and mass spectroscopy. After complexation with gadolinium, this ligand has been grafted on the polymer backbone by click chemistry reaction. The obtained macromolecular contrast agent was then coated on a polypropylene mesh using the airbrushing technique and the mesh was assessed for MRI visualization at 7 teslas. The polymeric contrast agent was also tested for cytocompatibility and stability to assess its suitability for biomedical applications.

Iterative Photoinduced Chain Functionalization as a Generic Platform for Advanced Polymeric Drug Delivery Systems

Advanced drug delivery systems (DDS) are easily designed following a photoiterative strategy. Multifunctional polymers are obtained by coupling building blocks of interest to an alkynated poly(ε-caprolactone) (PCL) platform via an efficient thiol-yne photoaddition. Fine-tuning over the design is achieved, as illustrated with targeting and enzyme-responsive DDS.