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.

Stealth properties of poly(ethylene oxide)-based triblock copolymer micelles: a prerequisite for a pH-triggered targeting system.

Evaluation of the biocompatibility of pH-triggered targeting micelles was performed with the goal of studying the effect of a poly(ethylene oxide) (PEO) coating on micelle stealth properties. Upon protonation under acidic conditions, pH-sensitive poly(2-vinylpyridine) (P2VP) blocks were stretched, exhibiting positive charges at the periphery of the micelles as well as being a model targeting unit. The polymer micelles were based on two different macromolecular architectures, an ABC miktoarm star terpolymer and an ABC linear triblock copolymer, which combined three different polymer blocks, i.e. hydrophobic poly(ε-caprolactone), PEO and P2VP. Neutral polymer micelles were formed at physiological pH. These systems were tested for their ability to avoid macrophage uptake, their complement activation and their pharmacological behavior after systemic injection in mice, as a function of their conformation (neutral or protonated). After protonation, complement activation and macrophage uptake were up to twofold higher than for neutral systems. By contrast, when P2VP blocks and the targeting unit were buried by the PEO shell at physiological pH, micelle stealth properties were improved, allowing their future systemic injection with an expected long circulation in blood. Smart systems responsive to pH were thus developed which therefore hold great promise for targeted drug delivery to an acidic tumoral environment.

Near infrared and Raman spectroscopy as Process Analytical Technology tools for the manufacturing of silicone-based drug reservoirs.

Using near infrared (NIR) and Raman spectroscopy as PAT tools, 3 critical quality attributes of a silicone-based drug reservoir were studied. First, the Active Pharmaceutical Ingredient (API) homogeneity in the reservoir was evaluated using Raman spectroscopy (mapping): the API distribution within the industrial drug reservoirs was found to be homogeneous while API aggregates were detected in laboratory scale samples manufactured with a non optimal mixing process. Second, the crosslinking process of the reservoirs was monitored at different temperatures with NIR spectroscopy. Conformity tests and Principal Component Analysis (PCA) were performed on the collected data to find out the relation between the temperature and the time necessary to reach the crosslinking endpoints. An agreement was found between the conformity test results and the PCA results. Compared to the conformity test method, PCA had the advantage to discriminate the heating effect from the crosslinking effect occurring together during the monitored process. Therefore the 2 approaches were found to be complementary. Third, based on the HPLC reference method, a NIR model able to quantify the API in the drug reservoir was developed and thoroughly validated. Partial Least Squares (PLS) regression on the calibration set was performed to build prediction models of which the ability to quantify accurately was tested with the external validation set. The 1.2% Root Mean Squared Error of Prediction (RMSEP) of the NIR model indicated the global accuracy of the model. The accuracy profile based on tolerance intervals was used to generate a complete validation report. The 95% tolerance interval calculated on the validation results indicated that each future result will have a relative error below ±5% with a probability of at least 95%. In conclusion, 3 critical quality attributes of silicone-based drug reservoirs were quickly and efficiently evaluated by NIR and Raman spectroscopy.

Self-Assembly and pH-Responsiveness of ABC Miktoarm Star Terpolymers.

This work deals with the self-assembly in water of ABC miktoarm star terpolymers consisting of hydrophobic poly(-caprolactone), hydrophilic poly(ethylene oxide) (PEO), and pH-sensitive poly(2-vinylpyridine) (P2VP). A variety of experimental techniques were used, including dynamic light scattering, transmission electron microscopy, and zeta potential. Special attention was paid to the pH dependency of the supramolecular self-assemblies. A key observation is the capability of the miktoarm terpolymers to form micelles stable over the whole range of pH, although a transition was observed from neutral to highly positively charged nanoobjects upon decreasing pH.

Synthesis and pH-dependent micellization of diblock copolymer mixtures.

This work focused on the preparation and the aqueous solution properties of hybrid polymeric micelles consisting of a hydrophobic poly(epsilon-caprolactone) (PCL) core and a mixed shell of hydrophilic poly(ethylene oxide) (PEO) and pH-sensitive poly(2-vinylpyridine) (P2VP). The hybrid micelles were successfully prepared by the rapid addition of acidic water to a binary solution of PCL(34)-b-PEO(114) and PCL(32)-b-P2VP(52) diblock copolymers in N,N-dimethylformamide. These micelles were pH-responsive as result of the pH-dependent ionization of the P2VP block. The impact of pH on the self-assembly of the binary mixture of diblocks-thus on the composition, shape, size and surface properties of the micelles-was studied by a variety of experimental techniques, i.e., dynamic and static light scattering, transmission electron microscopy, Zeta potential, fluorescence spectroscopy and complement hemolytic 50 test.

Versatile functionalization and grafting of poly(epsilon-caprolactone) by Michael-type addition.

The Michael-type addition of aliphatic (co)polyesters onto gamma-acryloyloxy epsilon-caprolactone units is a very straightforward technique of functionalization and grafting, which is tolerant to a variety of functional groups and does not require intermediate protection/deprotection steps.