Smart cross-linked polymer micelles for drug delivery

Nowadays, polymer crosslinking is widely used in industry to improve or to impart new properties to existing polymer material. In the pharmaceutical field, polymer crosslinking is of great interest for the elaboration of drug delivery devices, mostly hydrogels. Nevertheless, crosslinking is also very useful in nanovectorization of active principle. Indeed, each day, new drugs are synthesized and available on the market but in too many cases, the high hydrophobicity of some drugs makes them useless because of the absence of an appropriated administration method. The encapsulation of the drug into a nanocarrier, typically in the hydrophobic core of a polymer micelle, allows a significant increase of the drugs concentration in water in addition to the protection of the active principle against degradation. However, polymer micelles suffer of the main drawback to not be stable, leading to a premature release of the drug, when the concentration falls down the critical micellar concentration (CMC), which it is rapidly observed after intravenous injection. In order to get rid of the CMC, crosslinking of the micelle core is the most proposed strategy. Nevertheless, the crosslinking of the micelle core may have a non-negligible effect on the drug loading but mainly on the drug release due to the sequestration of the drug in the network. Over the last years, our lab investigated several strategies for the crosslinking of the micelle core made of amphiphilic and biocompatible block copolymers generally by UV radiation in order to fulfill the increasingly stringent requirements of biomedical applications. These strategies are very helpful to prepare injectable nanosized cross-linked particles loaded with an active particle. For some systems, the effect of the crosslinking rate on the drug loading and the drug release was evaluated using a model drug. As the crosslinking may interfere with the drug release after internalization of the carrier into the cell, a reversible crosslinking of the micelle core was proposed. Typically, the introduction of disulfide bond as inter-chain links allowed to delay the drug release by diffusion whereas into the cell, the reduction of the disulfide bridges into corresponding thiol led to the fast disassemble of the micelle and the specific release of the drug into cytoplasm.