Poly(disulfide)s

Supramolecular chemistry has developed over the last forty years as chemistry beyond the molecule. Starting with the investigation of the basis of molecular recognition, it has explored the implementation of molecular information in the programming of chemical systems towards self-organisation processes, that may occur either on the basis of design or with selection of their components. Supramolecular entities are by nature constitutionally dynamic by virtue of the lability of non-covalent interactions. Importing such features into molecular chemistry, through the introduction of reversible bonds into molecules, leads to the emergence of a constitutional dynamic chemistry, covering both the molecular and supramolecular levels. It considers chemical objects and systems capable of responding to external solicitations by modification of their constitution through component exchange or reorganisation. It thus opens the way towards an adaptive and evolutive chemistry, a further step towards the chemistry of complex matter.

Reduction-sensitive biodegradable polymers and conjugates have emerged as a fascinating class of biomedical materials that can be elegantly applied for intracellular triggered gene and drug delivery. The design rationale of reduction-sensitive polymers and conjugates usually involves incorporation of disulfide linkage(s) in the main chain, at the side chain, or in the cross-linker. Reduction-sensitive polymers and conjugates are characterized by an excellent stability in the circulation and in extracellular fluids, whereas they are prone to rapid degradation under a reductive environment present in intracellular compartments such as the cytoplasm and the cell nucleus. This remarkable feature renders them distinct from their hydrolytically degradable counterparts and extremely intriguing for the controlled cytoplasmic delivery of a variety of bioactive molecules including DNA, siRNA, antisense oligonucleotide (asODN), proteins, drugs, etc. This review presents recent advances in the development of reduction-sensitive biodegradable polymers and conjugates, with particular focus on the up-to-date design and chemistry of various reduction-sensitive delivery systems including liposomes, polymersomes, polymeric micelles, DNA containing nanoparticles, polyion complex micelles, nano- and micro-gels, nanotubes, and multi-layered thin films. It is evident that reduction-sensitive biodegradable polymers and conjugates are highly promising functional biomaterials that have enormous potential in formulating sophisticated drug and gene delivery systems.