Poly(amidoamine)s: Past, present, and perspectives

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.

Thiolated polymers or designated thiomers are mucoadhesive basis polymers, which display thiol bearing side chains. Based on thiol/disulfide exchange reactions and/or a simple oxidation process disulfide bonds are formed between such polymers and cysteine-rich subdomains of mucus glycoproteins building up the mucus gel layer. Thiomers mimic therefore the natural mechanism of secreted mucus glycoproteins, which are also covalently anchored in the mucus layer by the formation of disulfide bonds-the bridging structure most commonly encountered in biological systems. So far the cationic thiomers chitosan-cysteine, chitosan-thiobutylamidine as well as chitosan-thioglycolic acid and the anionic thiomers poly(acylic acid)-cysteine, poly(acrylic acid)-cysteamine, carboxy-methylcellulose-cysteine and alginate-cysteine have been generated. Due to the immobilization of thiol groups on mucoadhesive basis polymers, their mucoadhesive properties are 2- up to 140-fold improved. The higher efficacy of this new generation of mucoadhesive polymers in comparison to the corresponding unmodified mucoadhesive basis polymers could be verified via various in vivo studies on various mucosal membranes in different animal species and in humans. The development of first commercial available products comprising thiomers is in progress. Within this review an overview of the mechanism of adhesion and the design of thiomers as well as delivery systems comprising thiomers and their in vivo performance is provided.