Drug delivery represents one of the most important research fields within the pharmaceutical industry. Different strategies are reported every day in a dynamic search for carriers with the ability to transport drugs across the body, avoiding or decreasing toxic issues and improving therapeutic activity. One of the most interesting strategies currently under research is the development of drug delivery systems sensitive to different stimuli, due to the high potential attributed to the selective delivery of the payload. In this work, a stimuli-sensitive nanocarrier was built with a bifunctional acrylic polymer, linked by imine and disulfide bonds to thiolate chitosan, the latter being a biopolymer widely known in the field of tissue engineering and drug delivery by its biodegradability and biocompatibility. These polymer nanoparticles were exposed to different changes in pH and redox potential, which are environments commonly found inside cancer cells. The results proof the ability of the nanoparticles to keep the original structure when either changes in pH or redox potential were applied individually. However, when both stimuli were applied simultaneously, a disassembly of the nanoparticles was evident. These special characteristics make these nanoparticles suitable nanocarriers with potential for the selective delivery of anticancer drugs.

Polymeric nanoparticles whose disassembly into their component polymer chains is triggered by the simultaneous application of two different stimuli are described. Reversible addition–fragmentation chain transfer (RAFT) polymerization was utilized to prepare acrylamide-based linear copolymers displaying pyridyl disulfide appendages and either aldehyde or amine functional groups. These copolymer chains were intermolecularly cross-linked through imine bond formation at pH 8.0 and then through disulfide bond formation to afford polymeric nanoparticles possessing hydrodynamic radii of 76 nm consisting of multiple polymer chains cross-linked through both imine and disulfide bonds. By performing the cross-linking reactions in the presence of the hydrophobic dye Nile Red, it was demonstrated that these polymeric nanoparticles could encapsulate a cargo of small hydrophobic molecules. The disassembly of the polymeric nanoparticles into their component polymer chains was accomplished by lowing the pH to 5.5 in the presence of the disulfide reducing agent tris(2-carboxyethyl)phosphine (TCEP), causing hydrolysis of the imine cross-links and cleavage of the disulfide cross-links, respectively, and demonstrating that the simultaneous application of both low pH and a reducing environment are required to trigger the disassembly process. It was shown that application of either a low pH or the application of the reducing agent TCEP does not trigger the disassembly of the polymeric nanoparticle as there is sufficient density of the remaining imine or disulfide cross-links which are able to maintain the structural integrity of the polymeric nanoparticle. The formation and disassembly processes of these polymeric nanoparticles was monitored by gel permeation chromatography, and the release of the dye was monitored using fluorescence spectroscopy. A 5 kDa poly(ethylene glycol) was grafted onto the polymeric nanoparticle, demonstrating the potential of these polymeric nanoparticles to undergo post-assembly functionalization.

During the last few decades the nanomedicine sector has emerged as a feasible and effective solution to the problems faced by the high percentage of poorly water-soluble drugs. Decreasing the size of such drug compounds to the nanoscale can significantly change their physical properties, which lays the foundation for the use of nanomedicine for pharmaceutical applications. Various techniques have been developed to produce poorly water-soluble drug nanoparticles, mainly to address the poor water-soluble issues but also for the efficient and targeted delivery of such drugs. These techniques can be generally categorized into top-down, bottom-up and encapsulation approaches. Among them, the top-down approaches have been the main choice for industrial preparation of drug nanoparticles while other methods are actively investigated by researchers. In this review, we aim to give a comprehensive overview and latest progress of the top-down, bottom-up, and encapsulation methods for the preparation of poorly water-soluble drug nanoparticles and how solvents and additives can be selected for these methods. In addition to the more industrially applied top-down approaches, the review is focused more on bottom-up and encapsulation methods, particularly covering supercritical fluid-related methods, cryogenic techniques, and encapsulation with dendrimers and responsive block copolymers. Some of the approved and mostly used nanodrug formulations on the market are also covered to demonstrate the applications of poorly water-soluble drug nanoparticles. This review is complete with perspectives on the development and challenges of fabrication techniques for more effective nanomedicine.

Poly(alkyl)acrylates are a major class of nonbiodegradable polymers which are difficult to recycle due to an all-carbon backbone. Introducing a certain number of ester bonds in the backbone via radical ring opening copolymerization of acrylates with 2-methylene-1,3 dioxepane (MDO) improves its degradability and may be promising for chemical recycling. The current work examines the influence of monomer addition profiles on the copolymerization of acrylates with MDO. We improved the homogeneity of the MDO insertion through a semibatch approach, which was demonstrated by the molecular weight distribution of fragments after alkali degradation. By detailed NMR analysis, we identified the incorporation of MDO ring retained units, formation of branches on acrylate units, and formation of branches on MDO ring open units as the key side reactions. Theoretical calculations showed that mainly kinetic factors influence the outcome of the polymerization.

This review discusses the history of reversible-deactivation radical ring-opening polymerization of cyclic ketene acetals, focusing on the preparation of degradable complex polymeric architectures.