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.
Core cross-linked star polymers possessing responsiveness to pH and temperature stimuli have been prepared, and we demonstrate how changes to pH and temperature can be used to trigger the release and uptake of a hydrophobic dye.
Degradable analogues of polystyrene are synthesized via radical ring-opening (co)polymerization (rROP) between styrene and two cyclic ketene acetals, namely 2-methylene-1,3-dioxepane (MDO) and 5,6-benzo-2-methylene-1,3-dioxepane (BMDO). This approach periodically inserts ester bonds throughout the main chain of polystyrene, imparting a degradation pathway via ester hydrolysis. We discuss the historical record of this approach, with careful attention paid to the conflicting findings previously reported. We have found a common 1H NMR characterization error, repeated throughout the existing body of work. This misinterpretation is responsible for the discrepancies within the cyclic ketene acetal (CKA)-based degradable polystyrene literature. These inconsistencies, for the first time, are now understood and resolved through optimization of the polymerization conditions, and detailed characterization of the degradable copolymers and their corresponding oligomers after hydrolytic degradation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.