Exploiting topology-directed nanoparticle disassembly for triggered drug delivery

Abstract

The physical properties of cyclic and linear polymers are markedly different; however, there are few examples which exploit these differences in clinical applications. In this study, we demonstrate that self-assemblies comprised of cyclic-linear graft copolymers are significantly more stable than the equivalent linear-linear graft copolymer assemblies. This difference in stability can be exploited to allow for triggered disassembly by cleavage of just a single bond within the cyclic polymer backbone, via disulfide reduction, in the presence of intracellular levels of l-glutathione. This topological effect was exploited to demonstrate the first example of topology-controlled particle disassembly for the controlled release of an anti-cancer drug in vitro. This approach represents a markedly different strategy for controlled release from polymer nanoparticles and highlights for the first time that a change in polymer topology can be used as a trigger in the design of delivery vehicles. We propose such constructs, which demonstrate disassembly behavior upon a change in polymer topology, could find application in the targeted delivery of therapeutic agents.

Aliphatic Polycarbonates from Cyclic Carbonate Monomers and Their Application as Biomaterials

“…These nanocarriers stay intact when circulating in the blood and, upon being triggered by the unique tumoral extracellular environment, allow release of the carried drug or interaction with a specific target, which in turn increase their therapeutic efficacy while reducing adverse reactions. To this end, polycarbonate-derived nanocarriers have been designed to respond to various stimuli for achieving spatiotemporal control of drug release. ,− For example, an acid-labile acetal linkage was incorporated into CC monomers, such as TMBPEC, imparting pH-sensitivity to the micellar systems. The hydrolysis of the acetal bond in the polycarbonate segment under mild acidic condition, which characterizes the microenvironment of solid tumors, resulted in significant swelling of the nanocarriers and rapid drug release. , The following in vivo study revealed that the doxorubicin-loaded PEG- b -PTMBPEC nanoparticles could dramatically reduce the systemic toxicity of the anticancer drug and exert excellent tumor-killing activity .…”

Cyclic polymers: Advances in their synthesis, properties, and biomedical applications

“…This topology modification leads to the disassembly of the nanoparticles and, thus, the release of the encapsulated molecule ( Figure 5). [211] Gene therapy is another topic of interest in modern medicine, as it is believed that the delivery of "healthy" nucleic F I G U R E 4 Effect of the topology on the renal clearance acids into the nuclei of target cells may help to cure or prevent some genetic disorders. [212][213][214][215] Polycationic polymers have been widely investigated for that purpose, as they are able to complex DNA by electrostatic interactions to form the so-called "polyplexes."…”

“…This topology modification leads to the disassembly of the nanoparticles and, thus, the release of the encapsulated molecule (Figure 5). [ 211 ]…”

pH-Responsive Water-Soluble Cyclic Polymer

“…In bulk, cyclic polymers exhibit higher density and higher glass transition temperatures . Cyclic polymers often exhibit different properties in a biological complex, such as longer in vivo circulation times and higher tumor uptake − as drug carriers and increased stability, higher efficiency, and reduced cytotoxicity as gene carriers. , …”