Biodegradable supramolecular micelles via host-guest interaction of cyclodextrin-terminated polypeptides and adamantane-terminated polycaprolactones.

Biodegradable supramolecular micelles were prepared exploiting the host-guest interaction of cyclodextrin and adamantane. Cyclodextrin-initiated polypeptides acted as the hydrophilic corona, whereas adamantane-terminated polycaprolactones served as the hydrophobic core.

Biodegradable and Dual-Responsive Polypeptide-Shelled Cyclodextrin-Containers for Intracellular Delivery of Membrane-Impermeable Cargo.

The transport of membrane impermeable compounds into cells is a prerequisite for the efficient cellular delivery of hydrophilic and amphiphilic compounds and drugs. Transport into the cell's cytosolic compartment should ideally be controllable and it should involve biologically compatible and degradable vehicles. Addressing these challenges, nanocontainers based on cyclodextrin amphiphiles that are stabilized by a biodegradable peptide shell are developed and their potential to deliver fluorescently labeled cargo into human cells is analyzed. Host-guest mediated self-assembly of a thiol-containing short peptide or a cystamine-cross-linked polypeptide shell on cyclodextrin vesicles produce short peptide-shelled (SPSVss ) or polypeptide-shelled vesicles (PPSVss ), respectively, with redox-responsive and biodegradable features. Whereas SPSVss are permeable and less stable, PPSVss effectively encapsulate cargo and show a strictly regulated release of membrane impermeable cargo triggered by either reducing conditions or peptidase treatment. Live cell experiments reveal that the novel PPSVSS are readily internalized by primary human endothelial cells (human umbilical vein endothelial cells) and cervical cancer cells and that the reductive microenvironment of the cells' endosomes trigger release of the hydrophilic cargo into the cytosol. Thus, PPSVSS represent a highly efficient, biodegradable, and tunable system for overcoming the plasma membrane as a natural barrier for membrane-impermeable cargo.

Self-Assembled Cationic Polypeptide Supramolecular Nanogels for Intracellular DNA Delivery.

Supramolecular nanogels are an emerging class of polymer nanocarriers for intracellular delivery, due to their straightforward preparation, biocompatibility, and capability to spontaneously encapsulate biologically active components such as DNA. A completely biodegradable three-component cationic supramolecular nanogel was designed exploiting the multivalent host-guest interaction of cyclodextrin and adamantane attached to a polypeptide backbone. While cyclodextrin was conjugated to linear poly-L-lysine, adamantane was grafted to linear as well as star shaped poly-L-lysine. Size control of nanogels was obtained with the increase in the length of the host and guest polymer. Moreover, smaller nanogels were obtained using the star shaped polymers because of the compact nature of star polymers compared to linear polymers. Nanogels were loaded with anionic model cargoes, pyranine and carboxyfluorescein, and their enzyme responsive release was studied using protease trypsin. Confocal microscopy revealed successful transfection of mammalian HeLa cells and intracellular release of pyranine and plasmid DNA, as quantified using a luciferase assay, showing that supramolecular polypeptide nanogels have significant potential in gene therapy applications.

Host-guest interactions for extracting antibiotics with a γ-cyclodextrin poly(glycidyl-co-ethylene dimethacrylate) hybrid sorbent.

A procedure for the solid-phase extraction of antibiotics (enoxacin, ofloxacin, norfloxacin, ciprofloxacin, and sparfloxacin) in water has been developed. The sorbent used is based on a poly(glycidyl-co-ethylene dimethacrylate) network, whose previously modified surface has been functionalized with γ-cyclodextrin through a click-chemistry reaction. The architecture of the material has been characterized by thermogravimetric analysis, N2 adsorption-desorption, Raman spectroscopy, confocal microscopy, and scanning electron microscopy, showing good capability to be used as a filler for extraction cartridges. The optimization of the extraction methodology shows good intra-day and inter-day repeatability of the extraction procedure, with coefficients of variation between 2.5 and 5.1% and the possibility of reusing the material at least five times. The detection limits of the method have been established at the µg L-1 level, confirming the possibility of quantifying trace levels. To end, real groundwater samples have been analyzed and the results are comparable with those obtained with a reference method. The proposed material can be used for assessing the presence of antibiotics in aqueous environments through an extraction procedure taking advantage of the presence of γ-cyclodextrin on its structure.

Adamantane-Terminated Polypeptides: Synthesis by N-Carboxyanhydride Polymerization and Template-Based Self-Assembly of Responsive Nanocontainers via Host-Guest Complexation with ß-Cyclodextrin.

The synthesis of adamantane-terminated polypeptides by N-carboxyanhydride (NCA) polymerization and their use in the template-based self-assembly of redox-responsive nanocontainers is described. Cyclodextrin vesicles (CDV) serve as a supramolecular template to anchor adamantane terminated polypeptides on to the surface of CDV and to form polypeptide shelled vesicles (PPSVss) which are stabilized by crosslinking with cystamin. Polypeptides are characterized by nuclear magnetic resonance, matrix-assisted laser desorption/ionization (MALDI), and gel permeation chromatography, and nanocontainer formation at each step is confirmed by dynamic light scattering (DLS) and zeta potential measurements. MALDI confirms the presence of the adamantane at the end of the polymers, and isothermal titration calomatry (ITC) of the adamantane-terminated polypeptides with ß-cyclodextrin proves the capability of adamantane on the polypeptides to form host-guest inclusion complexes even with the longest polypeptides. Encapsulation of a model dye carboxyfluorescein in PPSVss and its redox-responsive release demonstrates the potential use of this novel type of completely biodegradable and biocompatible nanocontainer for the purpose of intracellullar delivery.

Polymer Nanocontainers for Intracellular Delivery.

Carriers for intracellular delivery are required to overcome limitations of therapeutic agents such as low specificity, systemic toxicity, high clearance rate, and low therapeutic index. Nanocontainers comprised of an aqueous core and a polymer shell have received increasing attention because they readily combine stimuli response to improve intracellular payload release and surface modification to enhance selectivity towards the desired region of action. This Minireview summarizes the design and properties of polymer nanocontainers for intracellular delivery, classified according to the polymer architecture.