2.B.60. The Interlocked Catenane/Rotaxane/Polyrotaxane (ICRP) Family
Due to their low cytotoxicity, controllable size, and unique architecture, cyclodextrin (CD)-based polyrotaxanes and polypseudorotaxanes have been considered for functions such as drug delivery, gene delivery, and tissue engineering (Li et al. 2011). CD-based biodegradable polypseudorotaxane hydrogels have been used as injectable drug delivery systems for sustained and controlled drug release. Polyrotaxanes with drug or ligand-conjugated CDs threaded on a polymer chain with biodegradable end groups may be useful for controlled, multivalent targeting delivery. Cationic polyrotaxanes consisting of multiple oligoethylenimine-grafted CDs threaded on a block copolymer chain are attractive non-viral gene carries due to the strong DNA-binding ability, low cytotoxicity, and high gene transfection efficiency. Cytocleavable end caps have been introduced in the polyrotaxane systems in order to ensure efficient endosomal escape for intracellular trafficking of DNA (Li et al. 2011).
DNA-based machines include transporters and interlocked cyclic DNA structures acting as reconfigurable catenanes, rotaxanes, and rotors (Wang et al. 2014). Interlocked circular DNA nanostructures, e.g., catenanes or rotaxanes, have been used for these and other functions (Lu et al. 2016). Naphthalene diimides (NDIs) have applications as biological sensors, molecular switching devices such as catenanes and rotaxanes and ligand-gated ion-channels (Kobaisi et al. 2016). Photoinduced electron transfer can occur in multiporphyrinic interlocked structures (Flamigni et al. 2004), and charge transfer through switchable interlinked molecules such as catenanes and rotaxanes can also occur (Jan van der Molen and Liljeroth 2010; Yang et al. 2012). Transition metal-complexed catenanes and rotaxanes are dynamic systems that can function as molecular machines (Durot et al. 2014), and interlocked cyclic DNA structures can act as reconfigurable catenanes and rotaxanes (Wang et al. 2014). Interlocked systems, rotaxanes and catenanes, have been incorporated into nanomedicine chemical platforms (Ornelas-Megiatto et al. 2015), and used as drug transporters (Wang et al. 2014; Casas-Hinestroza et al. 2019). Rotaxanes, pseudorotaxanes, and catenanes are supramolecular complexes with potential use in nanomachinery, molecular computing, and single-molecule studies and have been used to translocate proteins across ClyA nanopores (Biesemans et al. 2015). The rotaxanes described here may be structurally related to those in TC family 2.B.32.
Canton et al. 2021 described the modular design of a pseudorotaxane-based supramolecular pump and its photochemically driven autonomous nonequilibrium operation in a dissipative regime. These properties derive from careful engineering of the energy maxima and minima along the threading coordinate and their light-triggered modulation. Unlike its precursor, this second-generation system is amenable to functionalization for integration into more complex devices (Canton et al. 2021).
Rotaxanes are agents that can transport material into cells. A cleft-containing rotaxane exists in two dominant conformations ('closed' and 'open'). Conformational flexibility is important for the ability of the rotaxanes to bind guests and transport material into cells (Bao et al. 2006). A locked rotaxane exhibited a reduced capacity to transport a fluoresceinated peptide into cells, whereas the unmodified rotaxane efficiently delivers the peptide. Cellular uptake of the peptide was largely temperature and ATP independent, suggesting that the rotaxane-peptide complex passes through the cellular membrane without requiring active cell-mediated processes. The results show that the sliding motion of the wheel is necessary for the delivery of materials into cells and can enhance the association of guests (Bao et al. 2006).
Macrocyclic compounds can be transported across phospholipid bilayers by umbrella-rotaxanes (Chhun et al. 2013). They exhibit amphomorphic properties and have the ability to penetrate and cross phospholipid bilayers. An azobenzene-based molecular shuttle, PR2, can perform light-gated ion transport across lipid membranes (Wang et al. 2021). The amphiphilicity and membrane-spanning molecular length enable PR2 to insert into the bilayer membrane and efficiently transport K+ (EC50 =4.1 μm) through the thermally driven stochastic shuttle motion of the crown ether ring along the axle. The significant difference in shuttling rate between trans-PR2 and cis-PR2 induced by molecular isomerization enables a light-gated ion transport, i.e., ON/OFF in situ regulation of transport activity and single-channel current. Thus, a photoswitchable molecular machine to realize gated ion transport, demonstrates the value of molecular machines functioning in biomembranes (Wang et al. 2021). A nanopore-type machine promotes the vectorial transport of DNA across membranes (Franceschini et al. 2013). Moreover, calixarene-based artificial ionophores mediate chloride transport across natural liposomal bilayer membranes (Pilato et al. 2021).