Design of Water-Soluble Rotaxane-Capped Superparamagnetic, Ultrasmall Fe3O4 Nanoparticles for Targeted NIR Fluorescence Imaging in Combination with Magnetic Resonance Imaging.

Integrating an NIR fluorescent probe with a magnetic resonance imaging (MRI) agent to harvest complementary imaging information is challenging. Here, we have designed water-soluble, biocompatible, noncytotoxic, bright-NIR-emitting, sugar-functionalized, mechanically interlocked molecules (MIMs)-capped superparamagnetic ultrasmall Fe3O4 NPs for targeted multimodal imaging. Dual-functional stoppers containing an unsymmetrical NIR squaraine dye interlocked within a macrocycle to construct multifunctional MIMs are developed with enhanced NIR fluorescence efficiency and durability. One of the stoppers of the axle is composed of a lipophilic cationic TPP+ functionality to target mitochondria, and the other stopper comprises a dopamine-containing catechol group to anchor at the surface of the synthesized Fe3O4 NPs. Fe3O4 NPs surface-coated with targeted NIR rotaxanes help to deliver ultrasmall magnetic NPs specifically inside the mitochondria. Two carbohydrate moieties are conjugated with the macrocycle of the rotaxane via click chemistry to improve the water solubility of MitoSQRot-(Carb-OH)2-DOPA-Fe3O4 NPs. Water-soluble, rotaxane-capped Fe3O4 NPs are used for live-cell mitochondria-targeted NIR fluorescence confocal imaging, 3D and multicolor imaging in combination with T2-weighted MRI on a 9.4 T MR scanner with a high relaxation rate (r2) of 180.7 mM-1 s-1. Biocompatible, noncytotoxic, ultrabright NIR rotaxane-capped superparamagnetic ultrasmall monodisperse Fe3O4 NPs could be a promising agent for targeted multimodal imaging applications.

Dynamic nitric oxide/drug codelivery system based on polyrotaxane architecture for effective treatment of Candida albicans infection.

The low permeability of antifungal agents to fungal biofilms, which allows the continued survival of the fungus inside, is a key issue that makes fungal infections difficult to cure. Inspired by the unique dynamic molecule motion properties of the polyrotaxane (PR) nanomedicine, herein, a dynamic delivery system Clo@mPRP/NONOate was fabricated by co-loading nitric oxide (NO) and the antifungal drug clotrimazole (Clo) onto the α-cyclodextrin (α-CD) PR modified mesoporous polydopamine (mPDA) nanoparticles, in which pentaethylenehexamine (PEHA) was grafted to α-CDs. The cationic α-CDs endowed this dynamic NO/Clo codelivery system with the ability to effectively attach to fungal biofilms through electrostatic interaction, while the introduction of PRs with flexible molecule motion (slide and rotation of CDs) enhanced the permeability of nanoparticles to biofilms. Meanwhile, NO could effectively inhibit the formation of fungal hyphae, showing an dissipating effect on mature biofilms, and could be further combined with Clo to completely eradicate fungi inside the biofilms. In addition, the dynamic system Clo@mPRP/NONOate could efficiently and synergistically eliminate planktonic Candida albicans (C. albicans) in a safe and no toxic side effect manner, and effectively cured C. albicans-induced vaginal infection in mice. Therefore, this dynamic NO/Clo codelivery system provided an effective solution to the clinical treatment of C. albicans-induced vaginal infection, and the application prospect could even be extended to other microbial infectious diseases. STATEMENT OF SIGNIFICANCE: A dynamic codelivery system based on cationized cyclodextrin polyrotaxane combining nitric oxide and antifungal drugs clotrimazole was prepared to deal with the issue of clinical fungal biofilm infection. This dynamic codelivery system could be attached to the Candida albicans biofilms and penetrate into biofilm via flexible molecular mobility to effectively eradicate the fungi. This dynamic codelivery system could synergistically and efficiently eliminate planktonic-state Candida albicans, but did not show significant cytotoxicity to normal somatic cells.

Reactive Oxygen Species-Triggered Dissociation of a Polyrotaxane-Based Nanochelator for Enhanced Clearance of Systemic and Hepatic Iron.

Chronic blood transfusions are used to alleviate anemic symptoms in thalassemia and sickle cell anemia patients but can eventually result in iron overload (IO) and subsequently lead to severe oxidative stress in cells and tissues. Deferoxamine (DFO) is clinically approved to treat transfusional IO, but the use of the iron chelator is hindered by nonspecific toxicity and poor pharmacokinetic (PK) properties in humans, resulting in the need to administer the drug via long-term infusion regimens that can often lead to poor patient compliance. Herein, a nanochelator system that uses the characteristic IO physiological environment to dissociate was prepared through the incorporation of DFO and reactive oxygen species (ROS)-sensitive thioketal groups into an α-cyclodextrin-based polyrotaxane platform (rPR-DFO). ROS-induced dissociation of this nanochelator (ca. 10 nm) into constructs averaging 2 nm in diameter significantly increased urine and fecal elimination of excess iron in vivo. In addition to significantly improved PK properties, rPR-DFO was well-tolerated in mice and no adverse side effects were noted in single high dose or multiple dose acute toxicity studies. The overall features of rPR-DFO as a promising system for iron chelation therapy can be attributed to a combination of the nanochelator's improved PK, favorable distribution to the liver, and ROS-induced dissociation properties into constructs <6 nm for faster renal elimination. This ROS-responsive nanochelator design may serve as a promising alternative for safely prolonging the circulation of DFO and more rapidly eliminating iron chelates from the body in iron chelation therapy regimens requiring repeated dosing of nanochelators.

Provitamin supramolecular polymer micelle with pH responsiveness to control release, bioavailability enhancement and potentiation of cytotoxic efficacy.

Encapsulation techniques to generate core/shell systems provide a method that improves physicochemical properties, which are very important in biological applications. ß-carotene is a common carotenoid that has shown preventive effects in skin diseases and vitamin A deficiency but this compound has limited water solubility and bioavailability, which hinder its broad application. The use of polyrotaxane compounds formed from cyclodextrins has allowed supramolecular polymer micelles (SMPMs) to be synthesized to encapsulate ß-carotene. The polymeric compound Pluronic F127® was also used to create core/shell nanoparticles (NPs) that contain ß-carotene. Bioactive compound encapsulation was fully confirmed by nuclear magnetic resonance spectroscopy and by scanning and transmission electron microscopy. The method based on cyclodextrin and lecithin allow to release slowly when the systems were exposed to an aqueous medium by pH control, with an increase of 16 times of bioavailability comparing with free carotenoid. This allowed to potentiate the cytotoxic activity on a melanoma cell line by enhancing the water solubility to more than 28 mg/L, and present promising applications of SMPMs to provitamins.

A neptunium(v)-mediated interwoven transuranium-rotaxane network incorporating a mechanically interlocked [c2]daisy chain unit.

As an extension of actinide-rotaxane complexes from uranium to transuranium, we report the first crystal structure of a neptunium-rotaxane complex, NRCP-1, in which an interwoven neptunium(v)-rotaxane coordination network incorporating a mechanically-interlocked [c2]daisy chain unit is promoted via the simultaneous coordination of cucurbituril (CB6) and axle molecules in [2]pseudorotaxane to NpV.

Enzymatically Biodegradable Polyrotaxane-Deferoxamine Conjugates for Iron Chelation.

Chelation therapy is frequently used to help reduce excess iron in the body, but current chelators such as deferoxamine (DFO) are plagued by short blood circulation times, which necessitates infusions and can cause undesirable toxic side effects in patients. To address these issues, polyrotaxanes (PR) were synthesized by threading α-cyclodextrin (α-CD) onto poly(ethylene glycol) bis(amine) (PEG-BA, MW 3400 g/mol) capped with enzymatically cleavable bulky Z-L phenylalanine (Z-L Phe) moieties. The resulting PR was conjugated to DFO and hydroxypropylated to generate the final polyrotaxane-DFO (hPR-DFO). The iron chelating capability of hPR-DFO was verified by UV-vis absorption spectroscopy and the ability of materials to degrade into smaller CD-conjugated DFO fragments (hCD-DFO) in the presence of the protease was confirmed via gel permeation chromatography. In vitro studies in iron-overloaded macrophages reveal that hPR-DFO can significantly reduce the cytotoxicity of the drug while maintaining its chelation efficacy, and that it is more rapidly endocytosed and trafficked to lysosomes of iron-overloaded cells in comparison to non-iron-overloaded macrophages. In vivo studies indicate that iron-overloaded mice treated with hPR-DFO displayed lower serum ferritin levels (a measure of iron burden in the body) and could eliminate excess iron by both the renal and fecal routes. Moreover, there was no gross evidence of acute toxicological damage to the liver or spleen.

Pseudorotaxane-type n-hydrocarbon container. Metallacyclodimer of ionic palladium(II) complexes containing 1,3-bis(4-pyridyl)tetramethyldisiloxane.

An unusual "pseudorotaxaned n-alkane within a metalla-cyclodimer" system, C(n)H(2n+2)@[(Me(4)en)Pd(L)](2)(CF(3)SO(3))(4) (n = 5, 6, 7; Me(4)en = N,N,N',N'-tetramethylethylenediamine; L = 1,3-bis(4-pyridyl)tetramethyldisiloxane), was constructed. This system is the first pseudorotaxane-type petroleum container achieved via the appropriate size effect.

Photoinduced electron transfer in porphyrin- and fullerene/porphyrin-based rotaxanes as studied by time-resolved EPR spectroscopy.

Photoinduced intramolecular electron-transfer (ET) and energy-transfer (EnT) processes in two rotaxanes, one containing both zinc porphyrin and C(60) fullerene moieties incorporated around the Cu(I) bisphenanthroline core [(ZnP)(2)-Cu(I)(phen)(2)-C(60)] and a second complex lacking the fullerene [(ZnP)(2)-Cu(I)(phen)(2)], were studied by time-resolved electron paramagnetic resonance (TREPR) spectroscopy at 9.5 GHz (X-band) combined with a selective photoexcitation of the rotaxane moieties. The experiments were carried out in isotropic toluene and ethanol and in anisotropic nematic liquid-crystal (E-7) media over a wide range of temperatures corresponding to the different states of the solvents. The TREPR results are compared with those obtained previously by optical methods in dichloromethane at room temperature. It is demonstrated that the efficiencies and pathways of the light-driven ET and EnT processes in both rotaxanes strongly depend on the properties of their microenvironment, resulting in the formation of distinct charge-separated states under different experimental conditions. The complementary results revealed by the optical and TREPR techniques are attributed to the relatively high conformational mobility of the mechanically interlocked rotaxane systems. Because of the solute-solvent interactions, the rotaxanes are able to change conformation in different microenvironments, which affects the parameters of the photoinduced processes occurring in these systems.

Synthesis and characterization of nitric oxide generative polyrotaxane.

L-Arginine was immobilized into a supramolecular-structured polyrotaxane to examine the generation of nitric oxide, with a view to improving antithrombosis and the blood compatibility of polymeric biomaterials. L-Arginine was immobilized to the hydroxyl groups of alpha-cyclodextrins in the polyrotaxane via an ester linkage, and the nitric oxide generation and L-arginine release behavior were characterized. L-Arginine-immobilized polyrotaxane was insoluble in water, but was found to generate nitric oxide when placed in Tris-HCI buffer supplemented with activators. L-Arginine-immobilized polyrotaxane exhibited sustained nitric oxide generation for a period of 250 h. L-Arginine was completely released by non-enzymatic hydrolysis from 200 h to 700 h, with a lag-time for the first 200 h. Consequently, after the generation of nitric oxide and the release of L-arginine from the L-arginine-immobilized polyrotaxane, the residual component will be a polyrotaxane with superior biocompatibility and mechanical properties. These results suggest that L-arginine-immobilized polyrotaxane can be useful in a wide range of medical applications, including use as a nitric oxide generative system for antithrombosis, coating and blending materials of hydrophobic extracorporeal circuits, and implantable catheters.

Chemically induced contraction and stretching of a linear rotaxane dimer.

Copper(I)-induced assembly of two self-complementary identical units, which consist of a ring that incorporates a 1,10-phenanthroline group attached to a small filament containing a second 1,10-phenanthroline (phen) group, leads quantitatively to a doubly threaded complex. Each copper(I) center is four-coordinate and is located inside a ring and bound to a phen from the macrocyle. The two other coordination sites are occupied by a phen from the filament connected to the other ring. An X-ray structure of the dicopper(I) complex unambiguously demonstrates the doubly threaded nature of the system. The molecule has C(2) symmetry in the crystal. This is an extended form with a Cu small middle dot small middle dot small middle dotCu separation of 18.3 A and an overall length close to 40 A. Further synthetic work, which utilizes the two terminal phenolic functions of the previous dicopper(I) complex, gives rise to a more complex system in which both filaments have been prolonged in opposite directions by 2,2':6',2"-terpyridine (terpy) motifs and bulky stoppers. The organic backbone is that of a rotaxane dimer. Although redox cycling of Cu(I) to Cu(II) did not lead to intramolecular rearrangement, simple chemical reactions induced large conformational changes. The rotaxane dimer was set in motion as follows. The dicopper(I) complex, which is in an extended conformation, was demetallated by using KCN. From the free ligand, the dizinc complex was formed quantitatively at room temperature. (1)H NMR data show that a new conformation is obtained: each Zn(II) is five-coordinate (phen + terpy), and the molecule is in a contracted conformation. This process is reminiscent of biological muscles in the sense that the two filaments of this system can be moved along one another in a gliding motion that keeps the whole system together, but which converts a stretched compound (overall length approximately equal to 83 A) into a contracted species (overall length approximately equal to 65 A, according to CPK models). The motion is quantitatively reversed by the addition of an excess of copper(I) to the dizinc complex; this regenerates the extended starting form. Although the motivation of the present contribution was to illustrate that a muscle-like molecule may be stretched or contracted using electrochemistry and coordination chemistry, the main body of the work is organic synthesis. This is testified by the fact that the dicopper(I) rotaxane dimer was obtained in 23 steps from commercially available compounds.