Selective Fluorescent Sensing for Iron in Aqueous Solution by A Novel Functionalized Pillar[5]arene.

Iron ion is one of the most physiologically important elements in metabolic processes, indispensable for all living systems. Since its excess can lead to severe diseases, new approaches for its monitoring in water samples are urgently needed to meet requirements. Here, we firstly report a novel and universal route for the synthesis of a series of pillar[n]arene derivates containing one benzoquinone unit by photocatalysis. With this in hand, an anthracene - appended water - soluble pillar[5]arene (H) with excellent fluorescence sensing potency was prepared. H enabled the ultrasensitive detection of iron ions in aqueous solution with limits of detection of 10-8  M. Over a wide range of metal ions, H exhibited specific selectivity toward Fe3+ . More importantly, H could still properly operate in a simulated sewage sample, coexisting with multiple interference ions.

Host-Guest Formulation of Carboxylatopillar[6]arene with Ergothioneine as a New Antidote for Combinational Detoxification of Paraquat.

Paraquat (PQ) is exceptionally toxic to the human body. PQ ingestion can cause severe organ damage with a mortality rate of 50-80%, resulting from the absence of effective antidotes and detoxification solutions. Herein, a host-guest formulation is proposed, in which ergothioneine (EGT), an antioxidant drug, was encapsulated by carboxylatopillar[6]arene (CP6A) to achieve a combinational therapy for PQ poisoning. Nuclear magnetic resonance (NMR) and fluorescence titration were employed to confirm the complexation between CP6A and EGT as well as PQ with robust affinities. In vitro studies proved that EGT/CP6A significantly reduced PQ toxicity. Treatment with EGT/CP6A could effectively relieve organ damage caused by PQ ingestion and enhance the normalization of hematological and biochemical parameters. The host-guest formulation EGT/CP6A also improved the survival ratio in PQ-poisoned mice. These favorable outcomes originated from synergistic effects that PQ triggered the release of EGT to combat peroxidation damage and excess PQ was engulfed within the cavity of CP6A.

Synthesis of Cationic Biphen[4, 5]arenes as Biofilm Disruptors.

Since bacteria in biofilms are inherently resistant to antibiotics and biofilm-associated infections pose a serious threat to global public health, new therapeutic agents and schemes are urgently needed to meet clinical requirements. Here two quaternary ammonium-functionalized biphen[n]arenes (WBPn, n=4, 5) were designed and synthesized with excellent anti-biofilm potency. Not only could they inhibit the assembly of biofilms, but also eradicate intractable mature biofilms formed by Gram-positive S. aureus and Gram-negative E. coli bacterial strains. Moreover, they could strongly complex a conventional antibiotic, cefazolin sodium (CFZ) with complex stability constants of (7.41±0.29)×104  M-1 for CFZ/WBP4 and (4.98±0.49)×103  M-1 for CFZ/WBP5. Combination of CFZ by WBP4 and WBP5 synergistically enhanced biofilm eradication performance in vitro and statistically improved healing efficacy on E. coli-infected mice models, providing a novel supramolecular strategy for combating biofilm-associated infections.

A Biocompatible Liquid Pillar[n]arene-Based Drug Reservoir for Topical Drug Delivery.

Advanced external preparations that possess a sustained-release effect and integrate few irritant elements are urgently needed to satisfy the special requirements of topical administration in the clinic. Here, a series of liquid pillar[n]arene-bearing varying-length oligoethylene oxide chains (OEPns) were designed and synthesized. Following rheological property and biocompatibility investigations, pillar[6]arene with triethylene oxide substituents (TEP6) with satisfactory cavity size were screened as optimal candidate compounds. Then, a supramolecular liquid reservoir was constructed from host-guest complexes between TEP6 and econazole nitrate (ECN), an external antimicrobial agent without additional solvents. In vitro drug-release studies revealed that complexation by TEP6 could regulate the release rate of ECN and afford effective cumulative amounts. In vivo pharmacodynamic studies confirmed the formation of a supramolecular liquid reservoir contributed to the accelerated healing rate of a S. aureus-infected mouse wound model. Overall, these findings have provided the first insights into the construction of a supramolecular liquid reservoir for topical administration.

Host-guest synergistic enhancement of antibacterial effect by a supramolecular strategy.

A supramolecular synergistic antibacterial strategy involving direct complexation of a commercial antibacterial agent, azelaic acid (AzA) by a cationic pillar[5]arene (WP5A) is described. The formation of AzA/WP5A complex could exert synergistic antibacterial effect, leading to promote wound healing efficacy and reduce bacterial burden on S. aureus-infected mice models.

Supramolecular Detoxification of Macromolecular Biotoxin through the Complexation by a Large-Sized Macrocycle.

Biotoxins are diverse, complex, and hypertoxic, ultimately serving as grave and lasting menaces to humanity. Here, it is aimed to introduce a new detoxification methodology for macromolecular biotoxin through complexation by a very large macrocycle. A 25-mer peptide isolated from Lycosa erythrognatha spider venom (LyeTxI) is selected as the model macromolecular biotoxin. Quaterphen[4]arene, with a side length of ≈1.6 nm, has a sufficient cavity to bind LyeTxI. Hence, the water-soluble derivative of Quaterphen[4]arene (H) is designed and synthesized. H exhibits an overall host-guest complexation toward LyeTxI, resulting in a considerably high association constant of (7.01 ± 0.18) × 107  m-1 . This encapsulation of peptide is interesting as traditional macrocycles can only engulf the amino acid residues of peptides due to their limited cavity size. In vitro assay verifies that complexation by H inhibits the interactions of LyeTxI with cell membranes, thereby reducing its cytotoxicity, suppressing hemolysis, and decreasing the release of lactate dehydrogenase. Notably, the intravenous administration of H has a significant therapeutic effect on LyeTxI-poisoned mice, alleviating inflammation and tissue damage, and markedly improving the survival rate from 10% to 80%. An efficient and potentially versatile approach is provided to detoxify macromolecular biotoxins, with giant macrocycle serving as an antidote.

Complexation of specific residues by carboxylatopillar[6]arene for improving the zymolytic stability of arginine-containing peptides.

A general strategy for improving the zymolytic stability against proteases is reported. Carboxylatopillar[6]arene (CP6A) could effectively bind arginine and arginine-containing peptides, thereby improving the stability of angiotensin peptides in the presence of trypsin by the complexation of the side chain of the arginine residue.

Supramolecular Drug Delivery System from Macrocycle-Based Self-Assembled Amphiphiles for Effective Tumor Therapy.

Intelligent drug delivery systems (DDSs) that can improve therapeutic outcomes of antitumor agents and decrease their side effects are urgently needed to satisfy special requirements of treatment of malignant tumors in clinics. Here, the fabrication of supramolecular self-assembled amphiphiles based on the host-guest recognition between a cationic water-soluble pillar[6]arene (WP6A) host and a sodium decanesulfonate guest (G) is reported. The chemotherapeutic agent doxorubicin hydrochloride (DOX) can be encapsulated into the formed vesicle (G/WP6A) to construct supramolecular DDS (DOX@G/WP6A). WP6A affords strong affinities to G to avoid undesirable off-target leakage during delivery. Nanoscaled DOX@G/WP6A is capable of preferentially accumulating in tumor tissue via enhanced permeability and retention (EPR) effect. After internalization by tumor cells, the abundant adenosine triphosphate (ATP) binds competitively with WP6A to trigger the disintegration of self-assembled vesicles with the ensuing release of DOX. In vitro and in vivo research confirmed that DOX@G/WP6A is not only able to promote antitumor efficacy but also reduce DOX-related systemic toxicity. The above favorable findings are ascribed to the formation of ternary self-assembly, which profits from the combination of the factors of the EPR effect and the ATP-triggered release.