Supramolecular Organic Frameworks: Exploring Water-Soluble, Regular Nanopores for Biomedical Applications.

In past decades, regular porous architectures have received a great amount of attention because of their versatile functions and applications derived from their efficient adsorption of various guests. However, most reported porous architectures exist only in the solid state. Therefore, their applications as biomaterials may face several challenges, such as phase separation, slow degradation, and long-term accumulation in the body. This Account summarizes our efforts with respect to the development and biomedical applications of water-soluble 3D diamondoid supramolecular organic frameworks (dSOFs), a family of supramolecular polymers that possess intrinsic regular nanoscale porosity.dSOFs have been constructed from tetratopic components and cucurbit[8]uril (CB[8]) through hydrophobically driven encapsulation by CB[8] for intermolecular dimers formed by peripheral aromatic subunits of the tetratopic components in water. All dSOFs exhibit porosity regularity or periodicity in aqueous solution, which is confirmed by solution-phase synchrotron SAXS and XRD experiments. Dynamic light scattering (DLS) reveals that their sizes range from 50 to 150 nm, depending on the concentrations of the components. As nonequilibrium supramolecular architectures, dSOFs can maintain their nanoscale sizes at micromolar concentrations for dozens of hours. Their diamondoid pores have aperture sizes ranging from 2.1 to 3.6 nm, whereas their water solubility and porosity regularity allow them to rapidly include discrete guests driven by ion-pair electrostatic attraction, hydrophobicity, or a combination of the two interactions. The guests may be small molecule or large macromolecular drugs, photodynamic agents (PDAs), or DNA.The rapid inclusion of bioactive guests into dSOFs has led to two important biofunctions. The first is to function as antidotes through including residual drugs. For heparins, the inclusion results in full neutralization of their anticoagulant activity. For clinically used porphyrin PDAs, the inclusion can alleviate their long-term posttreatment phototoxicity but does not reduce their photodynamic efficacy. The second is to function as in situ loading carriers for the intracellular delivery of antitumor drugs or DNA. Their nanoscale sizes bring out their ability to overcome the multidrug resistance of tumor cells, which leads to a remarkable enhancement of the bioactivity of the included drugs. By conjugating aldoxorubicin to tetrahedral components, albumin-mimicking prodrugs have also been constructed, which conspicuously improves the efficacy of aldoxorubicin toward multi-drug-resistant tumors through the delivery of the frameworks. As new supramolecular drugs and carriers, dSOFs are generally biocompatible. Thus, further efforts might lead to medical benefits in the future.

Water-soluble and dispersible porous organic polymers: preparation, functions and applications.

Porous organic polymers (POPs) have attracted increasing attention and emerged as a new research area in polymer chemistry. During the past decade, the intense desirability for application in aqueous scenarios has spawned the development of a specific class of POPs, i.e., water-soluble or dispersible porous organic polymers (WS-POPs) that can allow the implementation of porosity-based functions in aqueous media. In this Tutorial Review, aiming at providing a practical guide to this area, we will discuss recent advances in the preparation of WS-POPs through covalent/dynamic covalent, coordination and supramolecular approaches. As a result of their intrinsic and well-defined porosity, diverse topological architectures as well as unique water-processable features, many water-soluble/dispersible POPs have been demonstrated to exhibit potential for various applications, which include drug, DNA and protein delivery, bioimaging, photocatalysis, explosive detection and membrane separation. We will also highlight the related function of the representative structures. Finally, we provide our perspective for the future research, with a focus on the development of new structures and biofunctions.

Two-Dimensional Covalent and Supramolecular Polymers: From Monolayer to Bilayer and the Thicker.

Selective preparation of two-dimensional polymers (2DPs) and supramolecular polymers (2DSPs) with defined thickness is crucially important for controlling and maximizing their functions, yet it has remained as a synthetic challenge. In the past decade, several approaches have been developed to allow selective preparation of discrete monolayer 2DPs and 2DSPs. Recently, crystal exfoliation and self-assembly strategies have been employed to successfully prepare bilayer 2DP and 2DSP, which represent the first step towards the controlled "growth" of 2D polymers from the thinnest monolayers to thicker few-layers along the third dimension. This Concept review discusses the concept of accurate synthesis of 2D polymers with defined layers. Advances in this research area will pave the way to rational synthetic strategies for 2D polymers with controlled thickness.

Polymeric Tubular Aromatic Amide Helices.

Conjugated polymers may be induced by intra- and/or intermolecular non-covalent forces to fold into helical conformations. Helices formed by aromatic amide, hydrazide, and urea polymers possess a well-organized cavity and depth, which is defined by their degree of polymerization. Driving forces may be intramolecular hydrogen bonding and/or solvophobicity, or guest induction. The resulting long helices represent a new class of unimacromolecular dynamic tubular architectures that exhibit unique properties or functions in, for example, molecular recognition, chirality transfer, and ion transporting. The recent advances are highlighted here.

Conjugating aldoxorubicin to supramolecular organic frameworks: polymeric prodrugs with enhanced therapeutic efficacy and safety.

Phase I-III clinical studies show that aldoxorubicin (AlDox), a prodrug of doxorubicin (Dox), displays reduced cardiotoxicity compared to Dox, but does not demonstrate an overall survival benefit in patients. Here we report that three-dimensional supramolecular organic frameworks (SOFs) can conjugate AlDox through quantitative thiol-maleimide addition to afford two polymeric prodrugs of Dox. The previously established ability of SOFs in overcoming the multidrug resistance of tumor cells is utilized to achieve efficient intracellular delivery of the conjugated AlDox, which releases Dox as an active agent through acid-responsive hydrolysis of the hydrazone bond of AlDox within tumor cells. In vitro and in vivo experiments show that conjugation to SOF significantly improves the antitumor efficacy of AlDox as compared with free AlDox of the identical dose. Moreover, the SOF prodrugs do not show cardiotoxicity, the major superiority of AlDox over Dox. Since free AlDox is conjugated to endogenous albumin in the blood through thiol-maleimide addition to achieve enhanced intracellular delivery and Dox release through acid-responsive hydrazone hydrolysis, SOF conjugation provides a surrogate strategy for prodrug design to gain improved efficacy.

Porous dynamic covalent polymers as promising reversal agents for heparin anticoagulants.

Heparins are natural and partially degraded polyelectrolytes that consist of sulfated polysaccharide backbones. However, as clinically used anticoagulants, heparins are associated with clinical bleeding risks and thus require rapid neutralization. Protamine sulfate is the only clinically approved antidote for unfractionated heparin (UFH), which not only may cause severe adverse reactions in patients, but also is only partially effective against low molecular weight heparins (LMWHs). We here present the facile synthesis of four porous multicationic dynamic covalent polymers (DCPs) from the condensation of tritopic aldehyde and acylhydrazine precursors. We show that, as new water-soluble polymeric antidotes, the new DCPs can effectively include both UFH and LMWHs and thus reverse their anticoagulating activity, which is confirmed by the activated partial thromboplastin time and thromboelastographic assays as well as mouse tail transection assay (bleeding model). The neutralization activities of two of the DCPs were found to be overall superior to that of protamine and have wider concentration windows and good biocompatibility. This pore-inclusion neutralization strategy paves the way for the development of water-soluble polymers as universal heparin binding agents.

Porous organic polymer overcomes the post-treatment phototoxicity of photodynamic agents and maintains their antitumor efficiency.

Since 1995, photodynamic therapy (PDT) has been utilized as an effective method for cancer treatment. However, the residues of photosensitizers in the normal tissues after PDT can be activated by sunlight to cause severe skin phototoxicity, for which currently there are no clinical solutions. As a result, post-PDT patients need to remain out of sunlight for up to five weeks, which produces great living and mental burdens for patients. Herein, we report that a biocompatible porous organic polymer (POP) with average 3.1 nm porosity is able to suppress the skin phototoxicity of clinically used porphyrin-based photodynamic agents (PDAs), including Photofrin, Talaporfin and Hiporfin, through an adsorption-elimination mechanism. Fluorescence titration and dialysis experiments show that POP can adsorb and retain the PDAs at a micromolar concentration. In vivo experiments demonstrate that POP can significantly suppress the skin phototoxicity caused by all the three PDAs without reducing their PDT efficacy. STATEMENT OF SIGNIFICANCE: Up to now, no efficient clinical treatment for the inhibition of post-PDT phototoxicity of clinically used porphyrin-based PDAs is available. In the manuscript, a water-soluble cationic porous organic polymer has been revealed to include three clinically used PDAs. In vivo experiments show that this inclusion remarkably reduces the content of PDAs in mouse skins, leading to significant alleviation of their post-PDT phototoxicity without no negative effect on their PDT efficacy. Thus, this work provides a strategy for overcoming the drawback of clinically used photodynamic agents.

Flexible Organic Framework-Based Anthracycline Prodrugs for Enhanced Tumor Growth Inhibition.

A water-soluble flexible organic framework FOF-hz of low cytotoxicity has been synthesized from a pyridinium-derived tetracationic tetraaldehyde and a citric acid-derived tritopic acylhydrazine (1:2) through the formation of a hydrazone bond. Dynamic light-scattering experiments reveal that FOF-hz has a hydrodynamic diameter of 79 nm at 0.1 mM concentration of the tetrahedral precursor. Dialysis experiments show that the free acylhydrazine units of FOF-hz can react with the C-13 ketone units of anthracycle drugs, including doxorubicin (DOX), daunorubicin, epirubicin, and pirarubicin, at pH = 3.0 to conjugate the drugs in 78-85% yields. The resulting FOF-prodrugs exhibit remarkable acid-responsive deconjugation of the conjugated active agents. Laser confocal scanning microscopy and flow cytometric analysis support that FOF-hz displays enhanced permeability and retention effect, which helps to overcome the multidrug resistance of MCF-7/ADR tumor cells and leads to enhanced cytotoxicity for MCF-7/ADR cells. In vivo studies reveal a considerable improvement of the efficacy of the prodrug FOF-DOX for the inhibition of the growth of the MCF-7/ADR tumor.

Children's Caregivers and Public Playgrounds: Potential Reservoirs of Infection of Hand-foot-and-mouth Disease.

Hand-foot-and-mouth disease (HFMD) is a common infectious disease, which has led to millions of clinical cases and hundreds of deaths every year in China. This study aimed to exploring the effects on HFMD transmission of children's caregivers and public area, as well as trying to locate the potential reservoirs of infections in primary cases. Total children's 257 samples (98 children's caregivers and 159 environmental samples) were tested for the presence of universal enterovirus, enterovirus 71, coxsackie virus A6 and A16 by real-time fluorescence quantitative polymerase chain reaction (qPCR). 5.84% (15/257, 95% confidence interval [CI]: 2.98%, 8.70%) of total samples had positive results of enterovirus. The enterovirus positive rates of children's caregiver samples and environmental samples were respectively 7.14% (7/98, 95% CI: 2.04%, 12.24%), and 5.03% (8/159, 95% CI: 1.63%, 8.43%); 7.61% (7/92, 95% CI: 2.21%, 13.01%) of wiping samples from playgrounds and 1.49% (1/67, 95% CI: 0, 7.00%) of air samples in indoor market places had positive result of enterovirus. High positive rates of enterovirus in children's caregivers and from playgrounds indicated that they would be potential reservoirs of HFMD infection, as children might be infected via contacting with asymptomatic-infected individuals or exposure of contaminated surface of public facilities.

Foldamer-based chiral supramolecular alternate block copolymers tuned by ion-pair binding.

A chiral supramolecular alternate block copolymer has been self-assembled from a ureidopyrimidinone (UPy)-terminated arylamide-based hydrogen bonded foldamer and a structurally flexible pentamer, which is driven by the ion-pair binding of the two arylamide segments toward chiral ammonium and carboxylate guests.