NIR-II cell endocytosis-activated fluorescent probes for in vivo high-contrast bioimaging diagnostics

Fluorescence probes have great potential to empower bioimaging, precision clinical diagnostics and surgery. However, current probes are limited to in vivo high-contrast diagnostics, due to the substantial background interference from tissue scattering and nonspecific activation in blood and normal tissues. Here, we developed a kind of cell endocytosis-activated fluorescence (CEAF) probe, which consists of a hydrophilic polymer unit and an acid pH-sensitive small-molecule fluorescent moiety that operates in the “tissue-transparent” second near-infrared (NIR-II) window. The CEAF probe stably presents in the form of quenched nanoaggregates in water and blood, and can be selectively activated and retained in lysosomes through cell endocytosis, driven by a synergetic mechanism of disaggregation and protonation. In vivo imaging of tumor and inflammation with a passive-targeting and affinity-tagged CEAF probe, respectively, yields highly specific signals with target-to-background ratios over 15 and prolonged observation time up to 35 hours, enabling positive implications for surgical, diagnostic and fundamental biomedical studies.

A Cell Endocytosis-Activated Fluorescent (CEAF) probe triggered by disaggregation and protonation is designed for high contrast in vivo bioimaging and diagnostics in the second near-infrared window (1000–1700 nm).     

Multiple-mRNA-controlled and heat-driven drug release from gold nanocages in targeted chemo-photothermal therapy for tumors

Multifunctional drug delivery systems enabling effective drug delivery and comprehensive treatment are critical to successful cancer treatment. Overcoming nonspecific release and off-target effects remains challenging in precise drug delivery. Here, we design triple-interlocked drug delivery systems to perform specific cancer cell recognition, controlled drug release and effective comprehensive therapy. Gold nanocages (AuNCs) comprise a novel class of nanostructures possessing hollow interiors and porous walls. AuNCs are employed as a drug carrier and photothermal transducer due to their unique structure and photothermal properties. A smart triple-interlocked I-type DNA nanostructure is modified on the surface of the AuNCs, and molecules of the anticancer drug doxorubicin (DOX) are loaded as molecular cargo and blocked. The triple-interlocked nanostructure can be unlocked by binding with three types of tumor-related mRNAs, which act as “keys” to the triple locks, sequentially, which leads to precise drug release. Additionally, fluorescence-imaging-oriented chemical–photothermal synergistic treatment is achieved under illumination with infrared light. This drug delivery system, which combines the advantages of AuNCs and interlocked I-type DNA, successfully demonstrates effective and precise imaging, drug release and photothermal therapy. This multifunctional triple-interlocked drug delivery system could be used as a potential carrier for effective cancer-targeting comprehensive chemotherapy and photothermal therapy treatments.

Schematic illustration of the multiple-mRNA-controlled and heat-driven drug release from gold nanocages.     

Design of an intelligent sub-50 nm nuclear-targeting nanotheranostic system for imaging guided intranuclear radiosensitization

Clinically applied chemotherapy and radiotherapy is sometimes not effective due to the limited dose acting on DNA chains resident in the nuclei of cancerous cells. Herein, we develop a new theranostic technique of “intranuclear radiosensitization” aimed at directly damaging the DNA within the nucleus by a remarkable synergetic chemo-/radiotherapeutic effect based on intranuclear chemodrug-sensitized radiation enhancement. To achieve this goal, a sub-50 nm nuclear-targeting rattle-structured upconversion core/mesoporous silica nanotheranostic system was firstly constructed to directly transport the radiosensitizing drug Mitomycin C (MMC) into the nucleus for substantially enhanced synergetic chemo-/radiotherapy and simultaneous magnetic/upconversion luminescent (MR/UCL) bimodal imaging, which can lead to efficient cancer treatment as well as multi-drug resistance circumvention in vitro and in vivo. We hope the technique of intranuclear radiosensitization along with the design of nuclear-targeting nanotheranostics will contribute greatly to the development of cancer theranostics as well as to the improvement of the overall therapeutic effectiveness.     

Non-metal with metal behavior: metal-free coordination-insertion ring-opening polymerization

The “coordination-insertion” ring-opening polymerization (ROP) mechanism has so far been the monopoly of metal catalysts. In this work, we present a metal-free “coordination-insertion” ROP of trimethylene carbonate (TMC) and ε-caprolactone (ε-CL), as well as their sequential block copolymerization, with N-trimethylsilyl-bis (trifluoromethanesulfonyl)imide (TMSNTf₂) as the non-metallic initiator/catalyst. TMSNTf₂ was proposed to work through an unprecedented metal-free “coordination-insertion” mechanism, which involves the coordination of monomer to the Si atom of TMSNTf₂, the nucleophilic attack of the –NTf₂ group on the coordinated monomer, and the cleavage of the acyl–oxygen bond of the monomer. The proposed metal-free “coordination-insertion” ROP was studied by NMR, SEC, and MALDI-TOF analyses. In addition, the TMSNTf₂-mediated ROP of TMC and ε-CL led to linear and cyclic polymers following two-stage first-order polymerization processes, as evidenced by structural analyses and kinetics study, which further demonstrated the metal-free “coordination-insertion” mechanism.

The first metal-free “coordination-insertion” ROP of cyclic carbonate and lactones mediated by N-trimethylsilyl-bis(trifluoromethanesulfonyl)imide (TMSNTf₂) was proposed, which in the past was exclusively the monopoly of metal complex catalysts.     

Precision photothermal therapy and photoacoustic imaging by in situ activatable thermoplasmonics

Phototherapy holds great promise for disease treatment; however, traditional “always-on” photoagents have been restricted to clinical translation due to their nonspecific response and side effects on normal tissues. Here, we show a tumor microenvironment activated photothermal and photoacoustic agent as an activatable prodrug and probe that allows precise cancer diagnosis and treatment. Such an in situ revitalized therapeutic and contrast agent is achieved via controllable plasmonic heating for thermoplasmonic activation. This enables monitoring of signal molecule dynamics, real-time photothermal and photoacoustic imaging of tumors and lymph node metastasis, and targeted photothermal therapy without unwanted phototoxicity to normal tissues. Our study provides a practical solution to the non-specificity problem in phototherapy and offers precision cancer therapeutic and theranostic strategies. This work may advance the development of ultrasensitive disease diagnosis and precision medicine.

A tumor microenvironment-activated photoagent is reported for precise photothermal therapy and photoacoustic imaging via controllable thermoplasmonics. The agent can sensitively image tumors and lymph node metastasis and specifically ablate tumors.     

Palladium-catalyzed asymmetric allylic alkylation (AAA) with alkyl sulfones as nucleophiles

An efficient palladium-catalyzed AAA reaction with a simple α-sulfonyl carbon anion as nucleophiles is presented for the first time. Allyl fluorides are used as superior precursors for the generation of π-allyl complexes that upon ionization liberate fluoride anions for activation of silylated nucleophiles. With the unique bidentate diamidophosphite ligand ligated palladium as catalyst, the in situ generated α-sulfonyl carbon anion was quickly captured by the allylic intermediates, affording a series of chiral homo-allylic sulfones with high efficiency and selectivity. This work provides a mild in situ desilylation strategy to reveal nucleophilic carbon centers that could be used to overcome the pK_a limitation of “hard” nucleophiles in enantioselective transformations.

A variety of “hard” α-sulfonyl carbanions of aryl, heteroaryl and alkyl sulfones were successfully employed as nucleophiles in palladium-catalyzed asymmetric allylic alkylation with excellent enantioselectivities.     

DNAzyme- and light-induced dissipative and gated DNA networks

Nucleic acid-based dissipative, out-of-equilibrium systems are introduced as functional assemblies emulating transient dissipative biological transformations. One system involves a Pb²⁺-ion-dependent DNAzyme fuel strand-driven network leading to the transient cleavage of the fuel strand to “waste” products. Applying the Pb²⁺-ion-dependent DNAzyme to two competitive fuel strand-driven systems yields two parallel operating networks. Blocking the competitively operating networks with selective inhibitors leads, however, to gated transient operation of dictated networks, yielding gated catalytic operations. A second system introduces a “non-waste” generating out-of-equilibrium, dissipative network driven by light. The system consists of a trans-azobenzene-functionalized photoactive module that is reconfigured by light to an intermediary state consisting of cis-azobenzene units that are thermally recovered to the original trans-azobenzene-modified module. The cyclic transient photoinduced operation of the device is demonstrated. The kinetic simulation of the systems allows the prediction of the transient behavior of the networks under different auxiliary conditions.

Functional DNA modules are triggered in the presence of appropriate inhibitors to yield transient gated catalytic functions, and a photoresponsive DNA module leads to “waste-free” operation of transient, dissipative dynamic transitions.     

A two-dimensional molecular beacon for mRNA-activated intelligent cancer theranostics

Ideal theranostics should possess directly correlated imaging and therapy modalities that could be simultaneously activated in the disease site to generate high imaging contrast and therapeutic efficacy with minimal side effects. However, so far it still remains challenging to engineer all these characteristics into a single theranostic probe. Herein, we report a new type of photosensitizer (PS)-derived “two-dimensional” molecular beacon (TMB) that could be specifically activated within tumor cells to exhibit both high imaging contrast and therapeutic efficacy that outperforms conventional photosensitizers for cancer theranostics. The TMB is constructed by integrating a photosensitizer (chlorin e6 (Ce6)), a quantum dot (QD), and a dark quencher (BHQ3) into a hairpin DNA molecule to generate multiple synergistic FRET modes. The imaging modality and therapy modality, which are mediated by FRET between the QD and BHQ3 and FRET between the QD and Ce6 respectively, are interconnected within the TMB and could be simultaneously activated by tumor mRNA molecules. We show that highly effective cancer imaging and therapy could be achieved for cancer cell lines and xenografted tumor models. The reported TMB represents an unprecedented theranostic platform for intelligent cancer theranostics.     

Design and recognition of cucurbituril-secured platinum-bound oligopeptides

Platinum terpyridyl complexes, stacked on top of one another and secured as dimers with cucurbit[8]uril (CB[8]) in aqueous medium, were functionalized quantitatively and in situ with a pair of pentapeptides Phe-(Gly)₃-Cys by grafting their cysteine residues to the Pt centers. The resulting CB[8]·(Pt·peptide)₂ assemblies were used to target secondary hosts CB[7] and CB[8] via their pair of phenylalanine residues, again in situ. A series of well-defined architectures, including a supramolecular “pendant necklace” with hybrid head-to-head and head-to-tail arrangements inside CB[8], were obtained during the self-sorting process after combining only 3 or 4 simple building units.

A platinum terpyridyl complex, pentapeptide Phe-(Gly)₃-Cys and cucurbit[8]uril assemble into a “pendant necklace” with hybrid head-to-head and head-to-tail arrangements in aqueous medium.     

Free three-dimensional carborane carbanions

Carbon atom functionalization via generation of carbanions is the cornerstone of carborane chemistry. In this work, we report the synthesis and structural characterization of free ortho-carboranyl [C₂B₁₀H₁₁]⁻, a three-dimensional inorganic analog of the elusive phenyl anion that features a “naked” carbanion center. The first example of a stable, discrete C(H)-deprotonated carborane anion was isolated as a completely separated ion pair with a crown ether-encapsulated potassium cation. An analogous approach led to the isolation and structural characterization of a doubly deprotonated 1,1′-bis(o-carborane) anion [C₂B₁₀H₁₀]₂²⁻, which is the first example of a discrete molecular dicarbanion. These reactive carbanions are key intermediates in carbon vertex chemistry of carborane clusters.

Free three-dimensional carborane carbanions, which are inorganic siblings of deprotonated aryls with the “naked” anionic carbon atom are reported.     

Linear Multiselenium Interactions in Dicationic Oligomers of 1,5‐(Diselena)canes: Behavior of Semc σ(mcc‐nee) (6≤mc≤16) Elucidated with QTAIM Dual Functional Analysis

Invited for this month''s cover picture is the group of Dr. Satoko Hayashi at Faculty of Systems Engineering and Chemistry at Wakayama University. The cover picture shows the linear Se₁₆ σ(16c–30e) interactions, illustrated by the molecular graph type on the optimized structure of the dicationic octamer of 1,5‐(diselena)cane. HOMO‐1 of ψ₄₆₂ is drawn on the structure, which is located predominantly on the Se atoms. The optimized structure is stable, due to the nice engagement between the (CH₂)₃ moieties. The contour maps of ρ(r) are also drawn on the molecular C _s planes of the dicationic dimer and trimer to demonstrate clearly the existence of the interactions between Se atoms. Read the full text of their Full Paper at 10.1002/open.202100017.

“… To improve the causality of experimental results, we have proposed a new concept, called “Keisan‐sendo…” Find out more about the story behind the front cover research at 10.1002/open.202100017.     

The Different Story of π Bonds

We revisit “classical” issues in multiply bonded systems between main groups elements, namely the structural distortions that may occur at the multiple bonds and that lead, e.g., to trans-bent and bond-length alternated structures. The focus is on the role that orbital hybridization and electron correlation play in this context, here analyzed with the help of simple models for σ- and π-bonds, numerically exact solutions of Hubbard Hamiltonians and first principles (density functional theory) investigations of an extended set of systems.     

A dendritic cell-like biomimetic nanoparticle enhances T cell activation for breast cancer immunotherapy

Cancer immunotherapy has remarkably improved the therapeutic effect of melanoma and non-small cell lung cancer in the clinic. Nevertheless, it showed disappointing clinical outcomes for treating immunosuppressive tumors, wherein aggressive T cells are rather limited in tumor sites. Therefore, regulating the behavior of T cells in tumor sites to increase their attack ability for suppressing the immunosuppressive tumor is highly desirable. Inspiringly, we designed a dendritic cell-like biomimetic nanoparticle (DMSNs³@HA) to regulate the behavior of T cells for improving the immunotherapy effect against immunosuppressive tumors. In this work, anti-CD3 and anti-CD28 were responsible for mimicking dendritic cells to activate T cells, and anti-PD-1 for blocking the pathway of PD-1/PD-L1 to break the immune “brake”, which synergistically regulated the behavior of T cells to attack cancer cells. Experimental results indicated that DMSNs³@HA can effectively activate T cells and improve their immune response to significantly inhibit the growth of breast cancer. Moreover, it also proved that T cell activation combining immune checkpoint blocking induced the “1 + 1 >2” immunotherapy effect against immunosuppressive tumors. We expect that this strategy will provide new insights into tumor immunotherapy by modulating T cell behavior.

A dendritic cell-like biomimetic nanoparticle has been designed to regulate the behavior of T cells for improving the immunotherapy effect against immunosuppressive tumors.     

Activation of apoptosis by rationally constructing NIR amphiphilic AIEgens: surmounting the shackle of mitochondrial membrane potential for amplified tumor ablation

In recent years, the use of aggregation-induced emission luminogens (AIEgens) for biological imaging and phototherapy has become an area of intense research. However, most traditional AIEgens suffer from undesired aggregation in aqueous media with “always on” fluorescence, or their targeting effects cannot be maintained accurately in live cells with the microenvironment changes. These drawbacks seriously impede their application in the fields of bio-imaging and antitumor therapy, which require a high signal-to-noise ratio. Herein, we propose a molecular design strategy to tune the dispersity of AIEgens in both lipophilic and hydrophilic systems to obtain the novel near-infrared (NIR, ∼737 nm) amphiphilic AIE photosensitizer (named TPA-S-TPP) with two positive charges as well as a triplet lifetime of 11.43 μs. The synergistic effects of lipophilicity, electrostatic interaction, and structure-anchoring enable the wider dynamic range of AIEgen TPA-S-TPP for mitochondrial targeting with tolerance to the changes of mitochondrial membrane potential (ΔΨ_m). Intriguingly, TPA-S-TPP was difficult for normal cells to be taken up, indicative of low inherent toxicity for normal cells and tissues. Deeper insight into the changes of mitochondrial membrane potential and cleaved caspase 3 levels further revealed the mechanism of tumor cell apoptosis activated by AIEgen TPA-S-TPP under light irradiation. With its advantages of low dark toxicity and good biocompatibility, acting as an efficient theranostic agent, TPA-S-TPP was successfully applied to kill cancer cells and to efficiently inhibit tumor growth in mice. This study will provide a new avenue for researchers to design more ideal amphiphilic AIE photosensitizers with NIR fluorescence.

In this contribution, based on a “step-by-step” molecular design strategy, a novel NIR amphiphilic AIEgen TPA-S-TPP with a triplet lifetime of 11.43 μs and surmounting the shackle of MMP was successfully fabricated for amplified tumor ablation.     

Rational design of an “all-in-one” phototheranostic

We report here porphodilactol derivatives and their corresponding metal complexes. These systems show promise as “all-in-one” phototheranostics and are predicated on a design strategy that involves controlling the relationship between intersystem crossing (ISC) and photothermal conversion efficiency following photoexcitation. The requisite balance was achieved by tuning the aromaticity of these porphyrinoid derivatives and forming complexes with one of two lanthanide cations, namely Gd³⁺ and Lu³⁺. The net result led to a metalloporphodilactol system, Gd-trans-2, with seemingly optimal ISC efficiency, photothermal conversion efficiency and fluorescence properties, as well as good chemical stability. Encapsulation of Gd-trans-2 within mesoporous silica nanoparticles (MSN) allowed its evaluation for tumour diagnosis and therapy. It was found to be effective as an “all-in-one” phototheranostic that allowed for NIR fluorescence/photoacoustic dual-modal imaging while providing an excellent combined PTT/PDT therapeutic efficacy in vitro and in vivo in 4T1-tumour-bearing mice.

We report here porphodilactol derivatives and their corresponding metal complexes as “all-in-one” phototheranostics by controlling the relationship between intersystem crossing (ISC) and photothermal conversion efficiency following photoexcitation.     

Fully synthetic Mincle-dependent self-adjuvanting cancer vaccines elicit robust humoral and T cell-dependent immune responses and protect mice from tumor development

A new strategy based on a macrophage-inducible C-type lectin (Mincle) agonist was established to construct synthetic cancer vaccines. Using sialyl-Tn (STn) as a model antigen, four conjugates with the Mincle agonist as a built-in adjuvant were designed and synthesized through a facile and efficient method. All conjugates could induce BMDMs to produce inflammatory cytokines in a Mincle-dependent manner and were found to elicit robust humoral and T cell-dependent immune responses alone in mice. The corresponding antibodies could recognize, bind and exhibit complement-dependent cytotoxicity to STn-positive cancer cells, leading to tumor cell lysis. Moreover, all conjugates could effectively inhibit tumor growth and prolong the mice survival time in vivo, with therapeutic effects better than STn-CRM197/Al. Notably, compared to conventional glycoprotein conjugate vaccines, these fully synthetic conjugate vaccines do not cause “epitope suppression.” Mincle ligands thus hold great potential as a platform for the development of new vaccine carriers with self-adjuvanting properties for cancer treatment. Preliminary structure–activity relationship analysis shows that a vaccine containing one STn antigen carried by vizantin exhibits the best efficacy, providing support for further optimization and additional investigation into Mincle agonists as the carrier of self-adjuvanting cancer vaccines.

A new strategy based on a Macrophage-inducible C-type lectin (Mincle) agonist was established to construct synthetic cancer vaccines.     

Study on the Influence of Chirality in the Threading of Calix[6]arene Hosts with Dialkylammonium Axles

The influence of chirality in calixarene threading has been studied by exploiting the “superweak anion approach”. In particular, the formation of chiral pseudo[2]rotaxanes bearing a classical stereogenic center in their axle and/or wheel components has been considered. Two kind of pseudo[2]rotaxane stereoadducts, the “endo-chiral” and “exo-chiral” ones, having the stereogenic center of a cationic axle inside or outside, respectively, the calix-cavity of a chiral calixarene were preferentially formed with specifically designed chiral axles by a fine exploitation of the so-called “endo-alkyl rule” and a newly defined “endo-α-methyl-benzyl rule” (threading of a hexaalkoxycalix[6]arene with a directional (α-methyl-benzyl)benzylammonium axle occurs with an endo-α-methyl-benzyl preference). The obtained pseudorotaxanes were studied in solution by 1D and 2D NMR, and in the gas-phase by means of the enantiomer-labeled (EL) mass spectrometry method, by combining enantiopure hosts with pseudoracemates of one deuterated and one unlabeled chiral axle enantiomer. In both instances, there was not a clear enantiodiscrimination in the threading process with the studied host/guest systems. Possible rationales are given to explain the scarce reciprocal influence between the guest and host chiral centers.     

Biomimetic nanochannels for the discrimination of sialylated glycans via a tug-of-war between glycan binding and polymer shrinkage

Sialylated glycans that are attached to cell surface mediate diverse cellular processes such as immune responses, pathogen binding, and cancer progression. Precise determination of sialylated glycans, particularly their linkage isomers that can trigger distinct biological events and are indicative of different cancer types, remains a challenge, due to their complicated composition and limited structural differences. Here, we present a biomimetic nanochannels system integrated with the responsive polymer polyethyleneimine-g-glucopyranoside (Glc-PEI) to solve this problem. By using a dramatic “OFF–ON” change in ion flux, the nanochannels system achieves specific recognition for N-acetylneuraminic acid (Neu5Ac, the predominant form of sialic acid) from various monosaccharides and sialic acid species. Importantly, different “OFF–ON” ratios of the conical nanochannels system allows the precise and sensitive discrimination of sialylated glycan linkage isomers, α2–3 and α2–6 linkage (the corresponding ion conductance increase ratios are 96.2% and 264%, respectively). Analyses revealed an unusual tug-of-war mechanism between polymer-glycan binding and polymer shrinkage. The low binding affinity of Glc-PEI for the α2–6-linked glycan caused considerable shrinkage of Glc-PEI layer, but the high affinity for the α2–3-linked glycan resulted in only a slight shrinkage. This competition mechanism provides a simple and versatile materials design principle for recognition or sensing systems that involve negatively charged target biomolecules. Furthermore, this work broadens the application of nanochannel systems in bioanalysis and biosensing, and opens a new route to glycan analysis that could help to uncover the mysterious and wonderful glycoworld.

A glycan-responsive polymer-modified nanochannels system enables the precise discrimination of sialylated glycan linkage isomers via the different “OFF–ON” changes resulting from a “tug-of-war” between polymer-glycan binding and polymer shrinkage.