Anti‐Stokes Stress Sensing: Mechanochemical Activation of Triplet–Triplet Annihilation Photon Upconversion

The development of methods to detect damage in macromolecular materials is of paramount importance to understand their mechanical failure and the structure–property relationships of polymers. Mechanofluorophores are useful and sensitive molecular motifs for this purpose. However, to date, tailoring of their optical properties remains challenging and correlating emission intensity to force induced material damage and the respective events on the molecular level is complicated by intrinsic limitations of fluorescence and its detection techniques. Now, this is tackled by developing the first stress‐sensing motif that relies on photon upconversion. By combining the Diels–Alder adduct of a π‐extended anthracene with the porphyrin‐based triplet sensitizer PtOEP in polymers, triplet–triplet annihilation photon upconversion of green to blue light is mechanochemically activated in solution as well as in the solid state.     

Activation of a Photodissociative Ruthenium Complex by Triplet–Triplet Annihilation Upconversion in Liposomes

Liposomes capable of generating photons of blue light in situ by triplet–triplet annihilation upconversion of either green or red light, were prepared. The red‐to‐blue upconverting liposomes were capable of triggering the photodissociation of ruthenium polypyridyl complexes from PEGylated liposomes using a clinical grade photodynamic therapy laser source (630 nm).     

NIR‐Light‐Activated Combination Therapy with a Precise Ratio of Photosensitizer and Prodrug Using a Host–Guest Strategy

The co‐delivery of photosensitizers with prodrugs sensitive to reactive oxygen species (ROS) for light‐triggered ROS generation and cascaded prodrug activation has drawn tremendous attention. However, the absence of a feasible method to deliver the two components at a precise ratio has impaired the application potential. Herein, we report an efficient method to produce a nanosized platform for the delivery of an optimized ratio of the two components by the means of host–guest strategy for maximizing the combination therapy efficacy of cancer treatment. The key features of this host–guest strategy for the combination therapy are that the ratio between photosensitizer and ROS‐sensitive prodrug can be easily tuned, near‐infrared (NIR) irradiation can sensitize the photosensitizer and activate the paclitaxel prodrug for its release, and the accumulation process can be tracked by NIR imaging to maximize the efficacy of photodynamic and chemotherapy.     

Iridium(III) Complexes Bearing Pyrene‐Functionalized 1,10‐Phenanthroline Ligands as Highly Efficient Sensitizers for Triplet–Triplet Annihilation Upconversion

“Chemistry‐on‐the‐complex” synthetic methods have allowed the selective addition of 1‐ethynylpyrene appendages to the 3‐, 5‐, 3,8‐ and 5,6‐positions of Ir^III‐coordinated 1,10‐phenanthroline via Sonogashira cross‐coupling. The resulting suite of complexes has given rise to the first rationalization of their absorption and emission properties as a function of the number and position of the pyrene moieties. Strong absorption in the visible region (e.g. 3,8‐substituted Ir‐3 : λ_abs=481 nm, ?=52 400 m ^?1 cm^?1) and long‐lived triplet excited states (e.g. 5‐substituted Ir‐2 : τ_T=367.7 μs) were observed for the complexes in deaerated CH₂Cl₂. On testing the series as triplet sensitizers for triplet–triplet annihilation upconversion, those Ir^III complexes bearing pyrenyl appendages at the 3‐ and 3,8‐positions ( Ir‐1 , Ir‐3 ) were found to give optimal upconversion quantum yields (30.2 % and 31.6 % respectively).     

Virus‐Inspired Polymer for Efficient In Vitro and In Vivo Gene Delivery

Clinical translation of nucleic acids drugs has been stunted by limited delivery options. Herein, we report a synthetic polymer designed to mimic viral mechanisms of delivery called VIPER (virus‐inspired polymer for endosomal release). VIPER is composed of a polycation block for condensation of nucleic acids, and a pH‐sensitive block for acid‐triggered display of a lytic peptide to promote trafficking to the cell cytosol. VIPER shows superior efficiencies compared to commercial agents when delivering genes to multiple immortalized cell lines. Importantly, in murine models, VIPER facilitates effective gene transfer to solid tumors.     

Tuning the In Vivo Transport of Anticancer Drugs Using Renal‐Clearable Gold Nanoparticles

Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics. This requires a fundamental understanding of how engineered nanoparticles impact the targeting‐clearance and permeation‐retention paradoxes in the anticancer‐drug delivery. Herein, we systematically investigated how renal‐clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues. Renal‐clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability. The renal‐clearable AuNPs also accelerated body clearance of off‐target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long‐standing paradoxes in the anticancer drug delivery.     

Cyclometalated Palladium(II) N‐Heterocyclic Carbene Complexes: Anticancer Agents for Potent In Vitro Cytotoxicity and In Vivo Tumor Growth Suppression

Palladium(II) complexes are generally reactive toward substitution/reduction, and their biological applications are seldom explored. A new series of palladium(II) N‐heterocyclic carbene (NHC) complexes that are stable in the presence of biological thiols are reported. A representative complex, [Pd(C^N^N)(N,N′‐nBu₂NHC)](CF₃SO₃) ( Pd1 d , HC^N^N=6‐phenyl‐2,2′‐bipyridine, N,N′‐nBu₂NHC=N,N′‐di‐n‐butylimidazolylidene), displays potent killing activity toward cancer cell lines (IC₅₀=0.09–0.5 μm ) but is less cytotoxic toward a normal human fibroblast cell line (CCD‐19Lu, IC₅₀=11.8 μm ). In vivo anticancer studies revealed that Pd1 d significantly inhibited tumor growth in a nude mice model. Proteomics data and in vitro biochemical assays reveal that Pd1 d exerts anticancer effects, including inhibition of an epidermal growth factor receptor pathway, induction of mitochondrial dysfunction, and antiangiogenic activity to endothelial cells.     

Low‐Fouling Fluoropolymers for Bioconjugation and In Vivo Tracking

The conjugation of hydrophilic low‐fouling polymers to therapeutic molecules and particles is an effective approach to improving their aqueous stability, solubility, and pharmacokinetics. Recent concerns over the immunogenicity of poly(ethylene glycol) has highlighted the importance of identifying alternative low fouling polymers. Now, a new class of synthetic water‐soluble homo‐fluoropolymers are reported with a sulfoxide side‐chain structure. The incorporation of fluorine enables direct imaging of the homopolymer by ¹⁹F MRI, negating the need for additional synthetic steps to attach an imaging moiety. These self‐reporting fluoropolymers show outstanding imaging sensitivity and remarkable hydrophilicity, and as such are a new class of low‐fouling polymer for bioconjugation and in vivo tracking.     

Gold Nanoclusters for Targeting Methicillin‐Resistant Staphylococcus aureus In Vivo

Widespread multidrug resistance caused by the abuse of antibiotics calls for novel strategies and materials. Gold nanoclusters (AuNCs) are scarcely explored for combating multidrug‐resistant (MDR) bacteria in vivo. We herein synthesized a novel class of AuNCs, namely quaternary ammonium (QA) capped AuNCs (QA‐AuNCs) as potent antibiotics selectively targeting MDR Gram‐positive bacteria, including methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococci (VRE), in vivo. QA‐AuNCs kill bacteria through a combined physicochemical mechanism, and show excellent therapeutic effects in both a skin infection model and a bacteremia model induced by MRSA. In addition, owing to their intense fluorescence, QA‐AuNCs can be used for the discrimination of live/dead bacteria and bacteria counting, suggesting their potential for clinical theranostics.     

Ruthenium(II)–Polyimine–Coumarin Light‐Harvesting Molecular Arrays: Design Rationale and Application for Triplet–Triplet‐Annihilation‐Based Upconversion

Ru^II–bis‐pyridine complexes typically absorb below 450 nm in the UV spectrum and their molar extinction coefficients are only moderate (ε<16 000 M ^?1 cm^?1). Thus, Ru^II–polyimine complexes that show intense visible‐light absorptions are of great interest. However, no effective light‐harvesting ruthenium(II)/organic chromophore arrays have been reported. Herein, we report the first visible‐light‐harvesting Ru^II–coumarin arrays, which absorb at 475 nm (ε up to 63 300 M ^?1 cm^?1, 4‐fold higher than typical Ru^II–polyimine complexes). The donor excited state in these arrays is efficiently converted into an acceptor excited state (i.e., efficient energy‐transfer) without losses in the phosphorescence quantum yield of the acceptor. Based on steady‐state and time‐resolved spectroscopy and DFT calculations, we proposed a general rule for the design of Ru^II–polypyridine–chromophore light‐harvesting arrays, which states that the ¹IL energy level of the ligand must be close to the respective energy level of the metal‐to‐ligand charge‐transfer (M LCT) states. Lower energy levels of ¹IL/³IL than the corresponding ¹M LCT/³M LCT states frustrate the cascade energy‐transfer process and, as a result, the harvested light energy cannot be efficiently transferred to the acceptor. We have also demonstrated that the light‐harvesting effect can be used to improve the upconversion quantum yield to 15.2 % (with 9,10‐diphenylanthracene as a triplet‐acceptor/annihilator), compared to the parent complex without the coumarin subunit, which showed an upconversion quantum yield of only 0.95 %.     

Chemiluminescent Probe for the In Vitro and In Vivo Imaging of Cancers Over‐Expressing NQO1

Activatable (turn‐on) probes that permit the rapid, sensitive, selective, and accurate identification of cancer‐associated biomarkers can help drive advances in cancer research. Herein, a NAD(P)H:quinone oxidoreductase‐1 (NQO1)‐specific chemiluminescent probe 1 is reported that allows the differentiation between cancer subtypes. Probe 1 incorporates an NQO1‐specific trimethyl‐locked quinone trigger moiety covalently tethered to a phenoxy‐dioxetane moiety through a para‐aminobenzyl alcohol linker. Bio‐reduction of the quinone to the corresponding hydroquinone results in a chemiluminescent signal. As inferred from a combination of in vitro cell culture analyses and in vivo mice studies, the probe is safe, cell permeable, and capable of producing a “turn‐on” luminescence response in an NQO1‐positive A549 lung cancer model. On this basis, probe 1 can be used to identify cancerous cells and tissues characterized by elevated NQO1 levels.     

Cathepsin B‐Specific Metabolic Precursor for In Vivo Tumor‐Specific Fluorescence Imaging

Recently, metabolic glycoengineering with bioorthogonal click reactions has focused on improving the tumor targeting efficiency of nanoparticles as delivery vehicles for anticancer drugs or imaging agents. It is the key technique for developing tumor‐specific metabolic precursors that can generate unnatural glycans on the tumor‐cell surface. A cathepsin B‐specific cleavable substrate (KGRR) conjugated with triacetylated N‐azidoacetyl‐d ‐mannosamine (RR‐S‐Ac₃ManNAz) was developed to enable tumor cells to generate unnatural glycans that contain azide groups. The generation of azide groups on the tumor cell surface was exogenously and specifically controlled by the amount of RR‐S‐Ac₃ManNAz that was fed to target tumor cells. Moreover, unnatural glycans on the tumor cell surface were conjugated with near infrared fluorescence (NIRF) dye‐labeled molecules by a bioorthogonal click reaction in cell cultures and in tumor‐bearing mice. Therefore, our RR‐S‐Ac₃ManNAz is promising for research in tumor‐specific imaging or drug delivery.