Huanxiang Yuan

Supramolecular photosensitizers with enhanced antibacterial efficiency.

Photosensitizers, a key component in photodynamic therapy (PDT), are compounds that can transfer the energy of light to surrounding oxygen, thereby producing highly reactive oxygen species, for example singlet oxygen (O2), to destroy diseased tissues or microorganisms. From a practical application point of view, readily accessible, highly fluorescent photosensitizers with strong absorbance at long wavelengths and high singlet oxygen quantum yields are highly desirable. In particular, porphyrins and their derivatives are popularly employed as one class of important photosensitizers owing to their excellent photophysical properties. They have very intense absorption bands in the visible region and high singlet oxygen quantum yield because of their large p-conjugated aromatic domains. However, the porphyrins easily form aggregates based on hydrophobic p–p interactions in aqueous medium, especially at high local concentrations induced by uptake and accumulation processes inside cells or microorganisms. The aggregation can produce a severe selfquenching effect of the excited state, leading to quenched fluorescence and greatly reducing the ability for O2 generation, and therefore lowering the efficiency for phototherapy. To address this issue, it has been common practice to introduce space-demanding hydrophilic substituents to the parent porphyrins, for example, segregate porphyrins into the focal core of hydrophilic dendrimers. In doing so, the quenching effect can be suppressed, which leads to an appreciable improvement of the photocytotoxicity. However, such covalent practice often involves time-consuming tedious chemical synthesis and purification processes, thus raising the costs of preparation. In addition, organic solvents and toxic reagents used in chemical synthesis may be incorporated into photosensitizers and reduce their biocompatibility. Cucurbit[n]uril (CB[n]), a family of barrel-shaped macrocyclic hosts, have been developed into an interesting research area, because of their rich host–guest chemistry. The CB[n] molecules possess a hydrophilic exterior and hydrophobic cavities. Because of the existence of the hydrophobic cavity, CB[n] has been widely used, for example, to encapsulate and solubilize dyes and to enhance weak supramolecular interactions. Generally, compared with other hosts, such as cyclodextrins and calixarenes, the binding constant of CB[n] with its guests is much larger, especially to the cationic species, driven by a combination of ion–dipole interactions, hydrogen bonds, and the hydrophobic effect. Herein, the large molecular volume and hydrophilic exterior of CB[n] molecules have encouraged us to explore the possibility of using CB[n] as bulky “noncovalent building blocks” to weaken the close stacking of porphyrins, thus suppressing the self-quenching of the excited states and improving the antibacterial efficiencies even upon aggregation. In addition, the rich host–guest chemistry of CB[n] can enable the bulky substituents to be noncovalently attached to the porphyrins, which is environmentally friendly and can greatly decrease the required steps of chemical synthesis. For this purpose, a new kind of supramolecular photosensitizer has been designed as shown in Figure 1. Porphyrins are readily modified with four positive charges (TPOR), so as to efficiently adsorb onto the negative charged surface of bacteria. The other building block, CB[7], is selected as the bulky hydrophilic heads of the supramolecular photosensitizers. The strong host–guest interaction between CB[7] and naphthalene–methylpyridinium moiety on TPOR is used as the driving force for the construction of the supramolecular photosensitizers. For the construction of the desired supramolecular photosensitizers, CB[7] was added to the aqueous solutions of TPOR in a molar ratio of TPOR:CB[7] = 1:4. Different methods were employed to confirm the formation of the desired supramolecular photosensitizers. Firstly, isothermal titration calorimetry (ITC) was carried out to provide information about the binding ability of CB[7] with TPOR. The obtained titration isotherm is shown in Figure 2 a. The binding stoichiometry between TPOR and CB[7] is calculated to be 1:4, indicating that the desired supramolecular photosensitizers shown in Figure 1 have been obtained. By fitting the data, the binding constant of the naphthalene–methylpyridinium subgroup with CB[7] is calculated to be K = 6.6 10m , indicating that the driving force is quite strong and efficient interactions can take place for the noncovalent construction of the TPOR/(CB[7])4 supramolecular photosensitizers. Secondly, the formation of the supramolecular photosensitizers is confirmed by dynamic light scattering [*] K. Liu, Y. L. Liu, Y. X. Yao, Prof. Z. Q. Wang, Prof. X. Zhang Key Lab of Organic Optoelectronics & Molecular Engineering Department of Chemistry, Tsinghua University Beijing 100084 (China) E-mail: xi@mail.tsinghua.edu.cn

Chemical molecule-induced light-activated system for anticancer and antifungal activities.

Except for chemotherapy, surgery, and radiotherapy, photodynamic therapy (PDT) as new therapy modality is already in wide clinic use for the treatment of various diseases. The major bottleneck of this technique is the requirement of outer light source, which always limits effective application of PDT to the lesions in deeper tissue. Here, we first report a new modality for treating cancer and microbial infections, which is activated by chemical molecules instead of outer light irradiation. In this system, in situ bioluminescence of luminol can be absorbed by a cationic oligo(p-phenylene vinylene) (OPV) that acts as the photosensitizer through bioluminescence resonance energy transfer (BRET) process. The excited OPV sensitizes oxygen molecule in the surroundings to produce reactive oxygen species (ROS) that kill the adjacent cancer cells in vitro and in vivo, and pathogenic microbes. By avoiding the use of light irradiation, this work opens a new therapy modality to tumor and pathogen infections.

Cationic Conjugated Polymers for Discrimination of Microbial Pathogens

H. Yuan, Dr. L. Liu, Dr. F. Lv, Prof. S. Wang Key Laboratory of Organic Solids Interface and Chemical Thermodynamics Institute of Chemistry Chinese Academy of Sciences Beijing 100190 , P. R. China Fax: (+86) 10-6263-6680 E-mail: liulibing@iccas.ac.cn; wangshu@iccas.ac.cn Z. Liu, Prof. Y. Wang Key Laboratory of Colloid Interface and Chemical Thermodynamics Institute of Chemistry Chinese Academy of Sciences Beijing 100190 , P. R. China E-mail: yilinwang@iccas.ac.cn DOI: 10.1002/adma.201400636 conjugated polymers have been used for detection and identifi cation of various bacteria mainly based on the analyte-induced displacement of fl uorophore with the aid of linear discriminant analysis (LDA). [ 26–29 ] The sensing elements in these systems must include one charged conjugated polymer (donors) and several (three to fi ve) gold nanoparticles or dye-labeled DNAs (acceptors). It will be ideal to develop new methods only based on single conjugated polymer to discriminate multiple pathogens rapidly and simply. In this work, we prepared a new cationic poly(phenylene vinylene) derivative (PPV-NMe 3 + , see Scheme 1 for its structure and synthesis). Through the specifi c interactions of PPV-NMe 3 + to microbial cell envelopes with different components, it is demonstrated that single PPV-NMe 3 +

Conjugated-polymer-based energy-transfer systems for antimicrobial and anticancer applications.

Conjugated polymers (CPs) attract a lot of attention in sensing, imaging, and biomedical applications because of recent achievements that are highlighted in this Research News article. A brief review of recent progress in the application of CP-based energy-transfer systems in antimicrobial and anticancer treatments is provided. The transfer of excitation energy from CPs to photosensitizers leads to the generation of reactive oxygen species (ROS) that are able to efficiently kill pathogenic microorganisms and cancer cells in the surroundings. Both fluorescence resonance energy transfer (FRET) and bioluminescence energy transfer (BRET) modes are discussed.

Polymer-drug conjugates for intracellar molecule-targeted photoinduced inactivation of protein and growth inhibition of cancer cells

For most molecule-targeted anticancer systems, intracellular protein targets are very difficult to be accessed by antibodies, and also most efforts are made to inhibit protein activity temporarily rather than inactivate them permanently. In this work we firstly designed and synthesized multifunctional polymer-drug conjugates (polythiophene-tamoxifen) for intracellular molecule-targeted binding and inactivation of protein (estrogen receptor α, ERα) for growth inhibition of MCF-7 cancer cells. Small molecule drug was conjugated to polymer side chain for intracellular signal protein targeting, and simultaneously the fluorescent characteristic of polymer for tracing the cellular uptake and localization of polythiophene-drug conjugates by cell imaging. Under light irradiation, the conjugated polymer can sensitize oxygen to produce reactive oxygen species (ROS) that specifically inactivate the targeted protein, and thus inhibit the growth of tumor cells. The conjugates showed selective growth inhibition of ERα positive cancer cells, which exhibits low side effect for our intracellular molecule-targeted therapy system.

Multicellular Assembly and Light-Regulation of Cell–Cell Communication by Conjugated Polymer Materials

Using cell-surface modification and biotin-streptavidin interactions, immune cells and target tumor cells are made to form multicellular assemblies. A polythiophene derivative can undergo cellular uptake, allowing the sensitization of oxygen under light irradiation. The subsequent generation of reactive oxygen species (ROS) regulates cell-cell communication in time and space.

Cationic oligo(p-phenylene vinylene) materials for combating drug resistance of cancer cells by light manipulation.

An unconventional strategy that can be temporally and remotely activated with light to combat the drug resistance of cancer cells is developed. A cell-membrane-anchored photosensitizer (OPV) is used to enhance anticancer drug uptake and restore toxicity in resistant cancer cells. This method recovers the activity of the already established anticancer drugs, and provides a new strategy for the development of light manipulation to combat anticancer resistance.

New conjugated polymers for photoinduced unwinding of DNA supercoiling and gene regulation.

Three cationic polythiophene derivatives (P1, P2, P3) were synthesized and characterized. Under white light irradiation (400-800 nm), they sensitize oxygen molecule in the surrounding to generate reactive oxygen species (ROS) that can efficiently unwind the supercoiled DNA in vitro. Further study shows that this relaxation of the DNA supercoiling results in the decrease of gene (pCX-EGFP plasmid) expression level. The ability of these conjugated polymers for regulating gene expression will add a new dimension to the function of conjugated polymers.

Conjugated Polymer Nanoparticles for Cell Membrane Imaging

The outstanding optical properties and biocompatibility of fluorescent conjugated polymer nanoparticles (CPNs) make them favorable for bioimaging application. However, few CPNs could achieve stable cell membrane labeling due to cell endocytosis. In this work, conjugated polymer nanoparticles (PFPNP-PLE) encapsulated with PFP and PLGA-PEG-N3 in the matrix and functionalized with the small-molecule drug plerixafor (PLE) on the surface were prepared by a mini-emulsion method. PFPNP-PLE exhibits excellent photophysical properties, low cytotoxicity, and specific cytomembrane location, which makes it a potential cell membrane labeling reagent with blue fluorescence emission, an important component for multilabel/multicolor bioimaging.

DNA Hydrogel by Multicomponent Assembly for Encapsulation and Killing of Cells

In this work, a new multifunctional assembled hydrogel was prepared by incorporating gadolinium ions (Gd(3+)) with salmon-sperm DNA and polythiophene derivative (PT-COOH) through chelation interactions. Efficient energy transfer from PT-COOH to Gd(3+) ions takes place followed by sensitization of oxygen molecule to generate reactive oxygen species (ROS) under light irradiation. Cancer cells can be encapsulated into the hydrogel in situ as the formation of hydrogel followed by killing by the ROS. Integration of imaging modality with therapeutic function within a single assembled hydrogel is therefore anticipated to be a new and challenging design element for new hydrogel materials.