Reactive oxygen species (ROS) play an essential role in regulating various physiological functions of living organisms. The intrinsic biochemical properties of ROS, which underlie the mechanisms ne...

Reactive Oxygen Species (ROS)-Based Nanomedicine.

The complexity, diversity, and heterogeneity of tumors seriously undermine the therapeutic potential of treatment. Therefore, the current trend in clinical research has gradually shifted from a focus on monotherapy to combination therapy for enhanced treatment efficacy. More importantly, the cooperative enhancement interactions between several types of monotherapy contribute to the naissance of multimodal synergistic therapy, which results in remarkable superadditive (namely “1 + 1 > 2”) effects, stronger than any single therapy or their theoretical combination. In this review, state-of-the-art studies concerning recent advances in nanotechnology-mediated multimodal synergistic therapy will be systematically discussed, with an emphasis on the construction of multifunctional nanomaterials for realizing bimodal and trimodal synergistic therapy as well as the intensive exploration of the underlying synergistic mechanisms for explaining the significant improvements in synergistic therapeutic outcome. Furtherm...

Nanotechnology for Multimodal Synergistic Cancer Therapy

Photodynamic therapy (PDT) has been applied to treat a wide range of medical conditions, including wet age-related macular degeneration psoriasis, atherosclerosis, viral infection and malignant cancers. However, the tissue penetration limitation of excitation light hinders the widespread clinical use of PDT. To overcome this “Achilles' heel”, deep PDT, a novel type of phototherapy, has been developed for the efficient treatment of deep-seated diseases. Based on the different excitation sources, including near-infrared (NIR) light, X-ray radiation, and internal self-luminescence, a series of deep PDT techniques have been explored to demonstrate the advantages of deep cancer therapy over conventional PDT excited by ultraviolet-visible (UV-Vis) light. In particular, the featured applications of deep PDT, such as organelle-targeted deep PDT, hypoxic deep PDT and deep PDT-involved multimodal synergistic therapy are discussed. Finally, the future development and potential challenges of deep PDT are also elucidated for clinical translation. It is highly expected that deep PDT will be developed as a versatile, depth/oxygen-independent and minimally invasive strategy for treating a variety of malignant tumours at deep locations.

Overcoming the Achilles' heel of photodynamic therapy.

Photoacoustic imaging (PAI) is an emerging tool that bridges the traditional depth limits of ballistic optical imaging and the resolution limits of diffuse optical imaging. Using the acoustic waves generated in response to the absorption of pulsed laser light, it provides noninvasive images of absorbed optical energy density at depths of several centimeters with a resolution of ∼100 μm. This versatile and scalable imaging modality has now shown potential for molecular imaging, which enables visualization of biological processes with systemically introduced contrast agents. Understanding the relative merits of the vast range of contrast agents available, from small-molecule dyes to gold and carbon nanostructures to liposome encapsulations, is a considerable challenge. Here we critically review the physical, chemical and biochemical characteristics of the existing photoacoustic contrast agents, highlighting key applications and present challenges for molecular PAI.

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Contrast agents for molecular photoacoustic imaging

Polymer encapsulated organic nanoparticles have recently attracted increasing attention in the biomedical field because of their unique optical properties, easy fabrication and outstanding performance as imaging and therapeutic agents. Of particular importance is the polymer encapsulated nanoparticles containing conjugated polymers (CP) or fluorogens with aggregation induced emission (AIE) characteristics as the core, which have shown significant advantages in terms of tunable brightness, superb photo- and physical stability, good biocompatibility, potential biodegradability and facile surface functionalization. In this review, we summarize the latest advances in the development of polymer encapsulated CP and AIE fluorogen nanoparticles, including preparation methods, material design and matrix selection, nanoparticle fabrication and surface functionalization for fluorescence and photoacoustic imaging. We also discuss their specific applications in cell labeling, targeted in vitro and in vivo imaging, blood vessel imaging, cell tracing, inflammation monitoring and molecular imaging. We specially focus on strategies to fine-tune the nanoparticle property (e.g. size and fluorescence quantum yield) through precise engineering of the organic cores and careful selection of polymer matrices. The review also highlights the merits and limitations of these nanoparticles as well as strategies used to overcome the limitations. The challenges and perspectives for the future development of polymer encapsulated organic nanoparticles are also discussed.

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Polymer-encapsulated organic nanoparticles for fluorescence and photoacoustic imaging

In the past few years, conjugated polymer nanoparticles (CPNs) have been successfully prepared and applied in the biological field because of their unique opto-electronic properties. The rapid development of CPNs is mainly attributed to their simple synthesis procedures and easy separation steps. The advantages of CPNs include high brightness, excellent photostability, low cytotoxicity, high quantum yield and versatile surface modification. The functionalization of CPNs with specific recognition elements imparts them good ability for targeted recognition and imaging in vitro and in vivo. CPNs can be applied to deliver drug and gene, and simultaneously to real-time monitor the release process due to their self-luminous characteristics. Moreover, CPNs can sensitize oxygen molecules to generate reactive oxygen species (ROS) which can kill adjacent bacteria and tumor cells. In this tutorial review, we provide a recent development of the preparation methods, properties, and functionalization strategies of CPNs, especially discussing their biological applications in targeted imaging, drug/gene delivery and biomedicine. The challenges and outlooks in this field will also be discussed.

Conjugated polymer nanoparticles: preparation, properties, functionalization and biological applications

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

Supramolecular Photosensitizers with Enhanced Antibacterial Efficiency

A supramolecular antibiotic switch is described that can reversibly "turn-on" and "turn-off" its antibacterial activity on demand, providing a proof-of-concept for a way to regulate antibacterial activity of biotics. The switch relies on supramolecular assembly and disassembly of cationic poly(phenylene vinylene) derivative (PPV) with cucurbit[7]uril (CB[7]) to regulate their different interactions with bacteria. This simple but efficient strategy does not require any chemical modification on the active sites of the antibacterial agent, and could also regulate the antibacterial activity of classical antibiotics or photosensitizers in photodynamic therapy. This supramolecular antibiotic switch may be a successful strategy to fight bacterial infections and decrease the emergence of bacterial resistance to antibiotics from a long-term point of view.

A Supramolecular Antibiotic Switch for Antibacterial Regulation

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 +

Cationic conjugated polymers for discrimination of microbial pathogens.

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.

Huanxiang Yuan

Papers

Conjugated polymer nanoparticles: preparation, properties, functionalization and biological applications

Supramolecular Photosensitizers with Enhanced Antibacterial Efficiency

A Supramolecular Antibiotic Switch for Antibacterial Regulation

Cationic conjugated polymers for discrimination of microbial pathogens.

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