Near-infrared light controlled protein degradation by photo-caged lenalidomide and pomalidomide.

Immunomodulatory drugs (e.g. thalidomide, lenalidomide and pomalidomide) have been proven highly successful in clinical treatment of multiple myeloma. However, systematic degradation of zinc finger transcriptional factors induced by these drugs could lead to severe systematic toxicity in patients. Previous reports of NVOC caged pomalidomide attempted to regulate its activity using UVA irradiation, but their application was limited by high cytotoxicity and low tissue penetration. Here, we reported red-shifted BODIPY caged lenalidomide and pomalidomide that enabled red-light controlled protein degradation with spatiotemporal precision.

An oxygen-economical nano-photosensitizer with a high photodynamic therapeutic outcome via simultaneous reduction of the cellular respiration and oxygen depletion of PDT.

The development of photodynamic nanomedicines that can alleviate intratumoral oxygen deficiency during photodynamic therapy (PDT) is of great significance for improving the therapeutic outcome of solid tumors characterized by severe hypoxia. Massive oxygen consumption due to vigorous cellular respiration, i.e., mitochondrial-associated oxidative phosphorylation (OXPHOS), is another major cause of severe tumor hypoxia in addition to insufficient oxygen supply. Moreover, oxygen depletion during PDT further exacerbates the shortage of intratumoral oxygen. In this work, we engineered a novel oxygen-economical nano-photosensitizer via co-encapsulation of an OXPHOS inhibitor (ATO) and a newly developed type-I photosensitizer (IPS) into a polymeric micelle of PEG-b-PCL. By controlling the length of hydrophobic PCL segments, we successfully optimized the micelle size to around 30 nm for enhanced tumor penetration. The orchestration of the two functional components, ATO and IPS, can simultaneously hinder the two major tumor oxygen-consuming pathways, where ATO targets mitochondrial complex III to inhibit cellular respiration, while IPS generates ROS through a low oxygen-consuming type-I photochemical pathway, enabling remarkable PDT efficacies in both hypoxic cells and a 4T1 tumor-bearing BALB/c mouse model. This work sheds new light on the construction of nano-photosensitizers to rejuvenate PDT against hypoxic solid tumors.

A Supramolecular Strategy to Engineering a Non-photobleaching and Near-Infrared Absorbing Nano-J-Aggregate for Efficient Photothermal Therapy.

The design of organic photothermal agents (PTAs) for in vivo applications face a demanding set of performance requirements, especially intense NIR-absorptivity and sufficient photobleaching resistance. J-aggregation offers a facile way to tune the optical properties of dyes, thus providing a general design platform for organic PTAs with the desired performance. Herein, we present a supramolecular strategy to build a water-stable, nonphotobleaching, and NIR-absorbing nano-PTA (J-NP) from J-aggregation of halogenated BODIPY dyes (BDP) for efficient in vivo photothermal therapy. Multiple intermolecular halogen-bonding and π-π stacking interactions triggered the formation of BDP J-aggregate, which adsorbed amphiphilic polymer chains on the surface to provide PEGylated sheetlike nano-J-aggregate (J-NS). We serendipitously discovered that the architecture of J-NS was remodeled during a long-time ultrafiltration process, generating a discrete spherical nano-J-aggregate (J-NP) with controlled size. Compared with J-NS, the remodeled J-NP significantly improved cellular uptake efficiency. J-aggregation brought J-NP striking photothermal performance, such as strong NIR-absorptivity, high photothermal conversion efficiency up to 72.0%, and favorable nonphotobleaching ability. PEGylation and shape-remodeling imparted by the polymer coating enabled J-NP to hold biocompatibility and stability in vivo, thereby exhibiting efficient antitumor photothermal activities. This work not only presents a facile J-aggregation strategy for preparing PTAs with high photothermal performance but also establishes a supramolecular platform that enables the appealing optical functions derived from J-aggregation to be applied in vivo.

Two Orthogonal Halogen-Bonding Interactions Directed 2D Crystalline Supramolecular J-Dimer Lamellae.

Dye assemblies exhibit fascinating properties and performances, both of which depend critically on the mutual packing arrangement of dyes and on the supramolecular architecture. Herein, we engineered, for the first time, an intriguing chlorosome-mimetic 2D crystalline J-dimer lamellar structure based on halogenated dyes in aqueous media by employing two distinct orthogonal halogen-bonding (XB) interactions. As the only building motif, antiparallel J-dimer was formed and stabilized by single π-stacking and dual halogen⋅⋅⋅π interactions. With two substituted halogen atoms acting as XB donors and the other two acting as acceptors, the constituent J-dimer units were linked by quadruple highly-directional halogen⋅⋅⋅halogen interactions in a staggered manner, resulting in unique 2D lamellar dye assemblies. This work champions and advances halogen-bonding as a remarkably potent tool for engineering dye aggregates with a controlled molecular packing arrangement and supramolecular architecture.

Oxygen Self-Production Red Blood Cell Carrier System for MRI Mediated Cancer Therapy: Ferryl-Hb, Sonodynamic, and Chemical Therapy.

Hypoxia in tumors can lead to insufficient oxygen supply during sonodynamic therapy (SDT), which in turn strengthens tumor resistance to sonodynamic efficacy. To conquer hypoxia in tumors and improve the treatment effectiveness, we developed oxygen self-production red blood cell (RBC) carrier system to decompose tumor endogenic H2O2 into O2 and combine triplex cancer therapy: ferryl-hemoglobin (ferryl-Hb), sonodynamic, and chemical therapy. Both hydrophilic sonosensitizer and doxorubicin (DOX) were encapsulated inside RBCs (DOX/Mn-TPPS@RBCs). The drug release can be improved by combining the effects of H2O2 and ultrasonic irradiation. Here, we introduced a contrast agent, meso-tetra (4-sulfonatephenyl) porphyrinate manganese(III) complex (Mn-TPPS), which could be used to enhance the signal intensity of magnetic resonance imaging (MRI) of the tumor site. The feasibility of Mn-TPPS as a sonosensitizer was investigated during SDT. Importantly, DOX/Mn-TPPS@RBCs overcame hypoxia in the tumor and improved the efficacy of SDT owing to the O2 generation by the catalase-catalyzed decomposition of tumor endogenic H2O2. Hemoglobin was simultaneously oxidized into highly oxidative ferryl-Hb species by H2O2 and reactive oxygen species, resulting in cytotoxicity. Overall, this drug delivery system is a promising therapeutic agent involving in situ production of oxygen inside the tumor, triplex therapy, and MRI.

A Smart Responsive Dual Aptamers-Targeted Bubble-Generating Nanosystem for Cancer Triplex Therapy and Ultrasound Imaging.

The absence of targeted, single treatment methods produces low therapeutic value for treating cancers. To increase the accumulation of drugs in tumors and improve the treatment effectiveness, near-infrared 808 nm photothermal responsive dual aptamers-targeted docetaxel (DTX)-containing nanoparticles is proposed. In this system, DTX and NH4 HCO3 are loaded in thermosensitive liposomes. The surface of liposomes is coated with gold nanoshells and connected with sulfydryl (SH) modified AS1411 and S2.2 aptamers. The nanosystem has good biocompatibility and uniform size (diameter about 200 nm). The drug is rapidly released, reaching a maximum amount (84%) at 4 h under 808 nm laser irradiation. The experiments conducted in vitro and in vivo demonstrate the nanosystem can synergistically inhibit tumor growth by combination of chemotherapy, photothermal therapy, and biological therapy. Dual ligand functionalization significantly increases cellular uptake on breast cancer cell line (MCF-7) cells and achieves ultrasound imaging (USI) at tumor site. The results indicate that this drug delivery system is a promising theranostic agent involving light-thermal response at tumor sites, dual ligand targeted triplex therapy, and USI.

CuS as a gatekeeper of mesoporous upconversion nanoparticles-based drug controlled release system for tumor-targeted multimodal imaging and synergetic chemo-thermotherapy.

In this work, a tumor-targeted multifunctional mesoporous upconversion nanoparticle-based drug controlled release system was developed for UCL/MRI/PAT guided synergetic chemo-thermotherapy. Herein, the core-shell mesoporous upconversion nanoparticles served as drug carrier exhibiting higher upconversion luminescence emission intensity, with CuS as a gatekeeper through a cleavable disulfide bond under the influence of glutathione. CuS could not only prevent drug from early release during the delivery but also improve the delivery system function with the ability of photothermal therapy and photoacoustic tomography. Hyaluronic acid grafted on the surface of mesoporous upconversion nanoparticles could interact with CD44 receptors over-expressed in tumor cells, facilitating the drug delivery system to accumulate in tumor tissues. The synergy between chemotherapy and photothermal therapy was studied in vitro and in vivo, showing powerful anti-tumor effect. In cooperation with the multi-mode imaging, the size, site and morphology of tumor were clearly observed throughout the disease's progression.

Multimodal imaging-guided, dual-targeted photothermal therapy for cancer.

The ability to selectively destroy cancer cells while sparing normal tissue is highly desirable during cancer therapy. Herein, dual-targeted photothermal therapy was achieved by the integration of upconversion nanoparticles, Fe3O4 nanoparticles (IONPs), Prussian blue nanoparticles (PBNPs) and hyaluronic acid (HA). PBNPs converted near-infrared (NIR) light into heat and HA/Fe3O4 NPs served as dual-targeting moieties. The as-obtained nanocomposites could also be applied as a multimodal probe for upconversion luminescence (UCL) imaging, enhanced T2-weighted magnetic resonance (MR) imaging and photoacoustic tomography (PAT) imaging. This multifunctional nanoparticle (MFNP) system prepared by a layer-by-layer (LBL) assembly method exhibited excellent dispersivity and low toxicity in vitro and in vivo. Furthermore, the research provided effective results for dual-targeted photothermal ablation of cancer with ∼4 fold higher tumor accumulation than that in the absence of HA/magnetic field. The photothermal therapeutic efficacy has been greatly improved in the S180 tumor model. We present a strategy for multimodal imaging-guided, dual-targeted physical cancer therapy and highlight the promise of using multifunctional nanostructures for cancer theranostics.

Graft-union development: a delicate process that involves cell-cell communication between scion and stock for local auxin accumulation.

Grafting is an ancient cloning method that has been used widely for thousands of years in agricultural practices. Graft-union development is also an intricate process that involves substantial changes such as organ regeneration and genetic material exchange. However, the molecular mechanisms for graft-union development are still largely unknown. Here, a micrografting method that has been used widely in Arabidopsis was improved to adapt it a smooth procedure to facilitate sample analysis and to allow it to easily be applied to various dicotyledonous plants. The developmental stage of the graft union was characterized based on this method. Histological analysis suggested that the transport activities of vasculature were recovered at 3 days after grafting (dag) and that auxin modulated the vascular reconnection at 2 dag. Microarray data revealed a signal-exchange process between cells of the scion and stock at 1 dag, which re-established the communication network in the graft union. This process was concomitant with the clearing of cell debris, and both processes were initiated by a wound-induced programme. The results demonstrate the feasibility and potential power of investigating various plant developmental processes by this method, and represent a primary and significant step in interpretation of the molecular mechanisms underlying graft-union development.