A ratiometric near-infrared fluorescence/photoacoustic dual-modal probe with strong donor dithienopyrrole for in vivo nitric oxide detection.

Integrating the imaging techniques of near-infrared fluorescence (NIRF) and photoacoustic (PA) can make up for each other and provide more useful medical information. Ratiometric imaging activated by disease-associated biomarkers can further augment imaging specificity. However, very few studies have employed the NIRF/PA dual-modal ratiometric imaging to improve the accuracy and specificity of disease diagnosis to date. In this paper, we present the synthesis of a nitric oxide (NO)-activated ratiometric NIRF/PA dual-modal nanoprobe RAPNP for in vivo NO imaging. The ratiometric imaging function was achieved jointly by a NO/acidity-responsive molecule DTP-BTDA and a nonresponsive fluorophore DTP-BBTD. In these fluorophores, the dithienopyrrole (DTP) moiety had strong electron-donating ability and imparted strong intramolecular charge transfer and relatively long emission wavelengths. The BTDA moiety in DTP-BTDA could be rapidly oxidized by NO under weak acidic environments, achieving the NIRF and PA signal activation. By using RAPNP as a contrast agent, we achieved the ratiometric detection of the endogenous NO in inflammatory bowel disease by NIRF/PA dual-modal imaging. This work provides the first case of the NIRF/PA dual-signal ratiometric probe for the real-time detection of NO in vivo.

Safety and biodistribution of exosomes derived from human induced pluripotent stem cells.

As a new cell-free therapy, exosomes have provided new ideas for the treatment of various diseases. Human induced pluripotent stem cells (hiPSCs) cannot be used in clinical trials because of tumorigenicity, but the exosomes derived from hiPSCs may combine the advantages of iPSC pluripotency and the nanoscale size of exosomes while avoiding tumorigenicity. Currently, the safety and biodistribution of hiPSC-exosomes in vivo are unclear. Here, we investigated the effects of hiPSC-exosomes on hemolysis, DNA damage, and cytotoxicity through cell experiments. We also explored the safety of vein injection of hiPSC-exosomes in rabbits and rats. Differences in organ distribution after nasal administration were compared in normal and Parkinson's disease model mice. This study may provide support for clinical therapy and research of intravenous and nasal administration of hiPSC-exosomes.

An Orthogonal Protection Strategy for Synthesizing Scaffold-Modifiable Dendrons and Their Application in Drug Delivery.

Dendrons have well-defined dendritic structures. However, it is a great challenge to preserve their high structural definition after multiple functionalization because the site-selective conjugation of different functional molecules is quite difficult. Scaffold-modifiable dendrons that have orthogonal reactive groups at the scaffold and periphery are ideal for achieving the site-specific bifunctionalization. In this paper, we present a new strategy for synthesizing scaffold-modifiable dendrons via orthogonal amino protection and a solid-phase synthesis method. This strategy renders the reactive sites at the scaffold and periphery of the dendrons a super selectivity, high reactivity, and wide applicability to various reaction types. The fourth-generation dendrons can be facilely synthesized within 2 days without structural defects as demonstrated by mass spectrometry. We conjugated doxorubicin (DOX) and phenylboronic acid (PBA) groups to the scaffold and periphery, respectively. Thanks to the PBA-enhanced lysosome escape, tumor targeting ability, and tumor permeability as well as the high drug loading content larger than 30%, the dendron-based prodrug exhibited extraordinary antitumor efficacy and could eradicate the tumors established in mice by multiple intravenous administration. This work provides a practical strategy for synthesizing scaffold-modifiable dendrons that can be a promising nanoplatform to achieve function integration in a precisely controlled manner.

Nanoscale Crystalline Sheets and Vesicles Assembled from Nonplanar Cyclic π-Conjugated Molecules.

A fundamental challenge in chemistry and materials science is to create new carbon nanomaterials by assembling structurally unique carbon building blocks, such as nonplanar π-conjugated cyclic molecules. However, self-assembly of such cyclic π-molecules to form organized nanostructures has been rarely explored despite intensive studies on their chemical synthesis. Here we synthesized a family of new cycloparaphenylenes and found that these fully hydrophobic and nonplanar cyclic π-molecules could self-assemble into structurally distinct two-dimensional crystalline multilayer nanosheets. Moreover, these crystalline multilayer nanosheets could overcome inherent rigidity to curve into closed crystalline vesicles in solution. These supramolecular assemblies show that the cyclic molecular scaffolds are homogeneously arranged on the surface of nanosheets and vesicles with their molecular isotropic x-y plane standing obliquely on the surface. These supramolecular architectures that combined exact crystalline order, orientation-specific arrangement of π-conjugated cycles, controllable morphology, uniform molecular pore, superior florescence quench ability, and photoluminescence are expected to give rise to a new class of functional materials displaying unique photonic, electronic, and biological functions.

Nanoscale vesicles assembled from non-planar cyclic molecules for efficient cell penetration.

A new approach to the development of functional biomaterials is to obtain a controllable nanostructure through supramolecular self-assembly. Although much effort has been devoted to supramolecular structures with different morphologies and properties, fluorescent macrocycle-based carbon material assembly into three-dimensional vesicle morphologies remains a challenge. Herein, the supramolecular properties of cycloparaphenylene (CPP) in a mixed solution are characterized and controlled successfully through the regulation of different concentrations and solvent ratios. The self-assembled CPP molecules form a three-dimensional hollow structure in different solutions. The assembled vesicle structure endows CPPs with cell biology application and it is found that CPPs could be internalized by cells via an energy- or temperature-independent mechanism. Even in the presence of different inhibitors, cellular uptake of [10]CPP could not be affected. These supramolecular and biological findings of CPPs extend the current understanding of cycloparaphenylene chemistry and will open up new and more attractive applications in nanotechnology, biology and materials science.