Effects of iRGD conjugation density on the in vitro and in vivo properties of cylindrical polymer brushes.

iRGD can significantly improve the tumor accumulation and tumor penetration of nanomaterials. However, it still remains unclear how far iRGD can enhance the properties of nanomaterials when its conjugation density is maximized. Herein, we synthesized three types of cylindrical polymer brushes (CPBs) with 0%, 50% and 100% of side chains terminated by iRGD, which were named CPBs-1, CPBs-2 and CPBs-3, respectively, and studied the effects of iRGD density on their cellular uptake, and tumor targeting ability and tumor permeability. It was demonstrated that compared with the iRGD-free CPBs-1, the cellular uptake of CPBs-3 was enhanced 5 times and their tumor accumulation was enhanced twice. The penetration depth of CPBs-3 in three-dimensional multicellular spheroids was larger than 100 µm. Our results provide useful information for the design of active tumor targeting nanomaterials as therapeutics or contrast agents.

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.

Phenylboronic Acid Modification Augments the Lysosome Escape and Antitumor Efficacy of a Cylindrical Polymer Brush-Based Prodrug.

Timely lysosome escape is of paramount importance for endocytosed nanomedicines to avoid premature degradation under the acidic and hydrolytic conditions in lysosomes. Herein, we report an exciting finding that phenylboronic acid (PBA) modification can greatly facilitate the lysosome escape of cylindrical polymer brushes (CPBs). On the basis of our experimental results, we speculate that the mechanism is associated with the specific interactions of the PBA groups with lysosomal membrane proteins and hot shock proteins. The featured advantage of the PBA modification over the known lysosome escape strategies is that it does not cause significant adverse effects on the properties of the CPBs; on the contrary, it enhances remarkably their tumor accumulation and penetration. Furthermore, doxorubicin was conjugated to the PBA-modified CPBs with a drug loading content larger than 20%. This CPBs-based prodrug could eradicate the tumors established in mice by multiple intravenous administrations. This work provides a novel strategy for facilitating the lysosome escape of nanomaterials and demonstrates that PBA modification is an effective way to improve the overall properties of nanomedicines including the tumor therapeutic efficacy.

Phenothiazine versus Phenoxazine: Structural Effects on the Photophysical Properties of NIR-II AIE Fluorophores.

Aggregation-induced emission (AIE) fluorophores with second near-infrared window (NIR-II) fluorescence are very promising for in vivo imaging because they emit fluorescence in an aggregated state and provide desirable imaging resolution and depth. Up to now, only a limited number of NIR-II AIE fluorophores have been developed. Therefore, synthesizing novel NIR-II AIE fluorophores and investigating structural effects on their photophysical properties are very important for the development of AIE probes. In this work, we synthesized two donor-acceptor-donor-type NIR fluorophores with emissions extending into the NIR-II window named DPTQ-PhPTZ and DPTQ-PhPXZ with phenothiazine (PTZ) and phenoxazine (PXZ) derivatives as the electron donors, respectively, and studied their photophysical properties via theoretical and experimental approaches as well as the properties in NIR-II in vivo imaging. The PTZ and PXZ moieties provided typical AIE characteristics. Despite the very similar chemical structures of PTZ and PXZ, DPTQ-PhPTZ and DPTQ-PhPXZ exhibited rather different photophysical properties, for example, compared to DPTQ-PhPTZ, DPTQ-PhPXZ had higher quantum yield (QY) both in solution and in the aggregated state and its QY was less sensitive to solvent polarity. After being coated with an amphiphilic copolymer F-127, the fluorophores maintained fluorescence, and the formed fluorescent polymer nanoparticles (NPs) had satisfactory tumor accumulation and biocompatibility, implying that they are applicable for in vivo tumor detection.

Second Near-Infrared Aggregation-Induced Emission Fluorophores with Phenothiazine Derivatives as the Donor and 6,7-Diphenyl-[1,2,5]Thiadiazolo[3,4-g]Quinoxaline as the Acceptor for In Vivo Imaging.

Traditional organic fluorophores generally have hydrophobic conjugated backbones and exhibit an aggregation-caused quenching emission property, which limits greatly their applications in the biological field. Aggregation-induced emission (AIE) fluorophores can breakthrough this shortcoming and are more promising in biological imaging. In this paper, we synthesized three novel donor-acceptor-donor-type second near-infrared (NIR-II) fluorophores and studied their geometric and electronic structures and photophysical properties by both theoretical and experimental studies. All the three fluorophores had typical AIE characteristics, and their emission wavelength spanned the traditional near-infrared and NIR-II regions. They exhibited much stronger fluorescence after being encapsulated in polymer nanoparticles (NPs) than in solutions, and the fluorophore-loaded NPs had desirable biosafety and significant tumor accumulation, indicating that they have great application potentials in tumor detection.

Modification of α-Cyclodextrin Polyrotaxanes by ATRP for Conjugating Drug and Prolonging Blood Circulation.

To enhance the water solubility of α-cyclodextrin (CD) polyrotaxanes (PRs) and achieve effective drug loading, we polymerized 2-hydroxyethyl methacrylate and 2-tert-butoxy-N-(2-(methacryloyloxy)ethyl)-N,N-dimethyl-2-oxoethanaminium successively from a α-CD-PR-based macroinitiator by a two-step ATRP followed by cleaving the tert-butyl ester groups, providing a α-CD-PR-cored multiarm copolymer. The multiarm copolymer had reactive hydroxyl pendant groups in the inner block of the arms, which were used to incorporate antitumor agent paclitaxel (PTX). The outer block of the arms was zwitterionic poly(carboxybetaine) and had high hydrophilicity and zero net electric charge in a neutral environment. This feature endowed the PTX-loaded multiarm copolymer with high water solubility and prolonged blood circulation. The blood circulation half-life of the PTX-loaded multiarm copolymer was determined to be about 7.7 h versus 18.8 ± 1.5 min of the reported blood circulation half-life of the PTX injected as commercial Taxol. The PTX-loaded multiarm copolymer was proved to be efficient in tumor accumulation and suppression.