Youshen Wu

High drug-loading nanomedicines: progress, current status, and prospects

Drug molecules transformed into nanoparticles or endowed with nanostructures with or without the aid of carrier materials are referred to as “nanomedicines” and can overcome some inherent drawbacks of free drugs, such as poor water solubility, high drug dosage, and short drug half-life in vivo. However, most of the existing nanomedicines possess the drawback of low drug-loading (generally less than 10%) associated with more carrier materials. For intravenous administration, the extensive use of carrier materials might cause systemic toxicity and impose an extra burden of degradation, metabolism, and excretion of the materials for patients. Therefore, on the premise of guaranteeing therapeutic effect and function, reducing or avoiding the use of carrier materials is a promising alternative approach to solve these problems. Recently, high drug-loading nanomedicines, which have a drug-loading content higher than 10%, are attracting increasing interest. According to the fabrication strategies of nanomedicines, high drug-loading nanomedicines are divided into four main classes: nanomedicines with inert porous material as carrier, nanomedicines with drug as part of carrier, carrier-free nanomedicines, and nanomedicines following niche and complex strategies. To date, most of the existing high drug-loading nanomedicines belong to the first class, and few research studies have focused on other classes. In this review, we investigate the research status of high drug-loading nanomedicines and discuss the features of their fabrication strategies and optimum proposal in detail. We also point out deficiencies and developing direction of high drug-loading nanomedicines. We envision that high drug-loading nanomedicines will occupy an important position in the field of drug-delivery systems, and hope that novel perspectives will be proposed for the development of high drug-loading nanomedicines.

Incorporating fluorescent dyes into monodisperse melamine–formaldehyde resin microspheres via an organic sol–gel process: a pre-polymer doping strategy

An organic sol-gel process was developed to incorporate fluorescent dyes into monodisperse melamine-formaldehyde (MF) resin microspheres. Various organic fluorescent dyes have been successfully incorporated by this process, and monodisperse fluorescent MF microspheres were prepared. Fluorescence-encoded microsphere arrays with dozens of sets were obtained by quantitatively incorporating several dyes at different doping concentrations. The characteristics and incorporating mechanism of these microspheres and their dyes were investigated by scanning electron microscopy, Malvern particle analysis, fluorescence spectroscopy, laser scanning confocal microscopy (LSCM), and flow cytometric analyses. Resonance energy transfer (RET) interactions of the doped dyes were investigated by steady-state and time-resolved fluorescence spectroscopy. The dye-incorporated microspheres were stable, and no leakage or deformation was found. With the occurrence of the RET effect among multi-doped dyes, prepared microspheres exhibited single excited, doping ratio-related emission signatures. The prepared dye-doped microspheres were coated with silica shells, which provided favorable surface properties for bioconjugate applications. This process of incorporating organic dyes could also be used to coat particles with dye-doped fluorescent MF shells. Multi-shell structured composite microspheres with fluorescent shells were also prepared by alternately repeating silica and MF coatings.

Ratiometric Nanothermometer Based on Rhodamine Dye-Incorporated F127-Melamine-Formaldehyde Polymer Nanoparticle: Preparation, Characterization, Wide-Range Temperature Sensing, and Precise Intracellular Thermometry

A series of fluorescent nanothermometers (FTs) was prepared with Rhodamine dye-incorporated Pluronic F-127-melamine-formaldehyde composite polymer nanoparticles (R-F127-MF NPs). The highly soluble Rhodamine dye molecules were bound with Pluronic F127 micelles and subsequently incorporated in the cross-linked MF resin NPs during high-temperature cross-link treatment. The morphology and chemical structure of R-F127-MF NPs were characterized with dynamic light scattering, electron microscopy, and Fourier-transform infrared (FTIR) spectra. Fluorescence properties and thermoresponsivities were analyzed using fluorescence spectra. R-F127-MF NPs are found to be monodispersed, presenting a size range of 88-105 nm, and have bright fluorescence and high stability in severe treatments such as autoclave sterilization and lyophilization. By simultaneously incorporating Rhodamine B and Rhodamine 110 (as reference) dyes at a doping ratio of 1:400 in the NPs, ratiometric FTs with a high sensibility of 7.6%·°C(-1) and a wide temperature sensing range from -20 to 110 °C were obtained. The FTs exhibit good stability in solutions with varied pH, ionic strengths, and viscosities and have similar working curves in both intracellular and extracellular environments. Cellular temperature variations in Hela cells during microwave exposure were successfully monitored using the FTs, indicating their considerable potential applications in the biomedical field.

Preparation and characterization of narrow-dispersed magnetic colloidal nanoparticle cluster/silica microspheres with controlled sizes, high saturation magnetization and MRI enhancement effect

A comprehensive method combining polymerization-induced colloid aggregation, silica coating, and high-temperature calcination is developed for the preparation of micro-sized magnetic colloidal nanoparticle cluster/silica (CNC/silica) microspheres. The silica shell stabilizes the inner micro-sized γ-Fe2O3 nanoparticle clusters without phase transformation during high-temperature calcination instead of acting as anti-sintering agents. Their morphologies and inner structures are observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The material characteristics are investigated by Fourier transfer infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), powder X-ray diffraction (XRD) and vibrating-sample magnetometer (VSM). The biocompatibility and MRI enhancement effect of CNC/silica microspheres are also evaluated by MTT assay and MRI imaging. The prepared CNC/silica microspheres are narrow-dispersed with a wide size range of 1.8 μm to 5.0 μm. These microspheres also have the advantages of higher saturation magnetization (61.38 emu g-1), easily modifiable surfaces, good biocompatibility, high cell-label efficiencies, and significantly enhanced T2 effect in MRI, indicating their various potential applications in biomedical fields.

Quantitative ratiometric phosphorescence hypoxia–sensing nanoprobes based on quantum dots/Ir(III) glycerol monoolein cubic-phase nanoparticles

A novel protocol is developed to prepare quantum dot (QD)/Ir(III) complex glycerol monoolein (GMO) cubic-phase nanoparticles (Qd/Ir GMCPNPs) as hypoxia nanoprobes, in which hypoxia probe Tris [1-phenylisoquinoline-C2, N] Iridium(III) [Ir(piq)3] and the reference QDs are separately loaded at hydrophilic and hydrophobic channels to avoid interference. Qd/Ir GMCPNPs were nearly spherical in shape, with an average size of 20-30nm. Their phosphorescence spectra showed that nanoprobes have a wide excited wave length range of 360-500nm, which is suitable for different types of measurement instruments. When the oxygen content decreased from 21% to 1%, the luminescent intensity ratio of Qd/Ir GMCPNPs in the solution and cells increased 4-fold and 2.8-fold, respectively, with an acceptable linear relationship. Particularly, extensive preliminary quantitative ratiometric oxygen sensing and long tumor imaging monitoring can be achieved with these nanoprobes.

Ultrasmall dopamine-coated nanogolds: preparation, characteristics, and CT imaging

ABSTRACT Water-dispersible ultrasmall nanogolds (WDU AuNPs) and their dopamine-coated nanogolds (WDU AuNPs@DPAs) were prepared by a reduction method with sodium borohydride as a reducing agent and a stabilised agent of 2-mercaptosuccinic acid in aqueous solution. The effects of these nanoparticles on computed tomography (CT) imaging were evaluated. The size distributions and Zeta potential of the nanoparticles were measured with a Malvern size analyser, and nanoparticle morphology was observed by transmission electron microscopy. These characteristics were confirmed by Fourier transform spectroscopy and ultraviolet/visible spectra. It was found that WDU AuNPs@DPAs were 5.4 nm in size with clear core–shell structure. The 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyltetrazolium bromide assay results showed that the WDU AuNPs and WDU AuNPs@DPAs were hypotoxic to different cells. The WDU AuNPs@DPAs showed a much longer circulation time and a larger CT attenuation coefficient than iohexol and could be excreted by the kidney and bladder. These nanoparticles showed considerable potential for future application in CT imaging.

Thermo-stable hollow magnetic microspheres: preparation, characterization and recyclable catalytic applications

Thermo-stable hollow magnetic microspheres are prepared by layer-by-layer (LbL) assembly on a uniform melamine–formaldehyde resin microsphere template coated by silica and calcination for burning off organic resin. Trypsin is immobilized by their coated polydopamine layer, and nanogold particles are assembled onto the microspheres by the LbL method for catalytic applications. The morphologies and hollow structures are observed by using a scanning electron microscope and transmission electron microscope. The characteristics are investigated by Fourier transfer infrared spectroscopy, thermo-gravimetric analysis and vibrating sample magnetometry. Meanwhile, the catalytic characteristics of nanogold particles and trypsin are evaluated by ultraviolet-visible spectra. The prepared hollow thermo-stable magnetic microspheres are narrow-dispersed with a relatively low coefficient of variation, and their size ranging from 0.5 μm to 5.0 μm and saturation magnetization (4–30 emu g−1) can be regulated by different conditions. Combined with magnetic separation and calcination activation or regeneration, these microspheres can also be reused over 20 times for nanogold catalyst and over 32 times for trypsin catalyst reconjugation without any significant loss in catalytic activity, indicating their considerable potential for recyclable catalytic applications.

Rewritable magnetic fluorescence-encoded microspheres: preparation, characterization, and recycling

Rewritable magnetic fluorescence-encoded microspheres were prepared by coating magnetic microspheres with a fluorescence-encoded melamine-formaldehyde (MF) shell. Fluorescence encoding was realized by varying the dye types and concentrations incorporated into the MF shell. Ten sets of magnetic fluorescence-encoded microspheres including four sets doped with single dye and six sets doped with two dyes were obtained and successfully identified through flow cytometric analysis. High encoding capacity could be achieved by increasing the dye number and intensity levels. More importantly, the original fluorescence-encoded MF shell could be removed via calcination. The inner magnetic microspheres remained unaffected and could be re-coated with a new fluorescence-encoded MF shell easily. The fluorescent MF coating (encoding writing) and calcination (encoding erasing) composed a cycle. Results demonstrated that the magnetic microspheres retained their original characteristics after writing–erasing cycles and the writing–erasing cycle could be repeated numerous times. These kinds of rewritable magnetic fluorescence-encoded microspheres enabled recycling and regeneration. Combining magnetic separation and re-encoding, which can significantly simplify the analysis processes and decrease the analysis cost, these microspheres are expected to be widely used in suspension arrays for high-throughput analyses.

Metabolizable dopamine-coated gold nanoparticle aggregates: preparation, characteristics, computed tomography imaging, acute toxicity, and metabolism in vivo

To improve the computed tomography (CT) imaging ability and the toxicity of gold nanoparticles (AuNPs), hydrophilic dopamine (DPA)-coated gold nanoparticle (AuNP) (MSA AuNPs@DPA) aggregates (42 ± 2.65 nm) were obtained by assembling MSA AuNPs@DPA (5-6 nm) with the use of polyethyleneimine (PEI). They rapidly degraded into MSA AuNPs@DPA with PEI in blood. The acute toxicity test showed that the maximum tolerated doses of MSA AuNPs@DPA and MSA AuNPs@DPA aggregates were larger than 4.8 and 4.6 g kg-1, respectively, which are much higher doses than those of the commonly used citric acid-stabilized AuNPs (CA AuNPs) (2.97 g kg-1). The metabolic test in vivo showed that the elimination rates of MSA AuNPs@DPA aggregates and MSA AuNPs@DPA were 0.848 and 0.955, respectively. Most of the aggregates were eliminated by the kidney after 5 days and excreted by urine, whereas CA AuNPs remained in vivo and concentrated in some organs. The t0.5 values of MSA AuNPs@DPA and MSA AuNPs@DPA aggregates were 24.28 and 43.68 h, respectively, meaning that MSA AuNPs@DPA aggregates had a much longer circulation time. Similarly, the CT absorption value of MSA AuNPs@DPA aggregates was much higher than that of the commonly used nonionic iodinated CT contrast agent iohexol and CA AuNPs at the same concentration. Thus, MSA AuNPs@DPA aggregates possess characteristics such as ease of fabrication, long circulation time, hypotoxicity, and excellent CT absorption value, which suggest their great potential applications in vivo.