Benqing Zhou

Synthesis and Characterization of PEGylated Polyethylenimine-Entrapped Gold Nanoparticles for Blood Pool and Tumor CT Imaging

The synthesis and characterization of gold nanoparticles (AuNPs) entrapped within polyethylene glycol (PEG)-modified polyethylenimine (PEI) for blood pool and tumor computed tomography (CT) imaging are reported. In this approach, partially PEGylated PEI was used as a template for AuNP synthesis, followed by acetylating the PEI remaining surface amines. The synthesized PEGylated PEI-entrapped AuNPs (Au PENPs) were characterized via different methods. Our results reveal that the synthesized Au PENPs can be tuned to have an Au core size in a range of 1.9-4.6 nm and to be water-soluble, stable, and noncytotoxic in a studied concentration range. With a demonstrated better X-ray attenuation property than that of clinically used iodinated small molecular contrast agent (e.g., Omnipaque) and the prolonged half-decay time (11.2 h in rat) confirmed by pharmacokinetics studies, the developed PEGylated Au PENPs enabled efficient and enhanced blood pool CT imaging with imaging time up to 75 min. Likewise, thanks to the enhanced permeability and retention effect, the PEGylated Au PENPs were also able to be used as a contrast agent for effective CT imaging of a tumor model. With the proven organ biocompatibility by histological studies, the designed PEGylated Au PENPs may hold great promise to be used as contrast agents for CT imaging of a variety of biological systems. The significance of this study is that rather than the use of dendrimers as templates, cost-effective branched polymers (e.g., PEI) can be used as templates to generate functionalized AuNPs for CT imaging applications.

Targeted tumor CT imaging using folic acid-modified PEGylated dendrimer-entrapped gold nanoparticles

The development of multifunctional nanoprobes with a targeting capability for efficient molecular imaging of tumors still remains a great challenge. Herein, we report the synthesis and characterization of folic acid (FA)-modified dendrimer-entrapped gold nanoparticles (Au DENPs) via a facile polyethylene glycol (PEG) linking strategy for in vivo targeted tumor computed tomography (CT) imaging applications. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) sequentially modified by two types of PEG moieties (PEG monomethyl ether with one end of carboxyl group (mPEG-COOH), and FA-modified PEG with one end of carboxyl group (FA-PEG-COOH)) were used as templates to synthesize AuNPs within the dendrimer interiors, followed by acetylation of the remaining dendrimer terminal amines. The formed multifunctional Au DENPs were characterized via different techniques. Cell viability assay, flow cytometric analysis of the cell cycles, and hemolysis assay were used to assess the cytotoxicity and hemocompatibility of the particles. We show that the formed multifunctional Au DENPs are stable at different pH and temperature conditions and in different aqueous media, cytocompatible and hemocompatible in the given Au concentration range, and display much higher X-ray attenuation intensity than Omnipaque (an iodine-based CT contrast agent) under similar concentrations of the active element (Au or iodine). Moreover, the developed Au DENPs enable targeted CT imaging of the model cancer cells with high FA receptor expression in vitro and the corresponding xenografted tumor model in vivo. These findings suggest that the designed Au DENPs may be used as promising contrast agents for targeted CT imaging of tumors.

Dendrimer-stabilized bismuth sulfide nanoparticles: synthesis, characterization, and potential computed tomography imaging applications

We report here a general approach to synthesizing dendrimer-stabilized bismuth sulfide nanoparticles (Bi2S3 DSNPs) for potential computed tomography (CT) imaging applications. In this study, ethylenediamine core glycidol hydroxyl-terminated generation 4 poly(amidoamine) dendrimers (G4.NGlyOH) were used as stabilizers to first complex the Bi(III) ions, followed by reaction with hydrogen sulfide to generate Bi2S3 DSNPs. By varying the molar ratio of Bi atom to dendrimer, stable Bi2S3 DSNPs with an average size range of 5.2-5.7 nm were formed. The formed Bi2S3 DSNPs were characterized via different techniques. X-ray absorption coefficient measurements show that the attenuation of Bi2S3 DSNPs is much higher than that of iodine-based CT contrast agent at the same molar concentration of the active element (Bi versus iodine). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay and hemolysis assay reveal that the formed Bi2S3 DSNPs are noncytotoxic and have a negligible hemolysis effect in the studied concentration range. Furthermore, we show that cells incubated with the Bi2S3 DSNPs are able to be imaged using CT, a prominent enhancement at the point of rabbit injected subcutaneously with the Bi2S3 DSNPs is able to be visualized via CT scanning, and the mouses pulmonary vein can be visualized via CT after intravenous injection of the Bi2S3 DSNPs. With the good biocompatibility, enhanced X-ray attenuation property, and tunable dendrimer chemistry, the designed Bi2S3 DSNPs should be able to be further functionalized, allowing them to be used as a highly efficient contrast agent for CT imaging of different biological systems.

PEGylated polyethylenimine-entrapped gold nanoparticles modified with folic acid for targeted tumor CT imaging.

Development of various cost-effective contrast agents for targeted tumor computed tomography (CT) imaging still remains a great challenge. Herein, we present a facile approach to forming folic acid (FA)-targeted multifunctional gold nanoparticles (AuNPs) using cost-effective branched polyethylenimine (PEI) modified with polyethylene glycol (PEG) as a template for tumor CT imaging applications. In this work, PEI sequentially modified with PEG monomethyl ether, FA-linked PEG, and fluorescein isothiocyanate was used as a template to synthesize AuNPs, followed by transformation of the remaining PEI surface amines to acetamides. The formed FA-targeted PEI-entrapped AuNPs (FA-Au PENPs) were fully characterized. We show that the formed FA-Au PENPs with an Au core size of 2.1 nm are water soluble, colloidally stable, and non-cytotoxic in a given concentration range. Flow cytometry and confocal microscopy data reveal that the FA-Au PENPs are able to target cancer cells overexpressing FA receptors (FAR). Importantly, the developed FA-Au PENPs can be used as a nanoprobe for targeted CT imaging of FAR-expressing cancer cells in vitro and the xenografted tumor model in vivo. With the demonstrated biocompatibility by organ biodistribution and histological studies, the designed FA-Au PENPs may hold great promise to be used as a nanoprobe for CT imaging of different FAR-overexpressing tumors.

PEGylated polyethylenimine-entrapped gold nanoparticles loaded with gadolinium for dual-mode CT/MR imaging applications

AIM To synthesize and characterize cost-efficient polyethylenimine-entrapped gold nanoparticles loaded with gadolinium (Gd@Au PENPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging applications. MATERIALS & METHODS PEGylated PEI modified with gadolinium (Gd) chelator (DOTA) was used as a template to synthesize the Gd@Au PENPs and the particles were well characterized in terms of their physicochemical properties, cytotoxicity and performances in CT and MR imaging in vitro and in vivo. RESULTS The formed Gd@Au PENPs with low cytotoxicity can be used as a highly efficient contrast agent for dual-mode CT/MR imaging of blood pool and major organs of animals. CONCLUSION The designed Gd@Au PENPs may be used as a versatile nanoplatform for dual-mode CT/MR imaging of different biological systems.

Formation of iron oxide nanoparticle-loaded γ-polyglutamic acid nanogels for MR imaging of tumors

We report a facile approach to form iron oxide nanoparticle (NP)-loaded γ-polyglutamic acid (γ-PGA) nanogels (NGs) for MR imaging of tumors. In this study, γ-PGA with carboxyl groups activated by 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC) in aqueous solution was firstly emulsified, followed by in situ chemical crosslinking with polyethyleneimine (PEI)-coated iron oxide NPs (PEI-Fe3O4 NPs) with a core size of 8.9 ± 2.1 nm synthesized via a mild reduction route. The formed γ-PGA NGs containing iron oxide NPs (γ-PGA/PEI-Fe3O4 NGs) with a size of 152.3 ± 13.1 nm are water-dispersible, colloidally stable, noncytotoxic in a given concentration range, and display a r2 relaxivity of 171.1 mM-1 s-1. Likewise, the hybrid NGs can be taken up by cancer cells with the uptake of Fe significantly higher than single Fe3O4 NPs. These properties render the formed γ-PGA/PEI-Fe3O4 NGs with an ability to be used as an effective contrast agent for MR imaging of cancer cells in vitro and the xenografted tumor model in vivo via the passive enhanced permeability and retention effect after intravenous injection. The developed γ-PGA/PEI-Fe3O4 hybrid NGs may hold great promise to be used as a novel contrast agent for MR imaging or other theranostic applications.

A multifunctional polyethylenimine-based nanoplatform for targeted anticancer drug delivery to tumors in vivo

The development of cost-effective targeted drug delivery systems for cancer chemotherapy still remains a great challenging task. Here, we describe the synthesis and characterization of multifunctional polyethylenimine (PEI) as an effective vehicle to load an anticancer drug doxorubicin (DOX) for in vivo targeted cancer therapy. In this study, PEI was sequentially conjugated with polyethylene glycol (PEG) monomethyl ether, PEGylated folic acid (FA), and fluorescein isothiocyanate (FI). This was followed by the acetylation of the remaining PEI surface amines. The formed FA-targeted multifunctional PEI (FA-mPEI) was used as a vehicle to encapsulate DOX. We show that the formed FA-mPEI/DOX complexes with each PEI encapsulating 6.9 DOX molecules are water dispersible and can sustainably release DOX in a pH-dependent manner, showing a higher release rate under acidic pH conditions than under physiological pH conditions. Furthermore, the complexes display specific therapeutic efficacy to cancer cells in vitro and a subcutaneous tumor model in vivo, and have good organ compatibility. The designed multifunctional PEI may be used as an effective vehicle for targeted cancer chemotherapy.

Antifouling Manganese Oxide Nanoparticles: Synthesis, Characterization, and Applications for Enhanced MR Imaging of Tumors

Antifouling manganese oxide (Mn3O4) nanoparticles (NPs) were synthesized by solvothermal decomposition of tris(2,4-pentanedionato) manganese(III) in the presence of trisodium citrate, followed by surface modification with polyethylene glycol and l-cysteine. The as-prepared nanoparticles have a uniform size distribution, good colloidal stability and good cytocompatibility. The modification of l-cysteine rendered the particles with much longer blood circulation time (half-decay time of 28.4 h) than those without l-cysteine modification (18.5 h), and decreased macrophage cellular uptake. Thanks to desirable antifouling property and relatively high r1 relaxivity (3.66 mM-1 s-1), the l-cysteine-modified Mn3O4 NPs can be used for enhanced tumor magnetic resonance imaging applications.

Branched polyethyleneimine modified with hyaluronic acid via a PEG spacer for targeted anticancer drug delivery

It is generally required to develop a nanocarrier system that is able to improve the water solubility of an anticancer drug and enable targeted delivery of the drug to cancer cells via a receptor-mediated endocytosis pathway. In this work, polyethyleneimine (PEI) was sequentially modified with dual functional polyethylene glycol (NH2–PEG–COOH), hyaluronic acid (HA), and fluorescein isothiocyanate (FI). The prepared PEI–FI–(PEG–HA) conjugate was then used as a nanoplatform to encapsulate the anticancer drug doxorubicin (DOX). We show that the formed PEI–FI–(PEG–HA) conjugate is able to encapsulate approximately 19 DOX molecules within each multifunctional PEI, and the formed PEI–FI–(PEG–HA)/DOX complexes can release DOX in a pH-dependent manner with a higher DOX release rate under an acidic pH condition than under a physiological pH condition. In addition, the PEI–FI–(PEG–HA)/DOX complexes are able to specifically target cancer cells overexpressing CD44 receptors as confirmed via flow cytometric analysis and confocal microscopic observation, and thus deliver DOX to the target cancer cells to inhibit their growth. The developed HA-targeted PEI may hold great promise to be used as an efficient nanoplatform for the targeted delivery of different anticancer drugs.

Targeted tumor dual mode CT/MR imaging using multifunctional polyethylenimine-entrapped gold nanoparticles loaded with gadolinium

Abstract We report the construction and characterization of polyethylenimine (PEI)-entrapped gold nanoparticles (AuNPs) chelated with gadolinium (Gd) ions for targeted dual mode tumor CT/MR imaging in vivo. In this work, polyethylene glycol (PEG) monomethyl ether-modified PEI was sequentially modified with Gd chelator and folic acid (FA)-linked PEG (FA-PEG) was used as a template to synthesize AuNPs, followed by Gd(III) chelation and acetylation of the remaining PEI surface amines. The formed FA-targeted PEI-entrapped AuNPs loaded with Gd (FA-Gd-Au PENPs) were well characterized in terms of structure, composition, morphology, and size distribution. We show that the FA-Gd-Au PENPs with an Au core size of 3.0 nm are water dispersible, colloidally stable, and noncytotoxic in a given concentration range. Thanks to the coexistence of Au and Gd elements within one nanoparticulate system, the FA-Gd-Au PENPs display a better X-ray attenuation property than clinical iodinated contrast agent (e.g. Omnipaque) and reasonable r1 relaxivity (1.1 mM−1s−1). These properties allow the FA-targeted particles to be used as an efficient nanoprobe for dual mode CT/MR imaging of tumors with excellent FA-mediated targeting specificity. With the demonstrated organ biocompatibility, the designed FA-Gd-Au PENPs may hold a great promise to be used as a nanoprobe for CT/MR dual mode imaging of different FA receptor-overexpressing tumors.