Preparation, characterization, and assessment of the antiglioma effects of liposomal celastrol.

The role of celastrol in the treatment of cancer has been an area of growing interest. To circumvent the issues of low solubility, poor bioavailability, and systemic toxicity of celastrol, we prepared liposomal celastrol using the thin-film dispersion method. We characterized particle size, encapsulation efficiency, and pharmacological parameters of liposomal celastrol. The drug concentration in plasma and tissues was measured using LC-MS/MS. In addition, the sulforhodamine B assay was used to determine the 50% inhibiting concentration. We assessed the effects of the compound in SHG-44 glioma subcutaneous xenografts in BALB/c nude mice. To compare the toxic effects of liposomal and free celastrol, the weight as well as hematologic, heart, liver, and kidney parameters were measured weekly and the morphology of organ tissues was observed pathologically. We found that liposomal celastrol had high encapsulation efficiency (71.67%) and liposomal celastrol had a higher C(max) and area under the curve, longer t(1/2), and better biodistribution than free celastrol. A cytotoxicity assay indicated that free celastrol had lower 50% inhibiting concentration values than the liposomal celastrol; however, treatment of subcutaneous xenografts with 1 mg/kg of liposomal celastrol induced greater antitumor activity than free celastrol at an equimolar concentration. In addition, a 4 mg/kg dose of liposomal celastrol had fewer severe side effects than free celastrol at the same dose. In this study, we found that the use of liposomes as a carrier of celastrol increased the bioavailability and reduced the side effects of the compound. Our findings suggest that liposomal celastrol should be further investigated in the clinical setting.

Redox-triggered aggregation of ESIONPs with switchable T1 to T2 contrast effect for T2-weighted magnetic resonance imaging.

Magnetic resonance imaging (MRI) contrast agents (CAs) have drawn increasing attention in cancer diagnosis. However, since the signals they generate are always "on" and may bring interfering background signals to the region of interest, their selectivity and sensitivity need further improvement. Herein, extremely small iron oxide nanoparticles (ESIONPs) conjugated through a disulfide bond with polyethylene glycol (PEG) that is terminally modified with folic acid (FA), namely ESIONPs-s-s-PEG-FA, were designed and synthesized to target tumor tissues and selectively activate the T2 MRI contrast effect in the reducing environment of tumor cells. Due to the breakage of disulfide bonds by the high glutathione (GSH) concentration in tumor cells, the hydrophilic PEG chains detached from the surface of ESIONPs, which led to the aggregation of ESIONPs and the activation of the T2 contrast effect. In vitro results showed that ESIONPs-s-s-PEG-FA could effectively target tumors to assemble in the reductive environment and switch from a T1 contrast agent (CA) to a T2 one. Furthermore, MRI in tumor-bearing mice also indicated the obvious targeting capacity and the "turn on" of the T2 contrast effect. In addition, the results of the biosafety assay suggest that the tumor-targeted T1/T2 switchable CA is equipped with favorable biocompatibility for cancer diagnosis.

Extremely Small Iron Oxide Nanoparticle-Encapsulated Nanogels as a Glutathione-Responsive T1 Contrast Agent for Tumor-Targeted Magnetic Resonance Imaging.

Activatable magnetic resonance imaging (MRI) contrast agents that can be selectively stimulated at a tumor region are urgently demanded to realize the efficient and accurate diagnosis of cancers. Here, extremely small iron oxide nanoparticles (ESIONPs) modified with citric acid (ESIONPs-CA) are encapsulated in disulfide-cross-linked poly(carboxybetaine methacrylate) (poly(CBMA)) nanogels, and a cyclo[Arg-Gly-Asp-d-Tyr-Lys] (c(RGD)) ligand is further introduced to obtain ESIONP-packaged poly(CBMA) nanogels equipped with tumor-targeted c(RGD) (ICNs-RGD). On the basis of the transformation of the clustered ESIONPs into dispersed ones induced by the reducing glutathione (GSH), ICNs-RGD can complete the conversion from a T2 contrast agent to a T1 one, realizing the selective activation of the T1 contrasting effect. The GSH-dependent MRI signal conversion of ICNs-RGD is feasible in the tumor cell and tissue. Moreover, ICNs-RGD exhibits obvious targeting specificity and favorable biocompatibility. In the MRI experiments of tumor-bearing mice, benefiting from the stimuli-responsiveness toward GSH and targeting specificity, the T1 contrasting effect of tumor tissues can be selectively enhanced after the intravenous injection of ICNs-RGD. Therefore, tumor-targeted ICNs-RGD with a switchable MRI signal derived from the activation of GSH is a potential contrast agent for the efficient and precise tumor diagnosis in the clinic.