A Self-Amplifying ROS-Responsive Nanoplatform for Simultaneous Cuproptosis and Cancer Immunotherapy.

Cuproptosis is an emerging cell death pathway that depends on the intracellular Cu ions. Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and trigger cuproptosis. However, ES can be rapidly removed and metabolized during intravenous administration, leading to a short half-life and limited tumor accumulation, which hampers its clinical application. Here, the study develops a reactive oxygen species (ROS)-responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG) to encapsulate ES-Cu compound (EC), forming ECPCP. ECPCP significantly prolongs the systemic circulation of EC and enhances its tumor accumulation. After cellular internalization, the PCP coating stimulatingly dissociates exposing to the high-level ROS, and releases ES and Cu, thereby triggering cell death via cuproptosis. Meanwhile, Cu2+-stimulated Fenton-like reaction together with CA-stimulated ROS production simultaneously breaks the redox homeostasis, which compensates for the insufficient oxidative stress treated with ES alone, in turn inducing immunogenic cell death of tumor cells, achieving simultaneous cuproptosis and immunotherapy. Furthermore, the excessive ROS accelerates the stimuli-dissociation of ECPCP, forming a positive feedback therapy loop against tumor self-alleviation. Therefore, ECPCP as a nanoplatform for cuproptosis and immunotherapy improves the dual antitumor mechanism of ES and provides a potential optimization for ES clinical application.

Glutamate affects self-assembly, protein corona, and anti-4 T1 tumor effects of melittin/vitamin E-succinic acid-(glutamate)n nanoparticles.

Melittin (M) has attracted increasing attention for its significant antitumor effects and various immunomodulatory effects. However, various obstacles such as the short plasma half-life and adverse reactions restrict its application. This study aimed to systematically investigate the self-assembly mechanism, components of the protein corona, targeting behavior, and anti-4 T1 tumor effect of vitamin E-succinic acid-(glutamate)n /melittin nanoparticles with varying amounts of glutamic acid. Here, we present a new vitamin E-succinic acid-(glutamate)5 (E5), vitamin E-succinic acid-(glutamate)10 (E10) or vitamin E-succinic acid-(glutamate)15 (E15), and their co-assembly system with positively charged melittin in water. The molecular dynamics simulations demonstrated that the electrostatic energy and van der Waals force in the system decreased significantly with the increase in the amount of glutamic acid. The melittin and E15 system exhibited the optimal stability for nanoparticle self-assembly. When nanoparticles derived from different self-assembly systems were co-incubated with plasma from patients with breast cancer, the protein corona showed heterogeneity. In vivo imaging demonstrated that an increase in the number of glutamic acid residues enhanced circulation duration and tumor-targeting effects. Both in vitro and in vivo antitumor evaluation indicated a significant increase in the antitumor effect with the addition of glutamic acid. According to our research findings, the number of glutamic acid residues plays a crucial role in the targeted delivery of melittin for immunomodulation and inhibition of 4 T1 breast cancer. Due to the self-assembly capabilities of vitamin E-succinic acid-(glutamate)n in water, these nanoparticles carry significant potential for delivering cationic peptides such as melittin.

Redox-responsive prodrug for improving oral bioavailability of paclitaxel through bile acid transporter-mediated pathway.

Most anticancer drugs are not orally bioavailable due to their undesirable physicochemical properties and inherent physiological barriers. In this study, a polymeric prodrug strategy was presented to enhance the oral bioavailability of BCS class IV drugs using paclitaxel (PTX) as the model drug. PTX was covalently conjugated with cholic acid-functionalized PEG by a redox-sensitive disulfide bond. Cholic acid-functionalized PEGylated PTX (CPP) achieved remarkably improved PTX solubility (>30,000-fold), as well as favorable stability under the physiological environment and controlled drug release in the tumor. Meanwhile, CPP could self-assemble into nanoparticles with an average size of 56.18 ± 2.06 nm and drug loading up to 17.6% (w/w). Then, permeability study on Caco-2 cell monolayers demonstrated that CPP obtained an approximately 4-fold increase by apical sodium-dependent bile acid transporter (ASBT) mediated transport, compared with Taxol®. Pharmacokinetic studies carried out in rats confirmed that the oral bioavailability of CPP was 10-fold higher than that of Taxol®. Finally, significant improvement in the antitumor efficacy of CPP against breast cancer was confirmed on MDA-MB-231 cells. In summary, this prodrug-based cascade strategy offers new ways for chemotherapeutic drugs whose oral delivery is limited by solubility and permeability, also endows drugs with the capacity of tumor-specific release.

Preparation and characterization of parthenolide nanocrystals for enhancing therapeutic effects of sorafenib against advanced hepatocellular carcinoma.

A novel nanocrystals delivery system of parthenolide (PTL) was designed to combined application with sorafenib (Sora) for advanced hepatocellular carcinoma (HCC) therapy, attempting to not only improve the poor aqueous solubility of PTL, but also enhance the synergistic therapeutic effects with Sora. The PTL nanocrystals (PTL-NCs) were prepared by precipitation-high-pressure homogenization method. The formed PTL-NCs with rod morphology possessed size of 126.9 ± 2.31 nm, zeta potential of -11.18 ± 0.59 mV and drug loading of 31.11 ± 1.99%. Meanwhile, PTL in PTL-NCs exhibited excellent storage stability and sustained release behavior. The combination therapy of Sora and PTL-NCs (Sora/PTL-NCs) in vitro for HepG2 cells presented superior therapeutic effects over that of individual PTL and Sora on intracellular uptake, cell proliferation inhibition and migration inhibition. Meanwhile the strongest anti-tumor effect with 81.86% inhibition rate and minimized systemic toxicity of Sora/PTL-NCs in vivo were obtained on tumor-bearing mice compared with that of PTL (48.84%) and Sora (58.83%). Thus, these findings suggested that PTL-NCs as an effective delivery system for the synergistically used with Sora to gain an optimal response against HCC, for referenced in the industrialization of nanocrystals products for intravenous administration.

Cholesterol-tuned liposomal membrane rigidity directs tumor penetration and anti-tumor effect.

Recently, liposomes have been widely used in cancer therapeutics, but their anti-tumor effects are suboptimal due to limited tumor penetration. To solve this problem, researchers have made significant efforts to optimize liposomal diameters and potentials, but little attention has been paid to liposomal membrane rigidity. Herein, we sought to demonstrate the effects of cholesterol-tuned liposomal membrane rigidity on tumor penetration and anti-tumor effects. In this study, liposomes composed of hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) and different concentrations of cholesterol were prepared. It was revealed that liposomal membrane rigidity decreased with the addition of cholesterol. Moderate cholesterol content conferred excellent diffusivity to liposomes in simulated diffusion medium, while excessive cholesterol limited the diffusion process. We concluded that the differences of the diffusion rates likely stemmed from the alterations in liposomal membrane rigidity, with moderate rigidity leading to improved diffusion. Next, the in vitro tumor penetration and the in vivo anti-tumor effects were analyzed. The results showed that liposomes with moderate rigidity gained excellent tumor penetration and enhanced anti-tumor effects. These findings illustrate a feasible and effective way to improve tumor penetration and therapeutic efficacy of liposomes by changing the cholesterol content, and highlight the importance of liposomal membrane rigidity.