Engineered therapeutic proteins for sustained-release drug delivery systems.

Proteins play a vital role in diverse biological processes in the human body, and protein therapeutics have been applied to treat different diseases such as cancers, genetic disorders, autoimmunity, and inflammation. Protein therapeutics have demonstrated their advantages, such as specific pharmaceutical effects, low toxicity, and strong solubility. However, several disadvantages arise in clinical applications, including short half-life, immunogenicity, and low permeation, leading to reduced drug effectiveness. The structure of protein therapeutics can be modified to increase molecular size, leading to prolonged stability and increased plasma half-life. Notably, the controlled-release delivery systems for the sustained release of protein drugs and preserving the stability of cargo proteins are envisioned as a potential approach to overcome these challenges. In this review, we summarize recent research progress related to structural modifications (PEGylation, glycosylation, poly amino acid modification, and molecular biology-based strategies) and promising long-term delivery systems, such as polymer-based systems (injectable gel/implants, microparticles, nanoparticles, micro/nanogels, functional polymers), lipid-based systems (liposomes, solid lipid nanoparticles, nanostructured lipid carriers), and inorganic nanoparticles exploited for protein therapeutics. STATEMENT OF SIGNIFICANCE: In this review, we highlight recent advances concerning modifying proteins directly to enhance their stability and functionality and discuss state-of-the-art methods for the delivery and controlled long-term release of active protein therapeutics to their target site. In terms of drug modifications, four widely used strategies, including PEGylation, poly amino acid modification, glycosylation, and genetic, are discussed. As for drug delivery systems, we emphasize recent progress relating to polymer-based systems, lipid-based systems developed, and inorganic nanoparticles for protein sustained-release delivery. This review points out the areas requiring focused research attention before the full potential of protein therapeutics for human health and disease can be realized.

Enhanced anticancer efficacy of TRAIL-conjugated and odanacatib-loaded PLGA nanoparticles in TRAIL resistant cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates unique characteristics in anticancer therapies as it selectively induces apoptosis in cancer cells. However, most cancer cells are TRAIL-resistant. Odanacatib (ODN), a cathepsin K inhibitor, is considered a novel sensitizer for cancer treatment. Combination therapy between TRAIL and sensitizers is considered a potent platform that improves TRAIL-based anticancer therapies beyond TRAIL monotherapy. Herein, we developed ODN loaded poly(lactic-co-glycolic) nanoparticles conjugated to GST-TRAIL (TRAIL-ODN-PLGA-NPs) to target and treat TRAIL-resistant cancer. TRAIL-ODN-PLGA-NPs demonstrated a significant increase in cellular uptake via death receptors (DR5 and DR4) on surface of cancer cells. TRAIL-ODN-PLGA-NPs exposure destroyed more TRAIL-resistant cells compared to a single treatment with free drugs. The released ODN decreased the Raptor protein, thereby increasing damage to mitochondria by elevating reactive oxygen species (ROS) generation. Additionally, Bim protein stabilization improved TRAIL-resistant cell sensitization to TRAIL-induced apoptosis. The in vivo biodistribution study revealed that TRAIL-ODN-PLGA-NPs demonstrated high location and retention in tumor sites via the intravenous route. Furthermore, TRAIL-ODN-PLGA-NPs significantly inhibited xenograft tumor models of TRAIL-resistant Caki-1 and TRAIL-sensitive MDA-MB-231 cells.The inhibition was associated with apoptosis activation, Raptor protein stabilizing Bim protein downregulation, Bax accumulation, and mitochondrial ROS generation elevation. Additionally, TRAIL-ODN-PLGA-NPs affected the tumor microenvironment by increasing tumor necrosis factor-α and reducing interleukin-6. In conclusion, we evealed that our formulation demonstrated synergistic effects against TRAIL compared with the combination of free drug in vitro and in vivo models. Therefore, TRAIL-ODN-PLGA-NPs may be a novel candidate for TRAIL-induced apoptosis in cancer treatment.