Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) in the liver due to chronic injuries and inflammation. These injuries activate and transform quiescent hepatic stellate cells (HSCs) into proliferative myofibroblast-like cells, which are the key contributors to the secretin of ECM in the fibrotic liver. The insulin-like growth factor 2 receptor (IGF2R) is a multifunctional receptor that is overexpressed on activated HSCs and is a specific molecular marker of activated HSCs in the fibrotic liver. We recently discovered an IGF2R-specific peptide that significantly increases the binding affinity and uptake of a protein-based siRNA nanocomplex to activated HSCs. However, there is a potential concern about the immunogenicity of protein-based siRNA delivery systems. In this study, we used the IGF2R-specific peptide to modify a small peptide-based siRNA nanocomplex for HSC-specific drug delivery. We incorporated a short spacer and glutamate residues into the IGF2R peptides. The siRNA nanocomplex modified with the IGF2R-3GK6E peptide demonstrated higher HSC specificity compared to an unmodified nanocomplex. This peptide-based nanocomplex provides a promising platform to effectively deliver Pcbp2 siRNA to activated HSCs for the treatment of liver fibrosis.
Lymphocyte activation gene-3 (LAG-3) has emerged as a promising target for cancer immunotherapy. It is expressed on activated CD4+ and CD8+ T cells, and on the surface of B cells, natural killer cells, and dendritic cells (DC). It has also been found to be highly expressed on activated T cells upon treatment with monoclonal antibodies targeting the PD-1/PD-L1 pathway, which may explain the resistance mechanism of monotherapy. Several anti-LAG-3 antibodies are being examined in clinical trials to treat different types of cancers. Despite their specificity and affinity, antibody-based checkpoint inhibitors are hampered by poor tumor permeability and high production costs. In this study, we aimed to discover a small peptide-based anti-LAG-3 inhibitor using a novel biopanning technique developed in our laboratory. We discovered several anti-LAG-3 inhibitor peptides, and the CMA16 peptide showed the highest stability and blocking efficacy. The peptides were synthesized by the solid-phase peptide synthesis using PurePepTM Chorus synthesizer (Gyros Protein Technologies, Tucson, AZ). The molecular weights and purity were confirmed by mass spectrometry and HPLC, respectively. To evaluate the function of the CMA16 peptide, a series of in vitro functional assays including binding ELISA, serum stability and cell viability assays were performed. In vivo anti-tumor activity of the peptides was examined in five-week-old C57BL/6 mice bearing MC38 cells. CMA16 significantly inhibited the growth of MC38 tumors. Quantification of CD8+ tumor-infiltrating cells revealed a significant increase in this type of immune cells in the group of mice treated with CMA16. These findings support the further development of the CMA16 peptide as potential anti-LAG-3 inhibitor for cancer immunotherapy. Citation Format: Mohammed Alahmari, Umar-Farouk Mamani, Yuhan Guo, Chien-Yu Lin, Mohammed Nurudeen Ibrahim, Yongren Li, Kun Cheng. A small molecular-weight anti-lag-3 peptide inhibits colon tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB194.
Lung cancer is one of the leading causes of cancer death and the second most cancer in the world. Compared to systematic administration, local delivery of therapeutic agents to the lung increases their accumulation in lung cancer cells and reduces the toxicity in other organs. We previously discovered an anti-PD-L1 peptide that can be potentially uses for lung cancer therapy. This project aims to develop an aerosolized formulation of the anti-PD-L1 peptide for the treatment of lung cancer. We hypothesize that the aerosolized peptide has higher accumulation in the lung compared to systematic formulations, leading to high therapeutic index with less side effects. We developed a spray freeze-drying procedure and optimized the formulation to prepare the peptide dry powders. The median mass aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the aerosols were determined by an 8-stage Andersen Cascade Impactor. The morphology of the aerosols was studied using a scanning electron microscope (SEM). The stability of the aerosols in lung fluid was evaluated. Blocking assay suggested that the aerosolized formulation maintains the blocking efficiency of the peptide. Intratracheal administration of the peptide dry powder shows a high accumulation of the peptide in the lung. Citation Format: Yongren Li, Zhen Zhao, John Fetse, Reaid Hasan, Umar-Farouk Mamani, Yuhan Guo, Kun Cheng. Development of an aerosol-based immunotherapy for lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5183.
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