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13
2021
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04
Progress has been made in the research of nano-medicines for pancreatic cancer.
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Pancreatic cancer has a high mortality rate, and its fundamentally difficult-to-treat nature lies in the fact that pancreatic cancer cells are wrapped in a dense stromal barrier, which hinders the infiltration of therapeutic drugs, making it difficult to eliminate tumor cells. To promote the penetration of therapeutic drugs through the stromal barrier, a widely studied strategy is to remodel the pancreatic cancer stroma with adjuvants before injecting gemcitabine; however, the stepwise use of adjuvants and gemcitabine can lead to inherent spatial and temporal distribution unevenness, which may increase the risk of tumor metastasis. Additionally, the use of the chemotherapeutic drug gemcitabine carries the risk of inducing drug resistance in cells. Therefore, there is an urgent need to explore new strategies for treating pancreatic cancer.
Host defense peptides (HDPs) are part of the innate immune system of eukaryotes and help the host resist microbial attacks by disrupting the integrity of bacterial cell membranes. Membrane-disrupting macromolecules mimic two structural features common to most HDPs (cationicity and hydrophobicity) to achieve the function of disrupting bacterial cell membrane integrity. Unlike conventional chemotherapy regimens that target specific intracellular substances or metabolic pathways to inhibit cell proliferation, membrane-disrupting macromolecules eliminate target cells by disrupting cell membrane integrity, and thus can effectively eliminate drug-resistant cancer cells, with no observed development of cell resistance even after repeated treatments, indicating that membrane-disrupting macromolecules have the potential to overcome cancer drug resistance. However, membrane-disrupting macromolecule drugs lack the ability to distinguish between cancer cells and normal cells. Achieving selective killing of cancer cells by membrane-disrupting macromolecule drugs is a significant challenge in the field of tumor treatment.
To address this challenge, the research group led by Associate Professor Yang Lihua at the Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, proposed the development of acid-sensitive nanoparticles composed entirely of membrane-disrupting polymers that can maintain a long circulation time in the blood and dissociate under the unique mildly acidic pH stimulus of the tumor microenvironment as a new strategy for treating pancreatic cancer. By using an acid-sensitive membrane-disrupting macromolecule micelle (M-14K) as a model for such nanoparticles, the research group experimentally demonstrated that these nanoparticles can be activated by the unique acidic pH of the tumor microenvironment, thereby indiscriminately eliminating pancreatic cancer cells and tumor-associated fibroblasts, with this cytotoxicity achieved through the disruption of cell membrane integrity. Experiments using three-dimensional cell spheroids and tumor-bearing mouse models showed that these nanoparticles can effectively eliminate tumor-associated stromal cells that encapsulate pancreatic cancer cells, penetrate the stromal barrier protecting pancreatic cancer cells, and subsequently eliminate pancreatic cancer cells tightly wrapped by the stroma and stromal cells. Further experiments in tumor-bearing mouse models showed that after intravenous administration of these nanoparticles, there was a significant reduction in the expression of extracellular matrix in the pancreatic cancer microenvironment, making the originally dense pancreatic tumor tissue more permeable, remodeling the structure of pancreatic cancer, improving the delivery efficiency of nanoparticles in tumor tissue, and no tumor metastasis was observed.
This study first proposed the idea of developing acid-sensitive nanoparticles formed by the self-assembly of a single membrane-disrupting macromolecule as a therapeutic prodrug that can simultaneously achieve the dual goals of remodeling the pancreatic cancer stroma and eliminating cancer cells, which is expected to aid in the development of new drugs that can eliminate pancreatic cancer without inducing tumor metastasis. The related research results were published in ACS Applied Materials & Interfaces under the title "pH-Sensitive Nanoparticles Composed Solely of Membrane-Disruptive Macromolecules for Treating Pancreatic Cancer." The first author of the paper is Fan Feng, a doctoral student at the School of Chemistry and Materials Science, University of Science and Technology of China, and the corresponding author is Yang Lihua. The research work was supported by the National Natural Science Foundation of China and the special funds for basic scientific research business expenses of central universities.
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