Pancreatic cancer is highly lethal. The fundamental reason for its refractory is that pancreatic cancer cells are wrapped in a dense matrix barrier, which hinders the infiltration of therapeutic drugs and makes it difficult to remove tumor cells. In order to promote the penetration of therapeutic drugs through the matrix barrier, adjuvant remodeling of pancreatic cancer matrix before gemcitabine treatment is a widely studied strategy; however, the stepwise use of adjuvants and gemcitabine will cause them to be distributed in space and time. There are inherent inhomogeneities in the above, which may increase the risk of tumor metastasis. In addition, the use of the chemotherapy drug gemcitabine has the risk of causing cell resistance. Therefore, there is an urgent need to explore new strategies for the treatment of pancreatic cancer.
Host defense peptides (HDP) are part of the innate immunity of eukaryotes, which can help the host resist the attack of microorganisms by destroying the integrity of the bacterial cell membrane. Membrane-breaking macromolecules mimic the two structural characteristics (cationicity and hydrophobicity) shared by most HDPs to mimic the function of HDP destroying the integrity of bacterial cell membranes. Different from conventional chemotherapy regimens that target specific intracellular substances or metabolic pathways to inhibit cell proliferation, rupture macromolecules destroy the integrity of cell membranes to eliminate target cells, and therefore can effectively eliminate drug-resistant cancer cells, and have been repeatedly treated No cell drug resistance was observed, indicating that ruptured membrane macromolecules have the potential to overcome the problem of cancer drug resistance. However, rupture macromolecular drugs lack the ability to distinguish cancer cells from normal cells. How to make rupture macromolecular drugs to selectively kill cancer cells is a major challenge in the field of tumor therapy.
In response to this challenge, Yang Lihua’s research group, Associate Professor Yang Lihua, University of Science and Technology of China, Hefei National Research Center for Microscale Material Science and School of Chemistry and Materials Science proposed to develop 100% of the membrane-breaking polymer, which can maintain a long circulation time in the blood, and can Acid-sensitive nanoparticles that dissociate under the unique slightly acidic pH stimulation of the tumor microenvironment are used as a new treatment for pancreatic cancer. By using an acid-sensitive ruptured membrane macromolecular micelle (M-14K) as a model of such nanoparticles, the research team proved through experiments that the nanoparticles can be activated by the unique acidic pH of the tumor microenvironment, thereby indiscriminately cleared Pancreatic cancer cancer cells and tumor-associated fibroblasts, and this cytotoxicity is achieved by disrupting the integrity of cell membranes. Three-dimensional cell spheres and tumor-bearing mouse model experiments have shown that this nanoparticle can effectively remove tumor-related stromal cells that wrap pancreatic cancer cells, penetrate and protect the stromal barrier of pancreatic cancer cells, and then remove tightly wrapped stromal cells and stromal cells. Pancreatic cancer cells. Tumor-bearing mouse model experiments further showed that after intravenous administration of the nanoparticles, the expression of extracellular matrix in the microenvironment of pancreatic cancer was significantly reduced, the originally dense pancreatic tumor tissue became permeable, and pancreatic cancer was reshaped Structure, improved the delivery efficiency of nanoparticles in tumor tissues, and did not cause tumor metastasis.
This study puts forward for the first time the idea of developing acid-sensitive nanoparticles formed by the self-assembly of a single rupture macromolecule as a therapeutic prodrug that can simultaneously achieve the dual goals of pancreatic cancer matrix remodeling and cancer cell removal. New drugs that eliminate pancreatic cancer without inducing tumor metastasis provide help. The related research results were published on ACS applied Materials & Interfaces with the title of pH-Sensitive Nanoparticles Composed Solely of Membrane-Disruptive Macromolecules for Treating Pancreatic Cancer. The first author of the paper is Feng Fan, a doctoral student from the School of Chemistry and Materials Science of the Chinese University of Science and Technology, and the corresponding author of the paper is Yang Lihua. The research work was funded by the National Natural Science Foundation of China and the special funds for basic scientific research operations of central universities.