pH-Sensitive Nanoparticles Composed Solely of Membrane-Disruptive Macromolecules for Treating Pancreatic Cancer
Feng Fan1, Lijun Jin1, Lihua Yang1
1Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Soft Matter Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui 230026, China.
Abstract:
Pancreatic tumor is extremely lethal because its cancerous structures are sheltered by dense stromal barriers that hinder the infiltration of therapeutics. To facilitate the infiltration of therapeutics through the stromal barrier, remodeling the stroma with an adjuvant prior to or together with gemcitabine-the current chemotherapeutic standard for pancreatic cancer-is a widely studied strategy; nevertheless, the intrinsic nonuniformity in distribution (spatial and/or temporal) of the adjuvant and gemcitabine has raised the increased risk of tumor metastasis as a major concern. In this work, we propose long-circulating, pH-sensitive nanoparticles composed solely of cellular membrane-disruptive molecules as a new approach for treating pancreatic cancer. Using a micelle of a polymeric mimetic of host defense peptides as the model for such nanoparticles, we showed that this nanoparticle exhibited acid-activated cytotoxicity indiscriminately to both cancerous and fibroblast cells, and the underlying activity mode was acid-activatable disruption of cellular membrane integrity. As a result, our acid-activatable nanoparticle effectively permeabilized the stromal barrier and eradicated the otherwise sheltered pancreatic cancer cells, as demonstrated with a three-dimensional spheroid in which a shell of fibroblast NIH-3T3 cells was cultured over a core of pancreatic BxPC-3 cells. When administered intravenously into mouse models bearing xenograft pancreatic BxPC-3 tumors, our acid-activatable nanoparticle efficiently inhibited tumor growth without causing noticeable off-target adverse effects or promoting tumor metastasis. Notably, this nanoparticle permeabilized the otherwise dense pancreatic tumor tissue while significantly suppressing the expression of extracellular matrix components and activated cancer-associated fibroblasts. Although the feasibility of our approach was demonstrated with a micelle of a polymeric molecule, we trust that future research efforts in this pathway may eventually offer translational formulations for improving the therapeutic efficacy of pancreatic cancer.
Insights
New pH-sensitive nanoparticles disrupt pancreatic cancer
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Pancreatic cancer is lethal due to dense stromal barriers hindering drug delivery.
- Current therapies face challenges with non-uniform drug distribution, increasing metastasis risk.
- There is a need for novel therapeutic strategies to overcome stromal barriers in pancreatic cancer.
Purpose of the Study:
- To develop and evaluate long-circulating, pH-sensitive nanoparticles for pancreatic cancer treatment.
- To investigate the efficacy of these nanoparticles in permeabilizing the tumor stroma and eradicating cancer cells.
- To assess the safety and anti-metastatic potential of the novel nanoparticle formulation.
Main Methods:
- Designed pH-sensitive nanoparticles using a micelle of a polymeric mimetic of host defense peptides.
- Evaluated acid-activated cytotoxicity against cancer and fibroblast cells, focusing on membrane disruption.
- Tested nanoparticle efficacy in a 3D spheroid model and in mouse models with xenograft pancreatic tumors.
Main Results:
- The nanoparticles demonstrated acid-activated cytotoxicity, disrupting cellular membrane integrity.
- Effective permeabilization of the stromal barrier and eradication of pancreatic cancer cells were observed.
- Intravenous administration in mouse models inhibited tumor growth without significant adverse effects or promoting metastasis.
Conclusions:
- Acid-activatable nanoparticles show promise in overcoming pancreatic cancer's stromal barrier.
- This approach effectively inhibits tumor growth and suppresses extracellular matrix components.
- Future research may lead to translational formulations for improved pancreatic cancer therapy.
