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MβCD@HA-Ad nanoparticles inhibit pancreatic cancer progression by targeting Caveolin-1/Piezo1/PLA2G4A-mediated lipid
Yan Xue1, Xi Chen2, Xingyu Jiang3
1Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong 226006, China; Research Center of Molecular Medicine, Nantong Health Vocational College, Nantong 226010, China.
Abstract:
Targeting lipid metabolism reprogramming presents a potential strategy to overcome drug resistance and enhance treatment outcomes in pancreatic cancer. Caveolin-1, a critical regulator of lipid metabolism, is highly expressed in pancreatic cancer, indicating its viability as a novel therapeutic target. To address the poor biocompatibility and inadequate tumor targeting associated with methyl-β-cyclodextrin (MβCD)-an indirect inhibitor of Caveolin-1 function through cholesterol chelation-novel MβCD@hyaluronic acid-adamantane (MβCD@HA-Ad) nanoparticles were developed to enhance therapeutic efficacy against pancreatic cancer. These nanoparticles achieve dual targeting via HA-mediated CD44 receptor binding and MβCD-driven Caveolin-1 metabolic inhibition, while exhibiting acid-responsive release properties that enhance their responsiveness to the pancreatic cancer microenvironment. In vitro studies suggest that MβCD@HA-Ad nanoparticles possess improved drug penetration capacity and enhanced antitumor effects. Inhibition of Caveolin-1 induces cell membrane stretching and increases Piezo1 sensitivity to mechanical stimuli, resulting in elevated intracellular Ca2+ influx, activation of PLA2G4A phosphorylation, and subsequent promotion of lipolysis. Concurrently, impaired endocytosis reduces fatty acid uptake, resulting in decreased lipid droplet accumulation. Non-targeted metabolomics analysis indicates that Caveolin-1 regulates glycerophospholipid and fatty acid metabolism in pancreatic cancer cells, influencing cellular growth, migration, and invasiveness. In a mouse model of pancreatic cancer, MβCD@HA-Ad nanoparticles exhibited excellent biosafety, efficient tumor-targeting capabilities, and sustained antitumor effects. By reducing lipid deposition in tumor tissues, these nanoparticles significantly delayed tumor progression and inhibited tumor cell proliferation. In summary, MβCD@HA-Ad nanoparticles exert precise antitumor effects by targeting Caveolin-1 and modulating the Piezo1/PLA2G4A signaling axis to disrupt lipid metabolism, thereby presenting a novel nanotherapeutic strategy for pancreatic cancer.
Insights
Novel nanoparticles target Caveolin-1 to disrupt lipid metabolism in pancreatic cancer, enhancing treatment efficacy and reducing tumor progression. This approach offers a promising nanotherapeutic strategy for pancreatic cancer.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Pancreatic cancer exhibits drug resistance often linked to lipid metabolism reprogramming.
- Caveolin-1 is a key regulator of lipid metabolism and is highly expressed in pancreatic cancer, making it a potential therapeutic target.
- Existing inhibitors like methyl-β-cyclodextrin (MβCD) have limitations in biocompatibility and tumor targeting.
Purpose of the Study:
- To develop novel MβCD@hyaluronic acid-adamantane (MβCD@HA-Ad) nanoparticles for enhanced pancreatic cancer therapy.
- To achieve dual targeting of pancreatic tumors via CD44 receptor binding and Caveolin-1 inhibition.
- To investigate the mechanism of action involving Caveolin-1, Piezo1/PLA2G4A signaling, and lipid metabolism disruption.
Main Methods:
- Synthesis and characterization of MβCD@HA-Ad nanoparticles with acid-responsive release.
- In vitro evaluation of nanoparticle drug penetration, antitumor effects, and cellular mechanisms.
- In vivo studies in a mouse model of pancreatic cancer to assess biosafety, tumor targeting, and therapeutic efficacy.
- Non-targeted metabolomics analysis to identify metabolic pathways affected by Caveolin-1 inhibition.
Main Results:
- MβCD@HA-Ad nanoparticles demonstrated improved drug penetration and enhanced antitumor effects in vitro.
- Caveolin-1 inhibition led to cell membrane stretching, increased Piezo1 sensitivity, Ca2+ influx, PLA2G4A phosphorylation, and lipolysis.
- Impaired endocytosis reduced fatty acid uptake and lipid droplet accumulation.
- Metabolomics revealed Caveolin-1's role in glycerophospholipid and fatty acid metabolism, impacting cancer cell growth and migration.
- In vivo studies showed excellent biosafety, efficient tumor targeting, and sustained antitumor effects, delaying tumor progression and inhibiting proliferation.
Conclusions:
- MβCD@HA-Ad nanoparticles offer a novel nanotherapeutic strategy for pancreatic cancer by precisely targeting Caveolin-1.
- The nanoparticles disrupt lipid metabolism through the Piezo1/PLA2G4A signaling axis.
- This approach reduces lipid deposition in tumors, delays progression, and inhibits proliferation, presenting a viable treatment option.
