development-efficacy-enzyme-responsive-squalene-chidamide

Development and Efficacy of Enzyme-Responsive Squalene-Chidamide Nanoparticles for Pancreatic Cancer

Here, we present a protocol to address the limited intratumoral penetration of small-molecule drugs caused by the dense extracellular matrix (ECM) of ...

Zhejiang Chinese Medical University

Inhibition of CDK7, a potent transcription regulator, may bring new hope for treating pancreatic ductal adenocarcinoma (PDAC), which is featured by large genetic heterogeneity and abundant KRAS mutations. This investigation aimed at exploring the discrepant efficacies of THZ1, a small-molecule covalent CDK7 inhibitor, on PDACs with different KRAS mutations and the underlying mechanisms.

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super-enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis-generating study.

Pancreatic cancer (PC) has a poor prognosis due to chemotherapy resistance and unfavorable drug transportation. Albumin conjugates are commonly used as drug carriers to overcome these obstacles. However, membrane-bound glycoprotein mucin 4 (MUC4) has emerged as a promising biomarker among the genetic mutations affecting albumin conjugates therapeutic window. Human serum albumin-conjugated arsenic trioxide (HSA-ATO) has shown potential in treating solid tumors but is limited in PC therapy due to unclear targets and mechanisms. This study investigated the transport mechanisms and therapeutic efficacy of HSA-ATO in PC cells with different MUC4 mutation statuses. Results revealed improved penetration of ATO into PC tumors through conjugated with HSA. However, MUC4 mutation significantly affected treatment sensitivity and HSA-ATO uptake both in vitro and in vivo. Mutant MUC4 cells exhibited over ten times higher IC50 for HSA-ATO and approximately half the uptake compared to wildtype cells. Further research demonstrated that ALPL activation by HSA-ATO enhanced transcytosis in wildtype MUC4 PC cells but not in mutant MUC4 cells, leading to impaired uptake and weaker antitumor effects. Reprogramming the transport process holds potential for enhancing albumin conjugate efficacy in PC patients with different MUC4 mutation statuses, paving the way for stratified treatment using these delivery vehicles.

Albumin conjugation promotes arsenic trioxide transport through alkaline phosphatase-associated transcytosis in MUC4 wildtype pancreatic cancer cells.

We explored the potential of overcoming the dense interstitial barrier in pancreatic cancer treatment by enhancing the uptake of hydrophilic chemotherapeutic drugs. In this study, we synthesized the squalenoyl-chidamide prodrug (SQ-CHI), linking lipophilic squalene (SQ) with the hydrophilic antitumor drug chidamide (CHI) through a trypsin-responsive bond. Self-assembled nanoparticles with sigma receptor-bound aminoethyl anisamide (AEAA) modification, forming AEAA-PEG-SQ-CHI NPs (A-C NPs, size 116.6 ± 0.4 nm), and reference nanoparticles without AEAA modification, forming mPEG-SQ-CHI NPs (M-C NPs, size 88.3 ± 0.3 nm), were prepared. A-C NPs exhibited significantly higher in vitro CHI release (74.7 %) in 0.5 % trypsin medium compared to release (20.2 %) in medium without trypsin. In vitro cell uptake assays revealed 3.6 and 2.3times higher permeation of A-C NPs into tumorspheres of PSN-1/HPSC or CFPAC-1/HPSC, respectively, compared to M-C NPs. Following intraperitoneal administration to subcutaneous tumor-bearing nude mice, the A-C NPs group demonstrated significant anti-pancreatic cancer efficacy, inducing cancer cell apoptosis and inhibiting proliferation in vivo. Mechanistic studies revealed that AEAA surface modification on nanoparticles promoted intracellular uptake through caveolin-mediated endocytosis. This nanoparticle system presents a novel therapeutic approach for pancreatic cancer treatment, offering a delivery strategy to enhance efficacy through improved tumor permeation, trypsin-responsive drug release, and specific cell surface receptor-mediated intracellular uptake.

Integration of caveolin-mediated cytosolic delivery and enzyme-responsive releasing of squalenoyl nanoparticles enhance the anti-cancer efficacy of chidamide in pancreatic cancer.

Erratum for the research article "The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super-enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis-generating study" by Huang et al.

Lipid nanoparticles (LNPs) are the primary non-viral vectors for siRNA delivery. However, synthetic lipids face issues, such as low lysosomal escape efficiency and high cost.

Delivery of small interfering RNA through lyophilized natural lipid nanoparticles: effects of natural lipid selection.

Chemotherapy remains the cornerstone for the treatment of pancreatic ductal adenocarcinoma (PDAC). However, their efficacy is often undermined by the emergence of drug resistance. Recent evidence has highlighted the critical role of ferroptosis inhibition in mediating this resistance. This study investigates the molecular mechanisms underlying PDAC resistance to arsenic trioxide (ATO), with a particular focus on the role of glutathione S-transferase theta 2 (GSTT2). Both in vivo and in vitro experiments have demonstrated that PDAC cells develop resistance to ATO through the suppression of drug-induced ferroptosis. The inhibition of nuclear factor erythroid 2-related factor 2 (NRF2) failed to restore ferroptosis. Transcriptomic analysis revealed significant upregulation of GSTT2 in ATO-resistant cells, implicating it as a key mediator of resistance. GSTT2 expression was markedly higher in ATO-resistant cells than in ATO-sensitive cells. Silencing GSTT2 enhances the sensitivity of resistant cells to ATO. Mechanistically, GSTT2, a downstream target of NRF2, regulates the expression of glutathione peroxidase 4 (GPX4) and ferritin light chain (FTL). Silencing GSTT2 can enhance drug sensitivity by activating ferroptosis in drug-resistant cells. Our study identifies the NRF2-GSTT2-GPX4 ferroptosis regulatory axis, demonstrating that GSTT2 is a negative regulator of ATO-induced ferroptosis. Targeting this axis may represent a promising therapeutic strategy for overcoming chemotherapy in PDAC.

Article	Year
The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super-enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypot... Clinical and translational medicine\| PubMed ID: 38037549	2023
Albumin conjugation promotes arsenic trioxide transport through alkaline phosphatase-associated transcytosis in MUC4 wildtype pancreatic cancer cells. International journal of biological macromolecules\| PubMed ID: 38092098	2024
Integration of caveolin-mediated cytosolic delivery and enzyme-responsive releasing of squalenoyl nanoparticles enhance the anti-cancer efficacy of chidamide in pancreatic cancer. International journal of pharmaceutics\| PubMed ID: 38561133	2024
Erratum for the research article "The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super-enhancer activity and the PI3K/AKT/mTOR signalling in pancrea... Clinical and translational medicine\| PubMed ID: 39731275	2025
Delivery of small interfering RNA through lyophilized natural lipid nanoparticles: effects of natural lipid selection. Pharmaceutical biology\| PubMed ID: 40314193	2025
Glutathione S-transferase Theta 2 causes drug resistance by inhibiting arsenic trioxide-induced ferroptosis in pancreatic ductal adenocarcinoma. Free radical biology & medicine\| PubMed ID: 40609804	2025

Kaidi Chen

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