Histone methyltransferase G9a inhibitor-loaded redox-responsive nanoparticles for pancreatic ductal adenocarcinoma therapy

Abstract

Survival data have shown little therapeutic improvement in pancreatic ductal adenocarcinoma (PDAC) over the past several decades, mostly due to aggressive growth and therapy resistance. Glutathione (GSH) depletion in PDAC...

The Proteoglycan Glypican-1 as a Possible Candidate for Innovative Targeted Therapeutic Strategies for Pancreatic Ductal Adenocarcinoma

“…The synergistic effect of NPs loaded with chemotherapeutic agents and siRNAs was also investigated, showing a greater effect compared to single-agent treatment [ 117 , 118 , 119 ]. In vivo studies confirmed the positive in vitro results, with the prolongation of drug circulation time, inhibition of tumor growth with, in some cases, necrotic areas, and impaired tumor progression [ 117 , 118 , 119 , 120 , 121 , 122 ]. Interestingly, Confeld and colleagues used an iRGD peptide as a targeting agent to redirect gemcitabine and napabucasin (STAT3 inhibitor)-loaded NPs to PDAC cells and, in particular, to cancer stem cells overexpressing the neuropilin-1 receptor [ 121 ].…”

“…Several studies have investigated the use of NPs to target PDAC cells or, in some cases, to remodel the tumor microenvironment [ 116 , 117 , 118 , 119 , 120 ]. In in vitro experiments, they all showed a biocompatible profile when empty and an enhanced effect against PDAC cell lines when loaded with chemotherapeutic agents, mostly gemcitabine, or siRNA, compared to their free counterparts [ 116 , 117 , 118 , 119 , 120 , 121 , 122 ]. The synergistic effect of NPs loaded with chemotherapeutic agents and siRNAs was also investigated, showing a greater effect compared to single-agent treatment [ 117 , 118 , 119 ].…”

Poly(disulfide)s: From Synthesis to Drug Delivery

“…14 With its excellent biocompatibility and selective GSH-responsive degradation in tumor cells, the optimized polymer, termed Cys-8E, was further used to deliver the histone methyltransferase G9a inhibitor UNC0638 and the BRD4 inhibitor JQ1 for pancreatic ductal adenocarcinoma and gall bladder cancer therapy, respectively. 103,104 Because of the complexity and heterogeneity of the tumor microenvironment, single-stimulusresponsive platforms cannot result in the most sufficient drug release and satisfying therapy efficacy. 105,106 Alternatively, multiple-stimuli-responsive delivery platforms are another solution and have been extensively investigated.…”

“…In non-covalent interactions, small-molecule drugs are encapsulated via hydrophobic interactions, hydrogen-bonding interactions, and electrostatic complexation. , For example, our group developed a hydrophobic l -cysteine-based poly­(disulfide amide) (Cys-PDSA) family for chemotherapeutic docetaxel delivery via hydrophobic interactions with a high loading capacity (25 wt %) (Figure A) . With its excellent biocompatibility and selective GSH-responsive degradation in tumor cells, the optimized polymer, termed Cys-8E, was further used to deliver the histone methyltransferase G9a inhibitor UNC0638 and the BRD4 inhibitor JQ1 for pancreatic ductal adenocarcinoma and gall bladder cancer therapy, respectively. , Because of the complexity and heterogeneity of the tumor microenvironment, single-stimulus-responsive platforms cannot result in the most sufficient drug release and satisfying therapy efficacy. , Alternatively, multiple-stimuli-responsive delivery platforms are another solution and have been extensively investigated. Lin et al described pH- and reduction-sensitive PEG–poly­(disulfide carbamate amine) copolymers (PEG-SSBAP) with disulfide bonds and 1,4-bis­(3-aminopropyl)­piperazine groups in the backbone .…”

Pirfenidone-loaded exosomes derived from pancreatic ductal adenocarcinoma cells alleviate fibrosis of premetastatic niches to inhibit liver metastasis

“…More recently, nanoparticles have been used effectively as vehicles to carry drugs or genes to receptor cells or positions, making great advances in the treatment of a myriad of important diseases (most notably cancer). [14][15][16] These nanocarriers still have some problems, such as their poor biocompatibility, potential cytotoxicity, short cycling times, and difficulty in crossing biological barriers. To solve these problems, some natural functional biomaterials, such as egg white 17 and cancer cell-platelet fusion membrane, 18 have been synchronously used.…”