Abstract
Pancreatic cancer is an aggressive, devastating disease due to its invasiveness, rapid progression, and resistance to surgical, pharmacological, chemotherapy, and radiotherapy treatments. The disease develops from PanINs lesions that progress through different stages. KRAS mutations are frequently observed in these lesions, accompanied by inactivation of PTEN, hyperactivation of the PI3K/AKT pathway, and chronic inflammation with overexpression of COX-2. Nimesulide is a selective COX-2 inhibitor that has shown anticancer effects in neoplastic pancreatic cells. This drug works by increasing the levels of PTEN expression and inhibiting proliferation and apoptosis. However, there is a need to improve nimesulide through its encapsulation by solid lipid nanoparticles to overcome problems related to the hepatotoxicity and bioavailability of the drug.
Highlights
The pancreas is a retroperitoneal organ formed by a connective tissue capsule, with the parenchyma and lobes separated by thin dividing walls containing nerves, excretory ducts, and lymphatic and blood vessels [1,2,3]
The results showed that the survival of HT-29 and SW480 cells decreased in a dose-dependent manner in the presence of free nimesulide or nanoparticles loaded with the drug, demonstrating that nimesulide activity is not reduced in the presence of the nanoparticle carrier [111]
Solid lipid nanoparticles have potential alternative for the treatment of pancreatic cancer, as they have the ability to interfere in the permeability of nimesulide at extra and intracellular levels
Summary
The pancreas is a retroperitoneal organ formed by a connective tissue capsule, with the parenchyma and lobes separated by thin dividing walls containing nerves, excretory ducts, and lymphatic and blood vessels [1,2,3]. The inactivation of CDKN2A by homozygous deletions, loss of single allele combined with intragenic mutation in the second allele, or hypermethylation of the promoter, causes the functional deactivation of the p16 protein and, increased cell proliferation, contributing to tumor formation and growth [8, 14] The mutation in this gene (a member of the large SMAD4 family) occurs in 55% of cases of pancreatic adenocarcinoma PanIN-3 lesions [8, 10, 14]. Uram et al [63] carried out studies with the third-generation poly (amidoamine) dendrimer (PAMAM) biotinylated conjugates with covalently linked 18 (G3B18N) and 31 (G3B31N), both linked to nimesulide This nanoparticle was evaluated for its biological properties, including in vitro cytotoxicity (MTT method), proliferation and caspase 3/7 activities in relation to COX-2/PGE2 (prostaglandin) signaling in normal human fibroblasts (BJ) and carcinoma of squamous cells (SCC-15). Drug accumulation was greater in pancreatic, breast, colon and stomach tumors [111,112,113]
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