Targeted nanoparticles for the delivery of novel bioactive molecules to pancreatic cancer cells

Pancreatic cancer (PaCa) is a multifaceted disorder with an extremely poor prognosis. There is an urgent need to identify new and safe drugs as well as to develop novel tumor-targeted controlled release systems for effective treatment of late stage and resistant PaCa. Active targeting via the inclusion of specific ligands on the nanoparticles (NPs) is envisioned to provide a powerful therapeutic strategy. Herein, we present a study on the design and the development of novel DFCencapsulated biocompatible polymeric NPs, functionalized with peptides to selectively bind to Plec-1 (PTP), or densely decorated by low molecular weight organic molecules as alternative targeting ligands (2-ABA), and evaluated a) the impact on ligand binding and b) the in vitro antiproliferative efficacy against a panel of PaCa cells

Applicazioni e rischi relativi all’uso dell’air-polishing nella pratica clinica: revisione della letteratura

Obiettivi: Lo scopo di questo lavoro consisteva in una revisione della letteratura scientifica internazionale sull’uso di dispositivi a getto d’aria/acqua (air-polishing) nei trattamenti di profilassi e lucidatura dentale, nonché nei trattamenti non chirurgici parodontali (perio-polishing). La relazione tra enfisemi facciali e l’uso di tali dispositivi di air-polishing è stata anche uno degli obbiettivi principali del presente studio. Materiali e metodi: Numerosi articoli scientifici pubblicati nel periodo compreso tra il 1945 e il 2012 sono stati selezionati dai principali database medici come Medline e Science Direct. Risultati: L'utilizzo di dispositivi a getto d'aria/acqua per i trattamenti di air-polishng e perio-polishing parodontali possono essere considerati un approccio clinico sicuro, vista la scarsa evidenza scientifica sui rischi per la salute degli operatori dentali e pazienti. I casi di enfisemi facciali riscontrati in seguito all’utilizzo di tali dispositivi a getto d’aria/acqua sembrano essere principalmente correlati all'uso inappropriato di tali dispositivi durante l’estrazione di terzi molari o in caso di particolari trattamenti endodontici. Conclusioni: Questo articolo ha messo in evidenza che i trattamenti con air-polishing e perio-polishing parodontali possono essere considerati approcci terapeutici innocui e confortevoli sia per i pazienti che per gli operatori dentali se eseguiti rispettando protocolli basati sull'evidenza scientifica. Objectives: The purpose of this article was to provide a comprehensive review of the literature regarding the safety and clinical efficiency of dental air polishing approaches. The connection between air-polishing treatments and the risk for facial emphysemas was also investigated. Materials and methods: For this literature review, several research and clinical scientific articles published in a period comprised between 1945 and 2012 were selected from international medical scientific platform such as Medline and Science direct. Results: The use of air polishing devices in dental and non-surgical periodontal treatments (perio-polishing) results a safe approach as there was not enough clinical and/or scientific evidences on the risks for the health of both clinicians and patients. Cervico-facial emphysema seems to be mainly correlated to use of air-abrasion devices during third molars extraction or endodontic treatments rather than prophylaxis and perio-polishing treatments. Conclusions: This article has highlighted that the treatments of dental air-polishing and perio-polishing may be considered safe and comfortable therapeutic approaches when performed through evidence-based applicative protocols

Polymeric nanoparticles encapsulating white tea extract for nutraceutical application

With the aim to obtain controlled release and to preserve the antioxidant activity of the polyphenols, nanoencapsulation of white tea extract into polymeric nanoparticles (NPs) based on poly(ε-caprolactone) (PCL) and alginate was successfully performed. NPs were prepared by nanoprecipitation method and were characterized in terms of morphology and chemical properties. Total polyphenols and catechins contents before and after encapsulation were determined. Moreover, in vitro release profiles of encapsulated polyphenols from NPs were investigated in simulated gastrointestinal fluids. The antioxidant activity and stability of encapsulated extract were further evaluated. Interestingly, NPs released 20% of the polyphenols in simulated gastric medium, and 80% after 5 h at pH 7.4, showing a good capacity to control the polyphenols delivery. Furthermore, DPPH• assay confirmed that white tea extract retained its antioxidant activity and NPs protected tea polyphenols from degradation, thus opening new perspectives for the exploitation of white tea extract-loaded NPs for nutraceutical applications

Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma

Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded <b>QD325</b> as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells. Furthermore, the QD compounds induced Nrf2-mediated oxidative stress and unfolded protein responses as demonstrated by dose-dependent increases in RNA synthesis of representative genes such as <i>NQO1, HMOX1, DDIT3</i>, and <i>HSPA5</i>. At higher concentrations, the QDs blocked mitochondrial function by inhibiting mtDNA transcription and downregulating the mtDNA-encoded OXPHOS enzymes. Importantly, treatments with <b>QD325</b> were well tolerated <i>in vivo</i> and significantly delayed tumor growth in mice. Our study supports the development of <b>QD325</b> as a new therapeutic in the treatment of PDAC

Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma

Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded <b>QD325</b> as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells. Furthermore, the QD compounds induced Nrf2-mediated oxidative stress and unfolded protein responses as demonstrated by dose-dependent increases in RNA synthesis of representative genes such as <i>NQO1, HMOX1, DDIT3</i>, and <i>HSPA5</i>. At higher concentrations, the QDs blocked mitochondrial function by inhibiting mtDNA transcription and downregulating the mtDNA-encoded OXPHOS enzymes. Importantly, treatments with <b>QD325</b> were well tolerated <i>in vivo</i> and significantly delayed tumor growth in mice. Our study supports the development of <b>QD325</b> as a new therapeutic in the treatment of PDAC

Targeted Nanoparticles for the Delivery of Novel Bioactive Molecules to Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis and limited therapeutic options. Therefore, there is an urgent need to identify new, safe, and targeted therapeutics for effective treatment of late as well as early stage disease. Plectin-1 (Plec-1) was recently identified as specific biomarker for detecting PDAC at an early stage. We envisioned that multivalent attachment of nanocarriers incorporating certain drugs to Plec-1-derived peptide would increase specific binding affinity and impart high specificity for PDAC cells. Previously, we discovered a novel class of compounds (e.g., quinazolinediones, QDs) that exert their cytotoxic effects by modulating ROS-mediated cell signaling. Herein, we prepared novel QD242-encapsulated polymeric nanoparticles (NPs) functionalized with a peptide to selectively bind to Plec-1. Similarly, we prepared QD-based NPs densely decorated with an isatoic anhydride derivative. Furthermore, we evaluated their impact on ligand binding and antiproliferative activity against PDAC cells. The targeted NPs were more potent than the nontargeted constructs in PDAC cells warranting further development

An integrated biological approach to guide the development of metal-chelating inhibitors of influenza virus PA endonuclease

The influenza virus PA endonuclease, which cleaves capped cellular pre-mRNAs to prime viral mRNA synthesis, is a promising target for novel anti-influenza virus therapeutics. The catalytic center of this enzyme resides in the N-terminal part of PA (PA-Nter) and contains two (or possibly one or three) Mg(2+) or Mn(2+) ions which are critical for its catalytic function. There is large interest in PA inhibitors that are optimally designed to occupy the active site and chelate the metal ions. We here focused on a series of β-diketo acid (DKA) and DKA-bioisosteric compounds containing different scaffolds, and determined their structure-activity relationship in an enzymatic assay with PA-Nter, to build a 3D pharmacophore model. Besides, we developed a molecular beacon (MB)-based PA-Nter assay which enables to compare the inhibition versus Mn(2+) or Mg(2+), the latter probably being the biologically relevant cofactor. This real-time MB assay allows to measure the enzyme kinetics of PA-Nter or perform high-throughput screening. Several DKA derivatives were found to cause strong inhibition of PA-Nter with IC50 values comparable to that of the prototype L-742,001 (i.e. below 2 μM). Among the different compounds tested, L-742,001 appeared unique in having equal activity against either Mg(2+) or Mn(2+). Three compounds ( 10: , with a pyrrole scaffold, and 40: and 41: , with an indole scaffold) exhibited moderate antiviral activity in cell culture (EC99 values: 64-95 μM), and were proven to affect viral RNA synthesis. Our approach to integrate complementary enzymatic, cellular and mechanistic assays should guide ongoing development of improved influenza virus PA inhibitors.status: publishe

An Integrated biological approach to guide the development of metal-chelating inhibitors of influenza virus pa endonuclease

The influenza virus PA endonuclease, which cleaves capped cellular pre-mRNAs to prime viral mRNA synthesis, is a promising target for novel anti–influenza virus therapeutics. The catalytic center of this enzyme resides in the N-terminal part of PA (PA-Nter) and contains two (or possibly one or three) Mg2+ or Mn2+ ions, which are critical for its catalytic function. There is great interest in PA inhibitors that are optimally designed to occupy the active site and chelate the metal ions. We focused here on a series of β-diketo acid (DKA) and DKA-bioisosteric compounds containing different scaffolds, and determined their structure-activity relationship in an enzymatic assay with PA-Nter, in order to build a three-dimensional pharmacophore model. In addition, we developed a molecular beacon (MB)–based PA-Nter assay that enabled us to compare the inhibition of Mn2+ versus Mg2+, the latter probably being the biologically relevant cofactor. This real-time MB assay allowed us to measure the enzyme kinetics of PA-Nter or perform high-throughput screening. Several DKA derivatives were found to cause strong inhibition of PA-Nter, with IC50 values comparable to that of the prototype L-742,001 (i.e., below 2 μM). Among the different compounds tested, L-742,001 appeared unique in having equal activity against either Mg2+ or Mn2+. Three compounds (10, with a pyrrole scaffold, and 40 and 41, with an indole scaffold) exhibited moderate antiviral activity in cell culture (EC99 values 64–95 μM) and were proven to affect viral RNA synthesis. Our approach of integrating complementary enzymatic, cellular, and mechanistic assays should guide ongoing development of improved influenza virus PA inhibitors