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Expression of Bcl-2 and Akt-1 has been associated with human cancer. G3139 and RX-0201, targeting Bcl-2 and Akt-1, respectively, are antisense oligonucleotides (ASOs) that have shown limited efficacy in clinical trials. Herein, we report a combination of newly designed ASOs based on these agents and was delivered by tumor cell-targeting lipid nanoparticles (LNPs). A "Gapmer" design strategy was applied to these ASOs with the addition of 2'-O-methyl modifications on the nucleotides at 5' and 3' ends. A dual-channel syringe pump-based system was developed for the synthesis of the LNPs. ASO-LNPs composed of DODMA, egg PC, cholesterol, T7-PEG-DSPE, and PEG-DMG at a molar ratio of 35:39.5:20:0.5:5 and carrying either individual ASOs or co-loaded ASO combinations (Co-ASOs) were synthesized and evaluated in both KB and A549 cancer cells and in an A549 murine xenograft model to determine their antitumor effects and biological activities. The ASO-LNPs exhibited excellent colloidal stability and high ASO encapsulation efficiency with relatively small mean particle sizes and moderately positive zeta potentials. Transferrin receptor-targeting T7-conjugated LNPs showed enhanced cellular uptake compared to nontargeted LNPs. In addition, both T7-conjugated Co-ASOs-LNPs and non-T7-conjugated Co-ASOs-LNPs at a molar ratio of (G3139-GAP to RX-0201-GAP at 1:2) showed efficient downregulation of both Bcl-2 and Akt-1 in both A549 and KB cells. Furthermore, T7-conjugated Co-ASOs-LNPs (Co-ASOs-LNPs) produced superior antitumor activity, prolonged the overall survival time, and demonstrated tumor targeting activity in an A549 xenograft model.

This work presents a numerical analysis of spray combustion and associated emissions formation for methyl esters of soybean (SME) and coconut (CME) in a constant volume bomb and a light-duty diesel...

Lipid-albumin nanoparticles (LAN) were synthesized for delivery of RX-0047, an antisense oligonucleotide (ASO) against the hypoxia inducible factor-1 alpha (HIF-1α) to solid tumor. These lipid nanoparticles (LNs) incorporated a human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate, which is cationic and can form electrostatic complexes with negatively charged oligonucleotides. The delivery efficiency of LAN-RX-0047 was investigated in KB cells and a KB murine xenograft model. When KB cells were treated with LAN-RX-0047, significant HIF-1α downregulation and enhanced cellular uptake were observed compared to LN-RX-0047. LN-RX-0047 and LAN-RX-0047 showed similar cytotoxicity against KB cells with IC50 values of 19.3 ± 3.8 and 20.1 ± 4.2 μM, respectively. LAN-RX-0047 was shown to be taken up by the cells via the macropinocytosis and caveolae-mediated endocytosis pathways while LN-RX-0047 was taken up by cells via caveolae-mediated endocytosis. In the KB xenograft tumor model, LAN-RX-0047 exhibited tumor suppressive activity and significantly reduced intratumoral HIF-1α expression compared to LN-RX-0047. Furthermore, LAN-RX-0047 greatly increased survival time of mice bearing KB-1 xenograft tumors at doses of either 3 mg/kg or 16 mg/kg. These results indicated that LAN-RX-0047 is a highly effective vehicle for therapeutic delivery of antisense agents to tumor.

MicroRNA-21 (miR-21) is an oncomiR that is frequently upregulated in human cancers. AntimiR-21 (AM-21) is an oligonucleotide complementary to miR-21 that is designed to inhibit its gene silencing activities. To facilitate efficient delivery of AM-21, a novel lipid nanoparticle formulation called QTsome, based on a combination of quaternary amine and tertiary amine cationic lipids, with a distinctive pH-responsive profile, was developed. QTsome/AM-21 comprising DODMA/DOTAP/DOPC/CHOL/mPEG-DPPE and AM-21 oligonucleotide exhibited a mean particle diameter of below 150 nm, moderate zeta potential (+13.2 mV), excellent colloidal stability, and high drug loading efficiency (above 80%). In vitro study showed QTsome/AM-21 induced upregulation of miR-21 targets, including PTEN and DDAH1, in A549 cells while increasing their sensitivity toward paclitaxel (PTX). Finally, tumor regression, prolonged survival, and miR-21 target upregulation were demonstrated in an A549 xenograft mouse model. These data suggest that QTsome/AM-21 warrants further evaluation as an anticancer agent.

In an effort to advance the knowledge and understanding of biodiesel combustion characteristics in compression ignition engines, computational fluid dynamics (CFD) modeling has been utilized to study the in-cylinder physical and chemical events. The development of combustion kinetics and thermophysical properties of biodiesel in CFD modeling is crucial, since both of these govern the in-cylinder combustion and emission formation processes. As such, this review reports on the advances attained within three key aspects of CFD modeling of in-cylinder biodiesel combustion. The key aspects are surrogate chemical kinetic mechanisms, mechanism reduction methods, and biodiesel thermophysical properties models. Because of the complex fuel compositions, combustion modeling of biodiesel fuel largely depends on the surrogate chemical kinetic mechanisms. Recent developments in biodiesel chemical kinetic mechanisms have shown a progression from small detailed mechanisms toward large detailed mechanisms. The main challe...