Lipid nanoparticles (LNPs) are the most advanced nonviral platforms for small interfering RNA (siRNA) delivery that are clinically approved. These LNPs, based on ionizable lipids, are found in the liver and are now gaining much attention in the field of RNA therapeutics. The previous generation of ionizable lipids varies in linker moieties, which greatly influences in vivo gene silencing efficiency. Here novel ionizable amino lipids based on the linker moieties such as hydrazine, hydroxylamine, and ethanolamine are designed and synthesized. These lipids are formulated into LNPs and screened for their efficiency to deliver siRNAs into leukocytes, which are among the hardest to transfect cell types. Two potent lipids based on their in vitro gene silencing efficiencies are also identified. These lipids are further evaluated for their biodistribution profile, efficient gene silencing, liver toxicity, and potential immune activation in mice. A robust gene silencing is also found in primary lymphocytes when one of these lipids is formulated into LNPs with a pan leukocyte selective targeting agent (β7 integrin). Taken together, these lipids have the potential to open new avenues in delivering RNAs into leukocytes.
Ovarian cancer is an aggressive tumor owing to its ability to metastasize from stage II onward. Herein, lipid nanoparticles (LNPs) that encapsulate combination of small interfering RNAs (siRNAs), polo‐like kinase‐1 (PLK1), and eukaryotic translation‐initiation factor 3c (eIF3c), to target different cellular pathways essential for ovarian cancer progression are generated. The LNPs are further modified with hyaluronan (tNPs) to target cluster of differentiation 44 (CD44) expressing cells. Interestingly, hyaluronan‐coated LNPs (tNPs) prolong functional activity and reduce growth kinetics of spheroids in in vitro assay as compared to uncoated LNPs (uNPs) due to ≈1500‐fold higher expression of CD44. Treatment of 2D and 3D cultured ovarian cancer cells with LNPs encapsulating both siRNAs result in 85% cell death and robust target gene silencing. In advanced orthotopic ovarian cancer model, intraperitoneal administration of LNPs demonstrates CD44 specific tumor targeting of tNPs compared to uNPs and robust gene silencing in tissues involved in ovarian cancer pathophysiology. At very low siRNA dose, enhanced overall survival of 60% for tNPs treated mice is observed compared to 10% and 20% for single siRNA‐, eIF3c‐tNP, and PLK1‐tNP treatment groups, respectively. Overall, LNPs represent promising platform in the treatment of advanced ovarian cancer by improving median‐ and overall‐survival.
Primary and secondary β‐alkoxy alcohols can be cleanly and efficiently oxidized into hemiacetal esters in a cascade two‐step process. mCPBA serves both as a stoichiometric oxidant in the first TEMPO‐catalyzed step, converting alcohols to aldehydes/ketones, and as a reagent in the second Baeyer–Villiger stoichiometric oxidation, transforming the aldehydes/ketones into hemiacetal esters. The use of an oxidant common to both steps enables the domino reaction to proceed under a single experimental setting. Longer oxidative cascade sequences are possible when this new methodology is applied to suitable substrates.
While comparing analogousp olystyrenesupported and homogeneous catalysts for the Baylis-Hillmanr eaction, we hypothesized that the hydrophobice nvelopment of the imidazole catalytic sites of the former is responsible for the significantly better chemoselectivity exhibited by the heterogeneous catalysts compared to theirh omogeneousc ounterparts.I no rder to test this hypothesis,w ep repared as eries of branched/dendritic homogeneousc atalysts,w ith an imidazole active site near the focal point andf lexiblet ails of various lengthsa nd polarities,c apable of providing partials hieldingo ft his site.T he design of the catalysts was based on a5 -hydroxyisophthalate scaffold,a nd they were prepared throughanumber of multistep synthetic pathways. Thec omparison of the catalysts under av arietyo f conditions in am odel Baylis-Hillman reactiond emonstrated that long hydrophobic tales enhance the chemoselectivity parameter of the catalysis,w hile reducing the rate of the consumptiono ft he substrates, and that the chemoselectivity is further improvedb y the presence of af ree phenolic moiety in the vicinity of the catalytic imidazole unit. Moreover, in secondgeneration catalysts,t he peripherall ong tails could be either hydrophobic or polar, since the dendritic inner backbone itself presumably partially provides the necessary isolation of the catalytic site.T hus,e xperimental results support our hypothesis.Synthesis of 1,3-bis(methoxymethyl)-5-(methoxymethoxy)benzene: Thec ompound was prepared according to the typical procedure for the benzylic alcohol alkylation, using the followingq uantities:i odomethane (1.68 mL, 28.0 mmol, 4.0 equiv.), [5-(methoxymethoxy)-1,3-phenylene]dimethanol
This article deals with facile synthesis of A2B2 porphyrins bearing carboxylate groups at 5,15‐ positions and different functional groups at 10,20‐ positions viz. 4‐iodophenyl (a), 4‐tert‐butylphenyl (b), 3,5‐dimethoxyphenyl (c) 3‐carboxyphenyl (d), 2‐thienyl (e) 4‐nitrophenyl (f), 4‐methoxy‐2,3,5,6‐tetrafluorophenyl (g) and 2‐pyrenyl (h) as single major component in scalable yields. It relates also to the supramolecular assembly modes of these species. The use of stoichiometric amounts of trifluoroacetic acid in condensation of 5‐(4‐methoxycarbonylphenyl)dipyrromethane and different aldehydes led to the formation of trans‐porphyrins as di‐esters (1 a‐1 h). These were transformed by hydrolysis to the corresponding di‐acids (2 a‐2 h). (1 a‐1 h) and (2 a‐2 h) were then core‐metalated to afford the corresponding metalloporphyrin species (3 a‐3 h) and (4 a‐4 h). The absorption and emission spectra of the free base (2 a‐2 h) and metallated porphyrins (4 a‐4 h) were found greatly influenced by the substituents at 10,20‐positions. SEM studies of solids deposited on surfaces from solution exhibited hydrogen‐bonded block‐shaped structures of 2 e and fibrous sheets of 2 f. Co‐crystallization of 2 a and 2 g with 4,4′‐bipyridyl yielded hetero‐molecular structures stabilized by both hydrogen O−H⋅⋅⋅N, and halogen N⋅⋅⋅I bonds in 2 a, and by O−H⋅⋅⋅N hydrogen bonds and C−F⋅⋅⋅π interactions in 2 g.
In article number 1906128, Dan Peer and co‐workers describe the design and synthesis of novel ionizable lipids based on a linker strategy. The lipids are formulated into lipid nanoparticles and are screened for their gene silencing efficacies in cell‐culture models in vitro. Potent lipids are identified and analyzed for in vivo gene silencing efficacy in murine primary lymphocytes. Furthermore, no liver toxicity and no potential immune activation are observed in mice.
Capitalizing on our experience in constructing branched and dendritic monomers with functionalizable aromatic moiety at the focal point and various terminal groups, we prepared lipophilic and water-soluble dendrimers with BODIPY fluorophore in the core, emitting in the green and near IR spectral regions. The dendrimers, incorporating aliphatic tails, exhibited excellent fluorescence properties in apolar organic solvents, while those with the triethylenglycol-based tails were highly fluorescent in polar organic solvents as well. The water solubility induced by the terminal hexaethyleneglycol tails enables fluorescence of the dyes also in aqueous media. The phenolic hydroxyls in the molecules enable attachment of linkers for prospective conjugation of additional units.
Lipid nanoparticles encapsulating two different small interfering ribonucleic acids are developed that block essential pathways for cancer cell survival. Targeting of metastasized ovarian cancer cells is further enhanced by coating nanoparticles with hyaluronan. Robust gene silencing in key tissues involved in ovarian cancer pathophysiology in an advanced ovarian cancer mouse model and improved median and overall survival are demonstrated by Dan Peer and co‐workers in article number 2100287.
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