Herein, we report effective, C‐type lectin mannose receptor (MR)‐selective, in vivo dendritic cell (DC)‐targeting lipid nanoparticles (LNPs) of a novel lipid‐containing mannose‐mimicking di‐shikimoyl‐ and guanidine head group and two n‐hexadecyl hydrophobic tails (DSG). Subcutaneous administration of LNPs of the DSG/p‐CMV‐GFP complex showed a significant expression of green fluorescence protein in the CD11c+ DCs of the neighboring lymph nodes compared to the control LNPs of the BBG/p‐CMV‐GFP complex. Mannose receptor‐facilitated in vivo DC‐targeted vaccination (s.c.) with the electrostatic complex of LNPs of DSG/pCMV‐MART1 stimulated long‐lasting (270 days post B16F10 tumor challenge) antimelanoma immunity under prophylactic conditions. Remarkably, under therapeutic settings, vaccination (s.c.) with LNPs of the DSG/pCMV‐MART1 complex significantly delayed melanoma growth and improved the survival of mice with melanoma. These findings demonstrate that this nonviral delivery system offers a resilient and potential approach to deliver DNA vaccines encoding tumor antigens to DCs in vivo with high efficacy.
In eukaryotes, transcriptional regulation occurs via chromatin remodeling, mainly through post translational modifications of histones that package DNA into structural units. Histone deacetylases (HDACs) are enzymes that play important role in various biological processes by repressing gene expression. Suberoylanilide hydroxamic acid (SAHA) is a known HDAC inhibitor that showed significant anti cancer activity by relieving gene silencing against hematologic and solid tumors. We have designed and synthesized a series of SAHA analogs C1-C4 and performed biological studies to elucidate its anti-cancer effects. It is observed that SAHA analogs significantly inhibited cell proliferation and induced apoptosis in hepatocellular carcinoma (HCC) cell lines HepG2 and SK-HEP-1. These analogs also showed non-toxic activity towards primary human hepatocytes, which describes its tumor specificity. SAHA analogs exhibited strong HDAC inhibition, which is 2-3 fold higher compared to SAHA. Moreover, these molecules induced hyper acetylation of histone H3 at various positions on the lysine residue. Further, it is observed that SAHA analogs are strong inducers of apoptosis, as they regulated the expression of various proteins involved in both extrinsic and intrinsic pathways. Interestingly, SAHA analogs induced upregulation of tumor suppressor miRNAs by activating its biogenesis pathway. Further, it is confirmed by microRNA (miRNA) prediction tools that these miRNAs are capable of targeting various anti-apoptotic genes. Based on these findings we conclude that SAHA analogs could be strong HDAC inhibitors with promising apoptosis inducing nature in HCC.
A variety of aldehydes undergo smooth coupling with 4-hydroxy-N-methyl-2-methylene-N-phenylbutanamide in the presence of BF3·OEt2 under ambient conditions to produce the corresponding spiro-oxindole derivatives in good yields with excellent selectivity. It is an entirely new strategy to construct the spirocycles in a one-pot operation through a Prins cascade process.
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