Biology subjects

Kulik, K.

Publications and source records attributed to Kulik, K..

3 recordsLinked to original sources

bioRxiv2026

Systemic delivery of cationic liposome-mediated siRNA EGFR enhances therapeutic efficacy in a human colorectal cancer model

The clinical translation of RNA interference (RNAi) therapeutics remains limited by inefficient delivery and cancer-target accumulation. Here, we report the development of a new cationic liposome (CLP) nanocarrier engineered for delivery and controlled-release of small interfering RNA (siRNA) targeting the epidermal growth factor receptor (EGFR) in human colorectal cancer. CLPs were synthesized from ethylphosphocholine-based lipids and PEGylated components, with folic acid (FA) tissue-specific ligand and fluorophore labelling. These nanocarriers exhibited robust physicochemical stability across a broad pH and temperature range, efficient siRNA complexation, and nuclease-protection of siRNA. Functional studies revealed that CLP-siEGFR achieved effective cytosolic siRNA cargo release and EGFR silencing in vitro, proving to be more effective than conventional lipid-based transfection systems. In human xenograft models, intravenously administered CLP-siEGFR showed enhanced tumor localization, prolonged siRNA retention, and significant tumor growth suppression, accompanied by marked downregulation of EGFR. Importantly, systemic dosing was well-tolerated, with no evidence of hepatotoxicity, nephrotoxicity, or hematological abnormalities. These results position CLP nanocarriers as an effective platform for targeted RNAi therapeutics, offering translational potential for precision oncology applications.

cancer biology↗

bioRxiv2025

EGFR-targeted antisense oligonucleotides modified with boron clusters offer an innovative approach to cancer chemo-radiotherapy

Suppression of cancer-associated EGFR expression by antisense oligonucleotides is an attractive strategy to augment the efficacy of radiotherapy in cancer treatment. Boron clusters act as selective ligands for the epidermal growth factor receptor (EGFR) and provide an innovative platform for the delivery of naked boron cluster-conjugated therapeutic nucleic acids to cancer cells. Here, we demonstrate that the novel inhibitor B-ASOLNA-CHOL can also enhance efficient and cancer cell-selective uptake via the low-density lipoprotein receptor (LDLR). This conjugate exhibit strong cytotoxic effects on skin and liver cancer cells in combination with BNCT or XRT. We confirmed that intratumoral injections of B-ASOLNA-CHOL combined with local XRT significantly reduced tumor size and EGFR expression in human A431 xenografts implanted in immunodeficient mice. Our findings suggest that B-ASO-CHOL containing a CpG ODN motif exhibits immune adjuvant properties. The results underscore the potential of B-ASOLNA-CHOL technology for therapeutic applications in radiation immuno-oncology. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/668562v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@a275edorg.highwire.dtl.DTLVardef@1ec2c5eorg.highwire.dtl.DTLVardef@54fc6aorg.highwire.dtl.DTLVardef@187bd60_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

biochemistry↗

bioRxiv2024

Evidence of Histone H2A.Z Deacetylation and Cardiomyocyte Dedifferentiation in Infarcted/Tip60-depleted Hearts

Approaches to regenerate cardiomyocytes (CMs) after cardiac injury have been insufficient. Toward this end we are targeting the acetyltransferase Tip60, encoded by the Kat5 gene, based on the rationale that its pleiotropic functions block CM proliferation at multiple checkpoints. We previously reported that genetic depletion or pharmacological inhibition of Tip60 in mice after myocardial infarction (post-MI) reduces scarring, restores function, and activates the cell-cycle in CMs, although it remains unresolved whether daughter CMs are generated. For pre-existing adult CMs in the infarcted adult heart to proliferate, they must first undergo dedifferentiation, a process characterized by loss of maturity, epithelial to mesenchymal transitioning (EMT), and a metabolic shift from fatty acid oxidation (FAO) to glycolysis. Recent studies indicate that Tip60 is required to maintain the differentiated state of hematopoietic stem cells and neurons via site-specific acetylation of the histone variant H2A.Z, specifically H2A.ZacK4/K7. Based on these findings we have examined H2A.ZacK4/K7 levels and the expression of dedifferentiation-associated markers in adult hearts following CM-specific knockout of Tip60. In infarcted/Tip60-depleted hearts, H2A.ZacK4/K7 was largely extinguished in CM nuclei, accompanied by the altered expression of genes consistent with EMT induction, extracellular matrix softening, and reduced FAO. Seahorse metabolic analyses of isolated CMs indicated that Tip60 depletion promotes an oxidative-toglycolytic metabolic transition. In parallel, CUT&Tag analysis of nuclei isolated from heart tissue revealed that Tip60 depletion significantly reduced H2A.ZacK4/K7 occupancy within the promoter/transcription start sites of 47 genes that are highly CM-enriched, including cardiac maturity genes that are preceded in development by the expression of embryonic isoforms. RNAseq and RT-qPCR revealed that expression of these genes adult isoforms, as well as [~]50% of maturity genes that are not preceded by embryonic isoforms, were downregulated in Tip60-depleted hearts. These findings are consistent with the hypothesis that the Tip60 H2A.ZacK4/K7 axis maintains the differentiated state of CMs, constituting a major barrier to cardiac regeneration, justifying clinical targeting.

cell biology↗