Cationic
lipid-guided nucleic acid delivery holds great promise
in gene therapy and genome-editing applications for treating genetic
diseases. However, the major challenge lies in achieving therapeutically
relevant efficiencies. Prior findings, including our own, demonstrated
that asymmetry in the hydrophobic core of cationic lipids imparted
superior transfection efficiencies. To this end, we have developed
a lipid nanocarrier system with an asymmetric hydrophobic core (PS-Lips) derived from a mixture of fatty acids of food-grade
palmstearin and compared its efficiency with symmetric palmitic acid-based
nanocarrier system (P-Lip). PS-Lips exhibited
superior transfection efficiencies with both plasmid DNA (pDNA) and
mRNA in multiple cultured cells than the control P-Lip. More importantly, PS-Lips exhibited 2-fold superior
transfections with linear nucleic acid, green fluorescent protein
(GFP) mRNA in hematopoietic cells, when compared with the commercial
control lipofectamine RNAiMAX. PS-Lips was also found
to be effective in delivering genome-editing tools (CRISPR/Cas9, sgRNA
encoded pDNA with a reporter GFP construct) than P-Lip in HEK-293 cells. In the present study, we report that cationic
liposomes derivatized from natural food-grade fat palmstearin with
a natural hydrophobic core asymmetry are efficient in delivering both
linear and circular nucleic acids. In particular, PS-Lips is efficient in delivering mRNA to hematopoietic cells. These findings
can be further exploited in the genome-editing approach for treating
β-globinopathies.
Endosomal escape is one of the barriers for the efficient liposomal gene delivery. To address this and based on earlier encouraging results using tocopherol cationic lipids, we elaborated chemical modifications on tocopherol cationic lipids by introducing a novel hybrid pH sensitive linker "ether-β-hydroxy-triazole" between tocopherol, the anchoring moiety and the basic tris(2-hydroxy ethyl)quaternary ammonium head group (Lp2). As control lipids we designed two lipids (Lp1 and Lp3), one is with only the ether-β-hydroxy linker in between α-tocopherol and quaternary tris(2-hydroxyethyl)ammonium (Lp1) and the other is with the same novel hybrid linker i.e. "ether-β-hydroxy-triazole" between the α-tocopherol linked and quaternary tris-ethyl ammonium head group (Lp3). Liposomes were formulated with a combination of a well-known co-lipid, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and biophysical characteristics such as DNA binding, hydrodynamic diameters and global surface charges for liposomes and lipoplexes of respective lipids were evaluated. Cell viability assay and in vitro transfection studies were carried out in NIH3 T3, B16F10, HEK-293, and HepG2 cell lines. In vitro transfection data for the liposomes of lipids (Lp1, Lp2 and Lp3) revealed that the Lp2 lipid with a novel hybrid pH sensitive linker showed superior transfection efficiency when compared with the remaining two analogues. More importantly, Lp2 has shown a similar pattern of transfection efficiency in HepG2 and HEK-293 cell lines when compared with commercially available Lipofectamine 3000.
Cationic lipids have been extensively studied for their ability to complex with nucleic acids to condense and consequently deliver them into the cells.
Background: Breast cancer is the most common cancer in women globally, and diagnosing it early and finding potential drug candidates against multi-drug resistant metastatic breast cancers provide the possibilities of better treatment and extending life. Methods: The current study aimed to evaluate the synergistic anti-metastatic activity of Curcumin (Cur) and Paclitaxel (Pacli) individually, the combination of Curcumin–Paclitaxel (CP), and also in conjugation with gold nanoparticles (AuNP–Curcumin (Au-C), AuNP–Paclitaxel (Au-P), and AuNP–Curcumin–Paclitaxel (Au-CP)) in various in vitro and in vivo models. Results: The results from combination treatments of CP and Au-CP demonstrated excellent synergistic cytotoxic effects in triple-negative breast cancer cell lines (MDA MB 231 and 4T1) in in vitro and in vivo mouse models. Detailed mechanistic studies were performed that reveal that the anti-cancer effects were associated with the downregulation of the expression of VEGF, CYCLIN-D1, and STAT-3 genes and upregulation of the apoptotic Caspase-9 gene. The group of mice that received CP combination therapy (with and without gold nanoparticles) showed a significant reduction in the size of tumor when compared to the Pacli alone treatment and control groups. Conclusions: Together, the results suggest that the delivery of gold conjugated Au-CP formulations may help in modulating the outcomes of chemotherapy. The present study is well supported with observations from cell-based assays, molecular and histopathological analyses.
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