Folate-Equipped Cationic Liposomes Deliver Anti-MDR1-siRNA to the Tumor and Increase the Efficiency of Chemotherapy

Abstract

In this study, we examined the in vivo toxicity of the liposomes F consisting of 1,26-bis(cholest-5-en-3-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride, lipid-helper 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine and folate lipoconjugate (O-{2-[rac-2,3-di(tetradecyloxy)prop-1-yloxycarbonyl]aminoethyl}-O’-[2-(pteroyl-L-glutam-5-yl)aminoethyl]octadecaethyleneglycol) and investigated the antitumor effect of combined antitumor therapy consisting of MDR1-targeted siMDR/F complexes and conventional polychemotherapy using tumor xenograft initiated in immunodeficient mice. Detailed analysis of acute and chronic toxicity of this liposomal formulation in healthy C57BL/6J mice demonstrated that formulation F and parent formulation L (without folate lipoconjugate) have no acute and chronic toxicity in mice. The study of the biodistribution of siMDR/F lipoplexes in SCID mice with xenograft tumors formed by tumor cells differing in the expression level of folate receptors showed that the accumulation in various types of tumors strongly depends on the abandons of folate receptors in tumor cells and effective accumulation occurs only in tumors formed by cells with the highest FR levels. Investigating the effects of combined therapy including anti-MDR1 siRNA/F complexes and polychemotherapy on a multidrug-resistant KB-8-5 tumor xenograft in SCID mice demonstrated that siMDR/F increases the efficiency of polychemotherapy: the treatment leads to pronounced inhibition of tumor growth, reduced necrosis and inflammation, and stimulates apoptosis in KB-8-5 tumor tissue. At the same time, it does not induce liver toxicity in tumor-bearing mice. These data confirm that folate-containing liposome F mediated the extremely efficient delivery of siRNA in FR-expressing tumors in vivo and ensured the safety and effectiveness of its action.

Single Shot vs. Cocktail: A Comparison of Mono- and Combinative Application of miRNA-Targeted Mesyl Oligonucleotides for Efficient Antitumor Therapy

“…In these experiments, lymphosarcoma RLS 40 cells were intramuscularly implanted into the mice thigh to initiate tumor formation; starting from day 4 of tumor development, oligonucleotides were peritumorally injected to mice ( Figure 4 b). Since RLS 40 cells are characterized by high abundance of folic acid receptors on the surface [ 47 ], folate-equipped liposomes F were used for targeted delivery of µ-oligonucleotides into the tumor [ 31 ]. According to preliminary flow cytometry data, these liposomes provided efficient delivery of µ-oligonucleotides into RLS 40 cells ( Figure S8 ).…”

Design of Folate-Containing Liposomal Nucleic Acid Delivery Systems for Antitumor Therapy

“…The decrease in transfection efficiency of FA-containing liposome in the presence of free FA suggests a receptor-mediated delivery of pDNA by this formulation [ 11 ]. Also, the same liposomal composition effectively delivered antisense oligonucleotides, siRNA, including in in vivo experiments [ 11 , 76 , 77 , 78 ].…”

“…Gladkikh et al examined siRNA delivery efficiency of lipoplexes containing polycationic lipid 2X3, DOPE, and FA lipoconjugate on several tumor xenografts that exhibited different levels of FR expression [ 78 ]. The highest accumulation was observed in L1210 cells with maximal FR expression among cell lines used.…”

A Novel 3-meta-Pyridine-1,2,4-oxadiazole Derivative of Glycyrrhetinic Acid as a Safe and Promising Candidate for Overcoming P-Glycoprotein-Mediated Multidrug Resistance in Tumor Cells

“…To verify our molecular modeling results, the MDR reversal activity of hit compounds was explored in human cervical carcinoma KB-8-5 cells with the MDR phenotype . First, to ensure the MDR status of KB-8-5 cells, a range of their MDR-related traits were evaluated.…”