Effect of Tumor Suppressor MiR-34a Loaded on ZSM-5 Nanozeolite in Hepatocellular Carcinoma: In Vitro and In Vivo Approach

Abstract

Background: MicroRNA modulation therapy has shown great promise to treat hepatocellular carcinoma (HCC), however Efficient tissue-specific and safe delivery remains a major challenge. Objective: We sought to develop an inorganic-organic hybrid vehicle for the systemic delivery of the tumor suppressor miR-34a, and to investigate the efficiency of the delivered miR-34a in the treatment of HCC in vitro and in vivo. Methods: In the present study, pEGP-miR cloning and expression vector, expressing miR-34a, was electrostatically bound to polyethyleneimine (PEI), and then loaded onto ZSM-5 zeolite nanoparticles (ZNP). Qualitative and quantitative assessment of the transfection efficiency of miR-34a construct in HepG2 cells was applied by GFP screening and qRT-PCR, respectively. The expression of miR-34a target genes was investigated by qRT-PCR in vitro and in vivo. Results: ZNP/PEI/miR-34a nano-formulation could efficiently deliver into HepG2 cells with low cytotoxicity, indicating good biocompatibility of generated nanozeolite. Furthermore, five injected doses of ZNP/PEI/miR-34a nano-formulation in HCC induced male Balb-c mice, significantly inhibited tumor growth, and demonstrated improved cell structure, in addition to a significant decrease in alphafetoprotein level and liver enzymes activities, as compared to the positive control group. Moreover, injected ZNP/PEI/miR-34a nano-formulation led to a noticeable decrease in the CD44 and c-Myc levels. Results also showed that ZNP/PEI/miR-34a nano-formulation inhibited several target oncogenes including AEG-1, and SOX-9, in vitro and in vivo. Conclusion: Our results suggested that miR-34a is a powerful candidate in HCC treatment and that AEG-1 and SOX-9 are novel oncotargets of miR-34a in HCC. Results also demonstrated that our nano-formulation may serve as a candidate approach for miR-34a restoration for HCC therapy, and generally for safe gene delivery.

Effects of Zeolite as a Drug Delivery System on Cancer Therapy: A Systematic Review

“…Through the literature search, it was determined that there is great heterogeneity in the experimental methods and conditions between studies reporting on zeolites/ZIFs as anticancer drug delivery systems. The most common anticancer drug loaded were doxorubicin (DOX) [ 21 , 22 , 25 , 32 , 37 , 38 , 40 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ], 5-fluorouracil (5-FU) [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ], curcumin [ 14 , 69 , 70 ], cisplatin [ 71 , 72 ], and miR-34a [ 73 , 74 ]. The articles also employed a variety of both ZIFs and natural/synthetic zeolites ( Table 1 ).…”

“…However, there are certain delivery challenges, mainly due to in vivo instability and low delivery efficiency, that impede the advancement of miRNA therapy [ 74 ]. Studies have incorporated miR-34a, a tumor-suppressing microRNA, into zeolites/ZIFs to enhance the tissue-specificity and safety of microRNA modulation therapy [ 73 , 74 ]. These novel nanoplatforms were successfully fabricated both with ZIF-8 and ZSM-5, thus demonstrating good biocompatibility in both ZIFs and zeolites.…”

Challenges identifying efficacious miRNA therapeutics for cancer

“…In some cases nanoparticles are used to deliver vectors expressing miRNAs. The plasmid vector expressing the miRNA were bound to a cationic polymer by electroststic interactions and then loaded on NPs [25].…”

Cell-Free Biological Approach for Corneal Stromal Wound Healing

“…The choice of a suitable delivery vehicle for miRNA should ideally inhibit immune response, improve targeting to the correct tissues and allow control over dosing. Different studies have described the administration of miRNAs in conjugation with modified cationic nanoparticles to enhance tissue penetrance, and escape from endosomal entrapping and degradation by lysosomes (Lee et al, 2019;Salah et al, 2019). In corneas, aside from nanoparticles, miRNAs can be packaged and delivered via exosomes as CSSC-derived EV have been shown to inhibit or reverse corneal scarring (Shojaati et al, 2019).…”