Gold nanoparticles functionalized with mRNA cap analogs as a strategy to inhibit eIF4E in cancer therapy

Eukaryotic messenger ribonucleic acids (mRNAs) universally exhibit a distinctive modification at their 5′ termini known as the "cap" (Fig. 1) [1]. The principal structural component of the cap is 7-methylguanosine (m7G) linked to the transcript residue through a 5′,5′-triphosphate bridge (m7GpppN, N-any nucleotide).

Functionally, the cap exerts its biological effects by engaging with diverse proteins that selectively recognize its configuration. The eukaryotic translation initiation factor 4E (eIF4E) forms a complex with the cap structure during the initiation of translation [2,3]. The intracellular levels of eIF4E are low and changes in the amount of eIF4E are one of the mechanisms of gene expression to be regulated at the translational level [4]. Elevated levels of eIF4E are associated with the formation and progression of human cancers which led to the idea of using cap analogs for therapeutic purposes [[5], [6], [7]]. Of the various strategies to counteract eIF4E overexpression, methods based on cap analogs have proven effective, according to recent reports [8,9]. By binding to eIF4E, synthetic analogs of the 5′ end cap of mRNA prevent the association of eIF4E with the mRNA cap, thereby inhibiting translation. To date, numerous modified cap analogs have been tested as inhibitors of the translation process in vitro [[10], [11], [12], [13], [14], [15], [16]]. Unfortunately, due to their ionic nature, the in vivo application of such analogs is strictly limited, and various methods are being explored to overcome this problem. These include the use of ProTide (PROdrug + nucleoTIDE), conjugates of a cap analog and a cell-penetrating peptide or adenovirus dodecahedron [[17], [18], [19], [20], [21], [22]]. However, these methods target the delivery of cap analogs to all cells, not just cancer cells. One effective method to overcome these problems may be to use of known carriers of various substances in the form of nanoparticles. Nanoparticles (NPs) are increasingly utilized to enhance drug delivery efficiency, biomedical imaging, and theragnostic [23]. Gold nanoparticles (AuNPs) have garnered significant attention for anticancer therapy due to their low toxicity, high stability, cellular uptake capability, excellent optical properties, and versatile surface functionality [[24], [25], [26], [27], [28], [29]]. AuNPs have the potential for passive anticancer drug delivery by leveraging the enhanced permeability and retention (EPR) effect [30,31]. To utilize a model drug-AuNPs conjugate effectively, it must exhibit sufficient stability to prevent aggregation and maintain its structure [[32], [33], [34], [35]]. Relatively simple and cost-effective stabilizers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), citrate, and silica are commonly employed to ensure oxidation resistance, enhanced colloidal stability, reproducible performance, or controlled assembly [[36], [37], [38], [39]]. However, some of these stabilizers may lead to undesired toxic side effects [[40], [41], [42], [43], [44], [45], [46], [47]]. Additionally, a significant issue to address is that many studies on the biomedical applications of nanoparticles focus on poorly characterized, purified, and monodispersed nanomaterial. This study introduces an accessible and effective cap analog-AuNP conjugate, thoroughly characterized from physicochemical and spectroscopic perspectives, exhibiting potential therapeutic applications without the need for additional nanoparticle surface stabilizing agents in its structure.

Comments (0)

No login
gif