The evolution of nucleosidic analogues: self-assembly of prodrugs into nanoparticles for cancer drug delivery

Abstract

Nucleoside and nucleotide analogs are essential tools in our limited arsenal in the fight against cancer. However, these structures face severe drawbacks such as rapid plasma degradation or hydrophilicity, limiting...

Overcoming MDR by Associating Doxorubicin and pH-Sensitive PLGA Nanoparticles Containing a Novel Organoselenium Compound—An In Vitro Study

“…Considering that ACAT-Se is an thymidine analogue, we suggest that its cytotoxicity can be related to inhibition of intracellular enzymes (like polymerases or ribonucleotide reductase), or to inhibition of DNA chain elongation, by the assimilation of its active form in DNA chain [9,65]. Cell viability studies were performed using MTT and NRU assays.…”

Azacitidine Omega-3 Self-Assemblies: Synthesis, Characterization, and Potent Applications for Myelodysplastic Syndromes

“…The organic solvent is then evaporated using a rotary evaporator, thus yielding an opalescent aqueous suspension. Nucleoside analogue derivatives that are coupled at the 4-(N)-position to various molecules exhibit enhanced metabolic stability in plasma, owing to the occupation of the deamination site, thus protecting these analogues from irreversible hydrolytic degradation [12,32,44,45]. As a consequence of their hydrophobic nature, both DHA and EPA can act as the scaffold in the synthesis of amphiphilic prodrugs [46,47].…”

“…The obtained amphiphilic prodrug would have an enhanced entry into the cells owing to the similar nature of the cell lipid bilayer membrane [23,24], with a specificity to the affected cells owing to their overexpression of cathepsin-B, an enzyme that can cleave the conjugating amide bond, specifically releasing the free azacitidine [25][26][27]. Additionally, the prodrug-based self-assemblies would be able to further protect the azacitidine from degradation by deaminases, increasing its circulation time and thus reducing the required dose to achieve an equal response [12].…”

“…Upon the entry of this DNA-hypomethylating cytidine analogue, via the action of human equilibrative nucleoside transporter 1 (hENT1), azacitidine undergoes successive phosphorylation steps via the regular nucleic acid kinases, to reach its final tri-phosphorylated form, allowing its integration into the DNA. It acts as well on the DNA methyltransferase, causing permanent inhibition of the enzyme, leading to the alteration of gene expression by decreasing the methylation levels of the cytosine, thus impacting the DNA epigenetic status and allowing the reactivation of tumor suppressor genes [12,13].…”

Nanodiscs: a versatile nanocarrier platform for cancer diagnosis and treatment

“…Besides carrying chemotherapeutics directly with the NDs for their selective delivery to cancer cells, another often used strategies is to modify anticancer drugs into prodrugs and deliver the prodrugs instead. 98 There are excellent recent reviews describing the application of prodrugs for cancerspecific targeting, [99][100][101] and linker-specific prodrugs such as nucleoside-based, 102 disulfides-based, 103 pH-sensitive, 104 reactive oxygen species sensitive prodrugs, 105 and many others. 1 Prodrug strategy uses chemical functional groups such as esters (such as carboxyl, carbamate, carbonate, phosphate, or sulfate esters), amide, oxime, imine, disulfide, or thioethers groups between the drug and the promoiety/nanocarrier system.…”