Synthesis and characterisation of a nucleotide based pro-drug formulated with a peptide into a nano-chemotherapy for colorectal cancer

• DOI: 10.1016/j.jconrel.2024.03.036
• Publication Date: 2024-03-23T04:45:42Z
• Authors: Jordan J. Wilson; Lindsey Bennie; Olga Eguaogie; Ahmed Elkashif; Patrick F. Conlon; Lynn Jena; Emma McErlean; Niamh Buckley; Klaudia Englert; Nicholas J. Dunne; James H.R. Tucker; Joseph S. Vyle; Helen O. McCarthy
• Keywords: name=Pharmaceutical Science; 0303 health sciences; Mechanochemsitry; /dk/atira/pure/subjectarea/asjc/3000/3003; name=Pharmaceutical Science; Dinucleoside tetraphosphate; 540; name=SDG 3 - Good Health and Well-being; dUTPase; Selenium; 03 medical and health sciences; Anticancer; RALA; Non-viral; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; Nanoparticles; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being; /dk/atira/pure/subjectarea/asjc/3000/3003

Recent studies in colorectal cancer patients (CRC) have shown that increased resistance to thymidylate synthase (TS) inhibitors such as 5-fluorouracil (5-FU), reduce the efficacy of standard care (SoC) treatment regimens. The nucleotide pool cleanser dUTPase is highly expressed CRC and an attractive target for potentiating anticancer activity chemotherapy. purpose current work was investigate P1, P4-di(2′,5′-dideoxy-5′-selenouridinyl)-tetraphosphate (P4-SedU2), a selenium-modified symmetrically capped dinucleoside with prodrug capabilities specifically activated by dUTPase. Using mechanochemistry, P4-SedU2 corresponding selenothymidine analogue P4-SeT2 were prepared yield 19% 30% respectively. phosphate functionality facilitated complexation amphipathic cell-penetrating peptide RALA produce nanoparticles (NPs). These NPs designed deliver intracellularly thereby maximise vivo activity. demonstrated effective anti-cancer selectivity HCT116 cell line, line overexpresses dUTPase; compared HT29 cells NCTC-929 fibroblast which reduced levels expression. In BALB/c SCID mice revealed no significant toxicity respect weight or organ histology. Pharmacokinetic analysis blood serum showed facilitates delivery rapid internalisation into surrounding tissues eliciting lower plasma Cmax than equivalent injection free P4-SedU2, translating vitro findings. Tumour growth delay inhibition dynamics tumour doubling time extended >2weeks. demonstrate action new pro-drug CRC.