posted on 2023-12-05, 15:05authored bySonal Deshpande, Yunqi Yang, Stefan Zauscher, Ashutosh Chilkoti
We
report a targeted prodrug delivery platform that can deliver
a cytostatic nucleobase analog with high drug loading. We chose fluorouracil
(5FU), a drug used to treat various cancers, whose active metabolite
5-fluorodeoxyuridine monophosphate (5-FdUMP) is the antineoplastic
agent. We use terminal deoxynucleotidyl transferase (TdT) to polymerize
5-fluorodeoxyuridine triphosphate (5-FdUTP) onto the 3′-end
of an aptamer. We find that (i) addition of hydrophobic, unnatural
nucleotides at the 3′-end of the 5-FdU polynucleotide by TdT
leads to their spontaneous self-assembly into nuclease resistant micelles,
(ii) aptamers presented on the micelle corona retain specificity for
their cognate receptor on tumor cells, and (iii) the micelles deliver
5FU to tumor cells and exhibit greater cytotoxicity than the free
drug. The modular design of our platform, consisting of a targeting
moiety, a polynucleotide drug, and a self-assembly domain, can be
adapted to encompass a range of polymerizable therapeutic nucleotides
and targeting units.