Evaluation of Floxuridine Oligonucleotide Conjugates Carrying Potential Enhancers of Cellular Uptake

Autor: Ramon Eritja, María José Bleda, Anna Aviñó, Carme Fàbrega, Anna Clua
Přispěvatelé: Ministerio de Ciencia e Innovación (España), Eritja Casadellà, Ramón, Eritja Casadellà, Ramón [0000-0001-5383-9334]
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Folic acid
5-fluoro-2′-deoxyuridine
Oligonucleotides
Apoptosis
Oligomer
Delivery enhancers
Palmitic acid
chemistry.chemical_compound
0302 clinical medicine
Floxuridine
palmitic acid
Biology (General)
Cytotoxicity
Internalization
Spectroscopy
media_common
Chemistry
Cytotoxins
General Medicine
Hep G2 Cells
Small molecule
Computer Science Applications
Cholesterol
Biochemistry
Cancer treatment
030220 oncology & carcinogenesis
medicine.drug
conjugation
QH301-705.5
media_common.quotation_subject
Catalysis
Article
cancer treatment
Inorganic Chemistry
03 medical and health sciences
folic acid
delivery enhancers
PEG ratio
medicine
Humans
Physical and Theoretical Chemistry
QD1-999
Molecular Biology
Cell Proliferation
Conjugation
Oligonucleotide
Organic Chemistry
cholesterol
GalNAc
030104 developmental biology
HeLa Cells
Zdroj: International Journal of Molecular Sciences
Volume 22
Issue 11
Digital.CSIC: Repositorio Institucional del CSIC
Consejo Superior de Investigaciones Científicas (CSIC)
Digital.CSIC. Repositorio Institucional del CSIC
instname
International Journal of Molecular Sciences, Vol 22, Iss 5678, p 5678 (2021)
ISSN: 1422-0067
2017-8441
Popis: Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, we studied adding cholesterol, palmitic acid, polyethyleneglycol (PEG 1000), folic acid and triantennary N-acetylgalactosamine (GalNAc) as potential enhancers of cellular uptake. As expected, all these molecules increased the internalization efficiency with different degrees depending on the cell line. The conjugates showed antiproliferative activity due to their metabolic activation by nuclease degradation generating floxuridine monophosphate. The cytotoxicity and apoptosis assays showed an increase in the anti-cancer activity of the conjugates related to the floxuridine oligomer, but this effect did not correlate with the internalization results. Palmitic and folic acid conjugates provide the highest antiproliferative activity without having the highest internalization results. On the contrary, cholesterol oligomers that were the best-internalized oligomers had poor antiproliferative activity, even worse than the unmodified floxuridine oligomer. Especially relevant is the effect induced by palmitic and folic acid derivatives generating the most active drugs. These results are of special interest for delivering other therapeutic oligonucleotides.
This research was funded by the Spanish Ministerio de Ciencia e Innovación (CTQ2017-84415-R) and Generalitat de Catalunya (2017SGR114) and and CIBER BBN (CB06/01/0019). A.C. was funded by a fellowship associated with the CTQ2017-84415-R project (PRE2018-084056).
Databáze: OpenAIRE
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