posted on 2023-01-12, 20:44authored byShravan Morla, Ongolu Ravikumar, Connor O’Hara, Rio Boothello, Alberto Vera, Elsamani I. Abdelfadiel, Rawan Fayyad, Daniel K. Afosah, Chetna Sharon, Leopoldo Fernandez, Syed Ammer Shah, Bhaumik B. Patel, Umesh R. Desai
Sulfated glycosaminoglycans
(GAGs), or synthetic mimetics thereof,
are not favorably viewed as orally bioavailable drugs owing to their
high number of anionic sulfate groups. Devising an approach for oral
delivery of such highly sulfated molecules would be very useful. This
work presents the concept that conjugating cholesterol to synthetic
sulfated GAG mimetics enables oral delivery. A focused library of
sulfated GAG mimetics was synthesized and found to inhibit the growth
of a colorectal cancer cell line under spheroid conditions with a
wide range of potencies ( 0.8 to 46 μM). Specific analogues
containing cholesterol, either alone or in combination with clinical
utilized drugs, exhibited pronounced in vivo anticancer
potential with intraperitoneal as well as oral administration, as
assessed by ex vivo tertiary and quaternary spheroid
growth, cancer stem cell (CSC) markers, and/or self-renewal factors.
Overall, cholesterol derivatization of highly sulfated GAG mimetics
affords an excellent approach for engineering oral activity.