Designing Synthetic, Sulfated Glycosaminoglycan Mimetics That Are Orally Bioavailable and Exhibiting In Vivo Anticancer Activity

Abstract

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.

Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors

“…For example, NSGMs are generally not orally bioavailable owing to the presence of their multiple sulfate groups. However, a recent article reports that covalent conjugation of cholesterol to an NSGM induces oral bioavailability, 222 an advance that could be implemented for developing orally bioavailable NSGMs as anti-coagulants. Another likely problem besetting the development of NSGMs as anti-coagulants, or drugs in general, is the possibility of their rapid clearance.…”