Biology subjects

Santi, D. V.

Publications and source records attributed to Santi, D. V..

2 recordsLinked to original sources

bioRxiv2024

The limitation of lipidation: conversion of semaglutide from once-weekly to once-monthly dosing

The objective of this work was to develop a long-acting form of the lipidated peptide semaglutide that can be administered to humans once-monthly. Semaglutide was attached to 50 diameter hydrogel microspheres by a cleavable linker with an expected in vivo release half-life of about one-month. After a single subcutaneous dose, the pharmacokinetic parameters of released semaglutide were determined in normal mice and the bodyweight loss was determined in diet induced obese mice. The results were used to simulate the pharmacokinetics of semaglutide released from the microspheres in humans.Semaglutide tethered to microspheres by a cleavable linker could be completely released with an in vitro half-life of [~]55 days at pH 7.4. The in vivo half-life of released semaglutide was [~]30 days, and a single dose in diet-induced obese mice resulted in a lean-sparing body weight loss of 20% over 1 month, statistically the same as semaglutide dosed twice daily. Simulations indicated the microsphere-semaglutide would permit once-monthly administration in humans. The microsphere-semaglutide conjugate described here should be suitable for once-monthly dosing in humans, and the same approach should enable conversion of other lipidated peptides from once-weekly to once-monthly administration.

bioengineering↗

bioRxiv2024

Releasable hydrogel microsphere-drug conjugates as generic prodrugs for long-acting intra-tumoral therapy

Intratumoral (IT) therapy is a powerful method of controlling tumor growth, but a major unsolved problem is the rapidity that injected drugs exit tumors, limiting on-target exposure and efficacy. We have developed a generic long acting IT delivery-system in which a drug is covalently tethered to hydrogel microspheres (MS) by a cleavable linker; upon injection the conjugate forms a depot that slowly releases the drug and "bathes" the tumor for long periods. We established technology to measure tissue pharmacokinetics and studied MSs attached to SN-38, a topoisomerase 1 inhibitor. When MS[~]SN-38 was injected locally, tissues showed high levels of SN-38 with a long half-life of [~]1 week. IT MS[~]SN-38 was [~]10-fold more efficacious as an anti-tumor agent than systemic SN-38. We also propose and provide an example that long-acting IT therapy might enable safe use of two drugs with overlapping toxicities. Here, long-acting IT MS[~]SN-38 is delivered with concurrent systemic PARP inhibitor. The tumor is exposed to both drugs whereas other tissues are exposed only to the systemic drug; synergistic anti-tumor activity supported the validity of this approach. We propose use of this approach to increase efficacy and reduce toxicities of combinations of immune checkpoint inhibitors such as CTLA4 and PD-1.

cancer biology↗