Novel Liposaccharide Conjugates for Drug and Peptide Delivery

Abstract

Sugar-lipid conjugates with general structure 1-4 were prepared by coupling amino sugars with N-Boc-protected lipoamino acids and oligomers. Conjugates with general structure 5 were also prepared from glucuronic acid and methyl 2-aminohexadecanoate. The physicochemical properties of the conjugates were modified by varying the nature and number of sugars or the number of lipoamino acids or their alkyl chain length. The ability of the liposaccharides to aggregate was examined. These preliminary experiments have demonstrated the ability of the liposaccharides to form particulate systems per se and also their ability to be incorporated into conventional liposomal systems. The structure of the respective liposaccharides and the molar ratio of liposaccharide to dimyristoyl lecithin and cholesterol were found to have a profound effect on the type of colloidal systems produced.

Oral absorption enhancement of dipeptide L‐Glu‐L‐Trp‐OH by lipid and glycosyl conjugation

“…The other half of the resin previously isolated was further reacted with GlcNS(OAc) 4 -OH (447 mg, 1 mmol) in the presence of 0.5M 0.5M HBTU in DMF (1.1 equiv) and DIPEA (1.2 equiv), and treated with a 12.5% hydrazine in MeOH (3 mL) solution to remove the acetyl groups. It was then washed twice with DMF, DCM, and MeOH and dried under vacuo overnight, before being cleaved with the TFA-based scavenging mixture, followed by precipitation in cold ether and purification by RP-HPLC, yielding the diastereomeric glycolipopeptide (35 and 39 mg, 38% total yield) as white solids.…”

“…The resin was then transferred into a peptide vessel and Fmoc-Glu(OtBu)-OH and Dde-C 12 -OH were successively coupled, alternating with removals of N a -Fmoc protecting groups with 20% piperidine in DMF, followed by the Dde deprotection with 2% hydrazine in DMF (3 3 3 mL). GlcNS(OAc) 4 -OH (447 mg, 1 mmol) was then added along with 0.5M HBTU in DMF (2 mL, 1 mmol) and DIPEA (0.2 mL, 1 mmol). Upon coupling, the resin was treated with 12.5% hydrazine in MeOH (3 mL) to remove the acetyl groups, then washed twice with DMF, DCM, and MeOH before being dried under vacuo overnight.…”

“…Half of the resin was reacted with GlcNS(OAc) 4 -OH (0.447 g, 1 mmol) in the presence of 0.5M HBTU in DMF (2 mL, 1 mmol) and DIPEA (0.2 mL, 1 mmol). Upon coupling, the resin was treated with 12.5% hydrazine in MeOH (3 mL) to remove the acetyl groups, then washed twice with DMF, DCM, and MeOH before being dried under vacuo overnight.…”

“…2,3 Toth et al thoroughly examined and reported the use of lipid-and carbohydrate-based delivery systems to enhance the absorption of a variety of poorly orally available drugs, including peptides. [4][5][6][7] In order for molecules to penetrate the intestinal epithelium and be absorbed through passive diffusion, a minimum level of lipophilicity is needed. 8 Lipid conjugation has proven to be effective in not only enhancing the…”

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

“…Use of both lipidation and glycosylation will confer a balance between the lipophilic and hydrophilic characteristics. This may result in higher potency by improving peptide stability against enzymatic hydrolysis and permeability through biological membranes (Drouillat et al, 1998;Koda et al, 2008;Nomoto et al, 1998).…”