The fatty acid conjugated exendin-4 analogs for type 2 antidiabetic therapeutics

Chae, Su Young; Choi, Yeong-Won; Son, Sohee; Jung, Sung Youb; Lee, Sang Soo; Lee, Kang Choon

doi:10.1016/j.jconrel.2010.01.024

Cited by 69 publications

(34 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Exendin-4 was conjugated to iron nanoparticles using the side chain of Lys27, which was the dominant reaction site on the peptide for conjugation to nanoparticles. The second potential reaction site on Lys12 side chain is hindered and could not serve as the major reaction site (31,32). The ratio of Cy5.5:exendin-4:nanoparticles was determined as 2.5:5:1 or 2.5:10:1 by spectrophotometric analysis and bicinchoninic acid protein assay.…”

Section: Resultsmentioning

confidence: 99%

GLP-1R–Targeting Magnetic Nanoparticles for Pancreatic Islet Imaging

et al. 2014

View full text Add to dashboard Cite

Noninvasive assessment of pancreatic β-cell mass would tremendously aid in managing type 1 diabetes (T1D). Toward this goal, we synthesized an exendin-4 conjugated magnetic iron oxide–based nanoparticle probe targeting glucagon-like peptide 1 receptor (GLP-1R), which is highly expressed on the surface of pancreatic β-cells. In vitro studies in βTC-6, the β-cell line, showed specific accumulation of the targeted probe (termed MN-Ex10-Cy5.5) compared with nontargeted (termed MN-Cy5.5). In vivo magnetic resonance imaging showed a significant transverse relaxation time (T2) shortening in the pancreata of mice injected with the MN-Ex10-Cy5.5 probe compared with control animals injected with the nontargeted probe at 7.5 and 24 h after injection. Furthermore, ΔT2 of the pancreata of prediabetic NOD mice was significantly higher than that of diabetic NOD mice after the injection of MN-Ex10-Cy5.5, indicating the decrease of probe accumulation in these animals due to β-cell loss. Of note, ΔT2 of prediabetic and diabetic NOD mice injected with MN-Cy5.5 was not significantly changed, reflecting the nonspecific mode of accumulation of nontargeted probe. We believe our results point to the potential for using this agent for monitoring the disease development and response of T1D to therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

GLP-1R–Targeting Magnetic Nanoparticles for Pancreatic Islet Imaging

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The resulting FA-exendin-4 conjugates were tested as regulators of blood glucose to cure type 2 diabetes, and showed a notably longer blood circulation profile over exendin-4 (Table 4). 113 Additionally, the FA acylated insulin has also been developed as a long-circulating anti-diabetic drug. It binds at the long-chain fatty acid binding sites, but the binding affinity is lower than that of the free fatty acids and depends to a relatively small degree on the number of carbon atoms in the fatty acid.…”

Section: General Strategy To Develop Hsa-conjugated Drugsmentioning

confidence: 99%

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

2016

View full text Add to dashboard Cite

Albumin is the most abundant circulating protein in plasma and has recently emerged as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptide or protein based drugs. Three drug delivery technologies related to albumin have been developed, which include the coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugating bioactive proteins by albumin fusion technology (AFT), and encapsulation of drugs into albumin nanoparticles. This review article starts with a brief introduction of human serum albumin (HSA), and then summarizes the mainstream chemical strategies of developing HSA binding molecules for coupling with drug molecules. Moreover, we also concisely condense the recent progress of the most important clinical applications of HSA-binding platforms, and specify the current challenges that need to be met for a bright future of HSA-binding.

show abstract

“…The strategies adopted to date include modifications of GLP-1 receptor agonists by poly(ethylene glycol) conjugation, known as PEGylation (15–17), or chemical or genetic modifications with serum albumin (13, 14). Other approaches involve the acylation of incretin (18), and its mimetics (9, 19–21), allowing for albumin binding and preventing rapid kidney elimination. An approach using a sustained-release formulation of GLP-1 receptor agonist based on biodegradable microsphere technology is also being investigated in the context of long-acting anti-diabetics (10).…”

Section: Introductionmentioning

confidence: 99%

Extending Residence Time and Stability of Peptides by Protected Graft Copolymer (PGC) Excipient: GLP-1 Example

2011

View full text Add to dashboard Cite

Purpose The purpose of this study is to determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes. Methods To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of 1) the binding of excipient to GLP-1, 2) the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, 3) the in vitro bio-activity of excipient-formulated GLP-1, 4) the in vivo pharmacokinetics of excipient-formulated GLP-1, and 5) the efficacy of the excipient-formulated GLP-1 in diabetic rats. Results We showed reproducible synthesis of PGC excipient, showed high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and showed that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day. Conclusions PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.

show abstract

The fatty acid conjugated exendin-4 analogs for type 2 antidiabetic therapeutics

Cited by 69 publications

References 28 publications

GLP-1R–Targeting Magnetic Nanoparticles for Pancreatic Islet Imaging

GLP-1R–Targeting Magnetic Nanoparticles for Pancreatic Islet Imaging

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

Extending Residence Time and Stability of Peptides by Protected Graft Copolymer (PGC) Excipient: GLP-1 Example

Contact Info

Product

Resources

About