A 4-arm polyethylene glycol derivative conjugated with exendin-4 peptide and palmitylamine having dual-function of size-increase and albumin-binding for long hypoglycemic action

Kim, In-Soo; Kim, Tae Hyung; Ma, Kyungwan; Park, Eun-Seok; Oh, Kyung Taek; Lee, Eun Seong; Lee, Kang Choon; Youn, Yu Seok

doi:10.1016/j.regpep.2011.02.008

Cited by 12 publications

(4 citation statements)

References 28 publications

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“…As expected, nanoparticles were avidly uptaken by liver, and the radioactivity associated with these organs reached the highest level at 4 h post-injection (20.05 ± 0.55% ID/g). This finding can be explained by the fact that nanostructures are normally engulfed by macrophages present in that organ [22][23][24]. These results are in agreement with data presented by other authors using nanoparticles as imaging probes [25][26][27].…”

Section: Biodistribution Studies and Scintigraphic Imagessupporting

confidence: 92%

Synthesis, characterization, and biodistribution studies of 99m Tc-labeled SBA-16 mesoporous silica nanoparticles

Barros

Ferraz

Dantas

et al. 2015

Materials Science and Engineering: C

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Section: Biodistribution Studies and Scintigraphic Imagessupporting

confidence: 92%

Synthesis, characterization, and biodistribution studies of 99m Tc-labeled SBA-16 mesoporous silica nanoparticles

Barros

Ferraz

Dantas

et al. 2015

Materials Science and Engineering: C

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“…The retained bioactivity and improved proteolytic stability was shown in vivo in a mouse model trial with PEG 5K ‐Ex4 and PEG 20K ‐Ex4. Consistent with prior studies, the present results demonstratedthat a PEGylated peptide offersmarkedly improved circulatory stability and therapeutic capacity.…”

Section: Discussionsupporting

confidence: 92%

Evaluation of PEGylated Exendin-4 Released from Poly (Lactic-co-Glycolic Acid) Microspheres for Antidiabetic Therapy

Lim

Eom

Jiang

et al. 2015

Journal of Pharmaceutical Sciences

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“…19 Recently, Kim et al prepared a conjugate containing two exendin-4 (Ex4) peptide molecules and two hexadecane moieties for the diabetes treatment using 4-arm PEG20K as the linker. 20 This method possessed the overall benefits of PEGylation and albumin binding. However, this method was not suitable to chemical modification of proteins for the following reasons: (i) the protein may denature and precipitate in the organic solvent, where Ex4 was mixed with palmitylamine and PEG in the organic solvent to prepare the conjugate; (ii) the succinimide groups of the 4-arm PEG20K may rapidly hydrolyze upon exchanging the organic solvent with the aqueous solution.…”

Section: ■ Introductionmentioning

confidence: 99%

“…On the basis of this technology, Novo Nordisk has developed a myristic acid-insulin (Levemir) and palmitic acid-glucagon-like peptide 1 (Liraglutide) to treat diabetes . Recently, Kim et al prepared a conjugate containing two exendin-4 (Ex4) peptide molecules and two hexadecane moieties for the diabetes treatment using 4-arm PEG20K as the linker . This method possessed the overall benefits of PEGylation and albumin binding.…”

Section: Introductionmentioning

confidence: 99%

N-Terminal Modification with Pseudo-Bifunctional PEG-Hexadecane Markedly Improves the Pharmacological Profile of Human Growth Hormone

2015

Mol. Pharmaceutics

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Human growth hormone (hGH) has been used to treat children with short stature, renal failure, and Turner's syndrome. However, clinical application of hGH suffers from its short plasma half-life and low bioavailability. PEGylation and albumin binding are two of the most effective approaches to prolong the plasma half-life of hGH. However, the steric shielding effects of polyethylene glycol (PEG) and albumin can drastically decrease the bioactivity of hGH, which is opposite to the increased pharmacokinetics (PK). In the present study, a long-acting hGH with markedly improved pharmacological profile was rationally designed and prepared by N-terminal modification of hGH with pseudo-bifunctional PEG-hexadecane by using PEG (3.5 kDa or 10 kDa) as the linker. PEGylation and albumin binding with hexadecane can increase the hydrodynamic volume and decrease the immunogenicity of hGH, which thereby markedly increases the PK of hGH. Since N-terminus is far from the bioactive domain of hGH, N-terminal modification of hGH can minimize the steric shielding effects on the bioactive domain of hGH. Hexadecane-bound albumin can be slowly released from hGH during the in vivo circulation, which can slowly restore the bioactivity of hGH. Thus, the high bioactivity of PEG-hexadecane modified hGH (hGH-PEG-HD) was synergistically achieved by N-terminal modification with pseudo-bifunctional PEG-hexadecane and slow-release of albumin. The high pharmacodynamics (PD) of hGH-PEG-HD was due to the synergistic effect of the high bioactivity and the overall increased PK.

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A 4-arm polyethylene glycol derivative conjugated with exendin-4 peptide and palmitylamine having dual-function of size-increase and albumin-binding for long hypoglycemic action

Cited by 12 publications

References 28 publications

Synthesis, characterization, and biodistribution studies of 99m Tc-labeled SBA-16 mesoporous silica nanoparticles

Synthesis, characterization, and biodistribution studies of 99m Tc-labeled SBA-16 mesoporous silica nanoparticles

Evaluation of PEGylated Exendin-4 Released from Poly (Lactic-co-Glycolic Acid) Microspheres for Antidiabetic Therapy

N-Terminal Modification with Pseudo-Bifunctional PEG-Hexadecane Markedly Improves the Pharmacological Profile of Human Growth Hormone

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