Monodisperse oligoethylene glycols modified Propofol prodrugs

Deng, Tao; Mao, Xianglan; Liu, Yu; Bo, Shaowei; Yang, Zhigang; Jiang, Zhong‐Xing

doi:10.1016/j.bmcl.2018.10.009

Cited by 13 publications

(7 citation statements)

References 22 publications

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“…19 Propofol infusion syndrome, a rare but serious side effect that more commonly occurs in patients with long-term infusion of high-dose propofol and is characterized by unexplained metabolic acidosis, rhabdomyolysis, cardiac failure and renal failure, has also been believed to be related with lipid formulations. 20 For these reasons, lipidfree formulations of these drugs have been widely exploited based on various strategies including prodrugs 21,22 and alternative carrier materials. [23][24][25] Furthermore, our group has synthesized ET26, an analog of etomidate to minimize its suppression of adrenal cortical function, 26 and it is also a hydrophobic molecule in need of suitable carrier materials to develop its effective formulation.…”

Section: Introductionmentioning

confidence: 99%

High-Loading Self-Assembling Peptide Nanoparticles as a Lipid-Free Carrier for Hydrophobic General Anesthetics

Peng¹,

Kang²,

Gong³

et al. 2021

IJN

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Purpose Typical hydrophobic amino acids (HAAs) are important motifs for self-assembling peptides (SAPs), but they lead to low water-solubility or compact packing of peptides, limiting their capacity for encapsulating hydrophobic drugs. As an alternative, we designed a peptide GQY based on atypical HAAs, which could encapsulate hydrophobic drugs more efficiently. Although hydrophobic general anesthetics (GAs) have been formulated as lipid emulsions, their lipid-free formulations have been pursued because of some side effects inherent to lipids. Using GAs as targets, potential application of GQY as a carrier for hydrophobic drugs was evaluated. Methods Thioflavin-T (ThT) binding test, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to examine the self-assembling ability of GQY. Pyrene and 8-Anilino-1-naphthalenesulfonic acid (ANS) were used to confirm formation of hydrophobic domain in GQY nanoparticles. Using pyrene as a model, GQY’s capacity to encapsulate hydrophobic drugs was evaluated. GAs including propofol, etomidate and ET26 were encapsulated by GQY. Loss of righting reflex (LORR) test was conducted to assess the anesthetic efficacy of these lipid-free formulations. Paw-licking test was used to evaluate pain-on-injection of propofol-GQY (PROP-GQY) formulation. Hemolytic and cytotoxicity assay were used to evaluate biocompatibility of GQY. Results Stable nanoparticles containing plenty of hydrophobic cavities could be formed by GQY, which could encapsulate hydrophobic drugs at very high concentration and form stable suspensions. Propofol, etomidate and ET26 formulated by GQY showed anesthetic efficacy comparable to their currently available formulations. Unlike clinic lipid emulsion, PROP-GQY formulation did not cause pain-on-injection in rats. Neither obvious cytotoxicity nor hemolytic activity of GQY was observed. Conclusion GQY could encapsulate GAs to obtain stable and effective formulations. As a lipid-free carrier, GQY exhibited considerable biocompatibility and other side benefits such as reducing pain-on-injection. More SAPs based on atypical HAAs could be designed as promising carriers for hydrophobic drugs.

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Section: Introductionmentioning

confidence: 99%

High-Loading Self-Assembling Peptide Nanoparticles as a Lipid-Free Carrier for Hydrophobic General Anesthetics

Peng¹,

Kang²,

Gong³

et al. 2021

IJN

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“…Recently, an oligoethylene glycol macrocyclic sulfate-based strategy for the efficient synthesis of monodisperse polyethylene glycols (M-PEGs) was developed in this group , with which a series of M-PEGylated small molecular drugs with improved solubility, quality, and drug efficacy have been developed. − In contrast, the development of M-PEGylated biologics is far more challenging because M-PEGs above 4000 Da are still beyond the reach of current synthetic methods, however PEGs above 4000 Da are crucial to achieve the valuable “stealth” effects for biologics. − To this end, solid phase peptide synthesis (SPPS) was employed to conveniently prepare M-OEG polyamides as amide bond-containing M-PEGs above 4000 Da, which showed high monodispersity, biocompatibility, and tunable biodegradability. , …”

Section: Introductionmentioning

confidence: 99%

Monodisperse and Polydisperse PEGylation of Peptides and Proteins: A Comparative Study

et al. 2020

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Although PEGylation is widely used in biomedicine with great success, it suffers from many drawbacks, such as polydispersity, nonbiodegradability, and loss of precursor potency. Recently, the search for polyethylene glycol (PEG) substitutes has attracted considerable attention. Some of the substitutes partially address the drawbacks of PEGs, but sacrifice the “stealth” effect of PEGs and bring in new issues. Herein, we developed monodisperse oligoethylene glycol (M-OEG) polyamides over 5000 Da as biodegradable and monodisperse PEGylation (M-PEGylation) agents, which provided M-PEGylated peptides and proteins with high monodispersity and a biodegradable PEG moiety. Compared to regular PEGylated proteins with a complex “stealth” cloud of PEG, the hydrogen bond interactions between the M-OEG polyamides and proteins provided the M-PEGylated protein with a biodegradable “stealth” cloak. The monodisperse and biodegradable M-PEGylation strategy as well as the peculiar protein–M-OEG polyamide interactions may shed light on many long-lasting issues during the development of PEGylated biologic drugs, such as monodispersity, biodegradability, and tunable conformation.

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“…A large number of water-soluble structural fragments have been introduced into the design of propofol prodrugs, such as amino acids, phosphates, , sugars, and polyethylene glycols . However, because of the huge steric hindrance of the isopropyl group of propofol, most of these prodrugs cannot release propofol quickly and completely in vivo.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Activity Study of Water-Soluble, Rapid-Release Propofol Prodrugs

et al. 2020

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In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma while preserving its safety. In animal experiments, prodrugs (3e, 3g, and 3j) were significantly better than fospropofol (the only water-soluble propofol prodrug that has been used clinically) in terms of safety, onset, and duration time of anesthesia. Their molar dose, onset time, and anesthesia duration time were comparable to those of propofol, helping to maintain the clinical benefits of propofol. The experimental results showed the potential of such compounds as water-soluble prodrugs of propofol.

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Monodisperse oligoethylene glycols modified Propofol prodrugs

Cited by 13 publications

References 22 publications

High-Loading Self-Assembling Peptide Nanoparticles as a Lipid-Free Carrier for Hydrophobic General Anesthetics

High-Loading Self-Assembling Peptide Nanoparticles as a Lipid-Free Carrier for Hydrophobic General Anesthetics

Monodisperse and Polydisperse PEGylation of Peptides and Proteins: A Comparative Study

Design, Synthesis, and Activity Study of Water-Soluble, Rapid-Release Propofol Prodrugs

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