A biomimetic approach for enhancing the in vivo half-life of peptides

Penchala, Sravan; Miller, Mark R.; Pal, Arindom; Dong, Jin; Madadi, Nikhil Reddy; Xie, Jinghang; Joo, Hyun; Tsai, Jerry; Batoon, Patrick; Samoshin, Vyacheslav V.; Franz, Andreas H.; Cox, Trevor; Miles, Jesse; Chan, William K.; Park, Miki S.; Alhamadsheh, Mamoun M.

doi:10.1038/nchembio.1907

Cited by 111 publications

(136 citation statements)

References 40 publications

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“…The t 1/2 of C‐peptide after intraperitoneal injection was long, whereas the t 1/2 of C‐peptide after intravenous injection was very short, as it is in most peptides . This result indicates that the C‐peptide slowly diffused from the peritoneal cavity to the venous circulation and rapidly eliminated from the peripheral blood.…”

Section: Discussionmentioning

confidence: 97%

The pharmacokinetics of porcine C‐peptide after intraperitoneal injection

Iizuka

Nishimura

Fujita

et al. 2019

Xenotransplantation

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Background Previously, we have demonstrated that there were very low C‐Peptide concentrations and normal blood glucose levels when we transplanted encapsulated islets in the abdominal cavity of diabetic nude mice. In addition, the C‐peptide concentration in the ascites fluid of the peritoneal cavity was 40 times higher than in the peripheral blood. In this study, we investigated the pharmacokinetics of intraperitoneal porcine C‐peptide. Methods To assess the pharmacokinetics of porcine C‐peptide, a synthesized porcine C‐peptide solution was injected into the peripheral circulation through the tail vein or into the peritoneal cavity in rats at low or high doses of either 200 or 2000 pmol/kg, respectively. Arterial blood samples were collected at time intervals of 1‐120 minutes after injection to calculate the terminal elimination half‐life (t1/2) and area under the time‐concentration curve (AUC0‐t). Results After intraperitoneal C‐peptide injection, the highest porcine C‐peptide concentration in peripheral blood was only one‐fortieth compared to after intravenous injection. The AUC0‐t for the intraperitoneal injection was 78% at the low dose and only 39% at the high dose compared to the intravenous injection. This finding indicates that C‐peptide remains in the abdominal cavity when intraperitoneally transplanted islets release C‐peptide via high glucose stimulation. Conclusions Porcine C‐peptide injected into a peritoneal cavity slowly and incompletely entered peripheral circulation, which resulted in very low concentration in peripheral blood.

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Section: Discussionmentioning

confidence: 97%

The pharmacokinetics of porcine C‐peptide after intraperitoneal injection

Iizuka

Nishimura

Fujita

et al. 2019

Xenotransplantation

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“…Another limitation of peptides, including CTX, is poor in vivo half‐life due to rapid renal clearance (molecules <30 kDa are excreted rapidly by glomerular filtration). There are now several strategies available to overcome this limitation, including conjugation to polyethylene glycol or affinity tags that bind serum proteins, which have been successful in enhancing in vivo half‐life . For example, liraglutide (marketed as Victoza®), which is used for treatment of type II diabetes or obesity, is an analog of the GLP‐1 peptide.…”

Section: Discussionmentioning

confidence: 99%

Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake

et al. 2017

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Chlorotoxin (CTX), a disulfide-rich peptide from the scorpion Leiurus quinquestriatus, has several promising biopharmaceutical properties, including preferential affinity for certain cancer cells, high serum stability, and cell penetration. These properties underpin its potential for use as a drug design scaffold, especially for the treatment of cancer; indeed, several analogs of CTX have reached clinical trials. Here, we focus on its ability to internalize into cells-a trait associated with a privileged subclass of peptides called cell-penetrating peptides-and whether it can be improved through conservative substitutions. Mutants of CTX were made using solid-phase peptide synthesis and internalization into human cervical carcinoma (HeLa) cells was monitored by fluorescence and confocal microscopy. CTX_M1 (ie, [K15R/K23R]CTX) and CTX_M2 (ie, [K15R/K23R/Y29W]CTX) mutants showed at least a twofold improvement in uptake compared to CTX. We further showed that these mutants internalize into HeLa cells largely via an energy-dependent mechanism. Importantly, the mutants have high stability, remaining intact in serum for over 24 h; thus, retaining the characteristic stability of their parent peptide. Overall, we have shown that simple conservative substitutions can enhance the cellular uptake of CTX, suggesting that such type of mutations might be useful for improving uptake of other peptide toxins.

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“…Compared with full-length proteins, peptide analogues maintaining the same or partial biological effects may serve as more desirable therapeutic agents because of improved stability, reduced manufacturing cost, fewer side effects and better delivery 15 . To improve the half-life of peptide analogues of BMP2, EPO and FGF2 in vivo as well as the retention of the injected cells, we hypothesized that peptide analogues could be covalently cross-linked to a collagen matrix scaffold via dendrimers (col×D×pep, in which col represents collagen, × represents crosslinked, D represents dendrimer and pep represents peptide) to provide a controlled delivery system.…”

mentioning

confidence: 99%

Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix

et al. 2018

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Stem-cell-based therapies hold considerable promise for regenerative medicine. However, acute donor-cell death within several weeks after cell delivery remains a critical hurdle for clinical translation. Co-transplantation of stem cells with pro-survival factors can improve cell engraftment, but this strategy has been hampered by the typically short half-lives of the factors and by the use of Matrigel and other scaffolds that are not chemically defined. Here, we report a collagen–dendrimer biomaterial crosslinked with pro-survival peptide analogues that adheres to the extracellular matrix and slowly releases the peptides, significantly prolonging stem cell survival in mouse models of ischaemic injury. The biomaterial can serve as a generic delivery system to improve functional outcomes in cell-replacement therapy.

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A biomimetic approach for enhancing the in vivo half-life of peptides

Cited by 111 publications

References 40 publications

The pharmacokinetics of porcine C‐peptide after intraperitoneal injection

The pharmacokinetics of porcine C‐peptide after intraperitoneal injection

Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake

Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix

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