Improving Eflornithine Oral Bioavailability and Brain Uptake by Modulating Intercellular Junctions With an E-cadherin Peptide

Yang, Sihyung; Chen, Yao; Feng, Mei; Rodriguez, Larry; Wu, Judy Qiju; Wang, Michael Zhuo

doi:10.1016/j.xphs.2019.09.015

Cited by 8 publications

(7 citation statements)

References 30 publications

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“…24 In addition, HAV6 also significantly enhanced oral and brain delivery of eflornithine, an efflux pump substrate, in rats. 25 These data support the idea that modulation of cadherin-mediated cell− cell adhesion in the intercellular junction can improve drug delivery across the biological barriers (i.e., intestinal mucosa barrier and BBB).…”

Section: ■ Introductionsupporting

confidence: 73%

“…HAV6 peptide can enhance the in vivo brain delivery of small molecules (e.g., 14 C-mannitol, 3 H daunomycin, gadopentetic acid (Gd-DTPA), IRdye R800, and adenanthin) and large molecules (e.g., 25 kDa IRdye800CW-polyethylene glycol and 65 kDa galbumin). − Similarly, ADTC5 peptide enhances brain delivery of 14 C-mannitol, Gd-DTPA, 8–12 amino acid peptides, and galbumin. , Recently, HAV6 has been shown to effectively deliver adenathin, an anticancer agent, into the brain to suppress medulloblastoma brain tumor in mice . In addition, HAV6 also significantly enhanced oral and brain delivery of eflornithine, an efflux pump substrate, in rats . These data support the idea that modulation of cadherin-mediated cell–cell adhesion in the intercellular junction can improve drug delivery across the biological barriers (i.e., intestinal mucosa barrier and BBB).…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Brain Delivery and Brain Deposition of Proteins with Various Sizes

2019

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It is very challenging to develop protein drugs for the treatment of brain diseases; this is due to the difficulty in delivering them into the brain because of the blood-brain barrier (BBB). Thus, alternative delivery methods need further exploration for brain delivery of proteins to diagnose and treat brain diseases. Previously, ADTC5 and HAV6 peptides have been shown to enhance the in vivo brain delivery of small-and medium-size molecules across the BBB. This study was carried out to evaluate ability of ADTC5 and HAV6 peptides to enhance delivery of proteins of various sizes, such as 15 kDa lysozyme, 65 kDa albumin, 150 kDa IgG mAb, and 220 kDa fibronectin, into the brains of C57BL/6 mice. Each protein was labeled with IRdye800CW, and a quantitative method using near IR fluorescence (NIRF) imaging was developed to determine the amount of protein delivered into the brain. ADTC5 peptide significantly enhanced brain delivery of lysozyme, albumin, and IgG mAb but not fibronectin compared to controls. In contrast, HAV6 peptide significantly enhanced the brain delivery of lysozyme but not albumin and IgG mAb. Thus, there is a cut-off size of proteins that can be delivered by each peptide. The distribution of delivered protein in other organs such as liver, spleen, lung, kidney, and heart could be influenced by HAV6 and ADTC5. In summary, ADTC5 is a better BBB modulator than HAV6 in delivering various sizes of proteins into the brain, and the size of the protein affects its brain delivery.

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Section: ■ Introductionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

In Vivo Brain Delivery and Brain Deposition of Proteins with Various Sizes

2019

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“…Treatments with a combination adenanthin and HAV6 increased survival and suppressed tumor growth compared to treatments with adenanthin alone or placebo [24]. Similarly, oral and brain deliveries of eflornithine in rats were simultaneously increased by HAV6 peptide [25].…”

Section: Introductionmentioning

confidence: 99%

Improving In Vivo Brain Delivery of Monoclonal Antibody Using Novel Cyclic Peptides

2019

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Many proteins can be used to treat brain diseases; however, the presence of the blood–brain barrier (BBB) creates an obstacle to delivering them into the brain. Previously, various molecules were delivered through the paracellular pathway of the BBB via its modulation, using ADTC5 and HAV6 peptides. This study goal was to design new cyclic peptides with N-to-C terminal cyclization for better plasma stability and modulation of the BBB. Cyclic HAVN1 and HAVN2 peptides were derived from a linear HAV6 peptide. Linear and N-to-C terminal cyclic ADTHAV peptides were designed by combining the sequences of ADTC5 and HAV6. These novel cyclic peptides were used to deliver an IRdye800CW-labeled IgG monoclonal antibody into the brain. Cyclic HAVN1 and HAVN2 peptides deliver IgG into the brain, while the parent linear HAV6 peptide does not. Cyclic and linear ADTHAV and ADTC5 peptides enhanced brain delivery of IgG mAb, in which cyclic ADTHAV peptide was better than linear ADTHAV (p = 0.07). Cyclic ADTHAV and ADTC5 influenced the distribution of IgG mAb in other organs while HAV6, HAVN1 and HAVN2 did not. In summary, the novel cyclic peptides are generally better BBB modulators than their linear counterparts for delivering IgG mAb into the brain.

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“…In 2019, one of those peptides was used to down-regulate claudin-1 at the BBB long-term after stroke as that particular claudin causes barrier instability [64]. Similarly, Yang et al [173] have used a peptide targeting E-cadherin to enhance brain uptake of eflornithine, a drug used to treat trypanosomiasis.…”

Section: Drug Deliverymentioning

confidence: 99%

This was the year that was: brain barriers and brain fluid research in 2019

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Jones²,

Drewes

2020

Fluids Barriers CNS

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This editorial highlights advances in brain barrier and brain fluid research published in 2019, as well as addressing current controversies and pressing needs. Topics include recent advances related to: the cerebral endothelium and the neurovascular unit; the choroid plexus, arachnoid membrane; cerebrospinal fluid and the glymphatic hypothesis; the impact of disease states on brain barriers and brain fluids; drug delivery to the brain; and translation of preclinical data to the clinic. This editorial also mourns the loss of two important figures in the field, Malcolm B. Segal and Edward G. Stopa.

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Improving Eflornithine Oral Bioavailability and Brain Uptake by Modulating Intercellular Junctions With an E-cadherin Peptide

Cited by 8 publications

References 30 publications

In Vivo Brain Delivery and Brain Deposition of Proteins with Various Sizes

In Vivo Brain Delivery and Brain Deposition of Proteins with Various Sizes

Improving In Vivo Brain Delivery of Monoclonal Antibody Using Novel Cyclic Peptides

This was the year that was: brain barriers and brain fluid research in 2019

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