Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application

Xie, Jing; Bi, Ye; Zhang, Huan; Dong, Shiyan; Teng, Lesheng; Lee, Robert J.; Yang, Zhaogang

doi:10.3389/fphar.2020.00697

Cited by 351 publications

(344 citation statements)

References 177 publications

(208 reference statements)

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“…While PTDs have shown promise in pre-clinical efforts for transporting cargo across the cellular membrane, many PTDs have demonstrated immunogenic potential. 29 In line with these findings, DAXI was shown to induce detectable antibody titers to RTP004 within 3 months of use in 30% of tested monkeys, but no long-term immunogenicity data in humans is available at this time. 30,33 Limitations of our study include low sample size (n=30) in the 20U group for Stage 1, that results in limited power for statistical comparisons to the higher doses.…”

Section: Safetymentioning

confidence: 92%

“…23 By utilizing the only state-of-the-art manufacturing process that employs a 2-step chromatographic purification process to extract from the complexing proteins and leave just the active 150kDa molecule, INCO provides the lowest protein load available compared to other BoNT/A formulations. 1,[24][25][26][27][28][29] INCO contains 0.44ng 150kDa neurotoxin per 100U (0.088 ng/20U dose) and has a high specific activity of 227U/ng, consistent with no denaturing of the BoNT complex during the INCO chromatographic purification process. [24][25][26][27][28][29] In contrast, ONA, ABO, and PRA all contain complexing proteins and/or denatured BoNT protein that may initiate an immune response, leading to production of neutralizing antibodies that can be associated with decreased effect over time or treatment non-response.…”

Section: Safetymentioning

confidence: 99%

“…1,[24][25][26][27][28][29] INCO contains 0.44ng 150kDa neurotoxin per 100U (0.088 ng/20U dose) and has a high specific activity of 227U/ng, consistent with no denaturing of the BoNT complex during the INCO chromatographic purification process. [24][25][26][27][28][29] In contrast, ONA, ABO, and PRA all contain complexing proteins and/or denatured BoNT protein that may initiate an immune response, leading to production of neutralizing antibodies that can be associated with decreased effect over time or treatment non-response. 24,31 Investigational drug DaxibotulinumtoxinA (DAXI; RT002, Revance Therapeutics Inc.) contains a virally-derived protein transduction domain (PTD), as part of an added excipient and stabilizer (RTP004).…”

Section: Safetymentioning

confidence: 99%

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IncobotulinumtoxinA Demonstrates Safety and Prolonged Duration of Effect in a Dose-Ranging Study for Glabellar Lines

Kerscher¹,

Fabi²,

Fischer³

et al. 2020

JDD

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Background: Recently reported clinical data provides evidence that increasing the dose of botulinum toxin A increases the duration of efficacy. A 2-stage Phase 2, randomized, double-blind study investigated the duration of effect and safety of IncobotulinumtoxinA (INCO; Xeomin ® , Bocouture ® ; Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) at doses higher than the approved 20 units (U) for glabellar frown lines (GFL). Primary safety and efficacy endpoints of Stage 1 are reported here. Methods: 151 subjects with moderate-to-severe GFL were randomized 1:2:2 to receive a single treatment with 20U, 50U, or 75U INCO. The primary efficacy endpoint was median duration of at least 1-point improvement from baseline as assessed by investigator at maximum frown on the Facial Wrinkle Scale. Results: The median duration of effect was 185 days for the 50U dose group (95% CI:[182, 205]) and 210 days for the 75U dose group (95% CI:[182, 217]). Duration of effect was significantly longer for 75U vs 50U (P=0.0400) and 20U (P=0.0166) despite the study not being powered for confirmatory statistical significance testing between the dose groups. Duration of effect was also longer for 50U vs 20U, however; statistical significance was not reached (P=0.4349). The incidence of treatment-related adverse events was low across all doses (20U:2[6.7%], 50U:6[10.0%] and 75U:8[13.1%]). Conclusions: These results demonstrate a dose effect of at least 6 months duration with higher doses in the majority of GFL subjects. All doses were well tolerated and safety was consistent with the known safety profile of 20U INCO for GFL.

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Section: Safetymentioning

confidence: 92%

Section: Safetymentioning

confidence: 99%

Section: Safetymentioning

confidence: 99%

See 1 more Smart Citation

IncobotulinumtoxinA Demonstrates Safety and Prolonged Duration of Effect in a Dose-Ranging Study for Glabellar Lines

Kerscher¹,

Fabi²,

Fischer³

et al. 2020

JDD

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“…Closely related to antimicrobial peptides are, what have been termed, “cell-penetrating peptides” (CPPs) [ 36 , 37 ]. As previously noted, the difference in the functioning of antimicrobial peptides and cell-penetrating peptides may simply be a matter of the concentrations that are employed [ 38 ].…”

Section: Discovery Of a Membrane Rupture And Leakage Dichotomymentioning

confidence: 99%

Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming

Regen

2021

Molecules

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Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories involving membrane-disrupting agents. A major discovery that we made, using a Triton X-100 as a prototypical membrane-disrupting molecule and cholesterol-rich liposomes as model systems, was that membrane disruption can occur by two distinct processes, depending on the state of aggregation of the attacking agent. Specifically, we found that monomers induced leakage, while attack by aggregates resulted in a catastrophic rupture of the membrane. This discovery led us to design of a series of derivatives of the clinically important antifungal agent, Amphotericin B, where we demonstrated the feasibility of separating antifungal from hemolytic activity by decreasing the molecule’s tendency to aggregate, i.e., by controlling its monomer concentration. Using an entirely different approach (i.e., a “taming” strategy), we found that by covalently attaching one or more facial amphiphiles (“floats”) to Amphotericin B, its aggregate forms were much less active in lysing red blood cells while maintaining high antifungal activity. The possibility of applying such “monomer control” and “taming” strategies to other membrane-disrupting antimicrobial agents is briefly discussed.

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“…Other approaches use non-endocytic mechanisms to deliver cargo to cells such as through conjugation with cell penetrating peptides (CPPs), also termed protein transduction domains (PTDs); however, these mostly suffer from toxicity, unclear mechanistic understanding, and low efficiency [ 3 , 5 , 7 , 8 , 9 ]. Recent developments in the field have led to the design of less toxic and more stable cyclic CPPs, CPP prodrugs that can be programmed to release their cargo at specific tissue sites, as well as fusions with subcellular targeting moieties to achieve organelle targeting or with fusogenic peptides to achieve endosomal escape [ 10 ]. In fact, CPPs are under testing in several clinical trials where the cargo is conjugated to the CPP or generated as a chimeric fusion [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Intracellular Delivery of Active Proteins by Polyphosphazene Polymers

et al. 2021

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Achieving intracellular delivery of protein therapeutics within cells remains a significant challenge. Although custom formulations are available for some protein therapeutics, the development of non-toxic delivery systems that can incorporate a variety of active protein cargo and maintain their stability, is a topic of great relevance. This study utilized ionic polyphosphazenes (PZ) that can assemble into supramolecular complexes through non-covalent interactions with different types of protein cargo. We tested a PEGylated graft copolymer (PZ-PEG) and a pyrrolidone containing linear derivative (PZ-PYR) for their ability to intracellularly deliver FITC-avidin, a model protein. In endothelial cells, PZ-PYR/protein exhibited both faster internalization and higher uptake levels than PZ-PEG/protein, while in cancer cells both polymers achieved similar uptake levels over time, although the internalization rate was slower for PZ-PYR/protein. Uptake was mediated by endocytosis through multiple mechanisms, PZ-PEG/avidin colocalized more profusely with endo-lysosomes, and PZ-PYR/avidin achieved greater cytosolic delivery. Consequently, a PZ-PYR-delivered anti-F-actin antibody was able to bind to cytosolic actin filaments without needing cell permeabilization. Similarly, a cell-impermeable Bax-BH3 peptide known to induce apoptosis, decreased cell viability when complexed with PZ-PYR, demonstrating endo-lysosomal escape. These biodegradable PZs were non-toxic to cells and represent a promising platform for drug delivery of protein therapeutics.

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Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application

Cited by 351 publications

References 177 publications

IncobotulinumtoxinA Demonstrates Safety and Prolonged Duration of Effect in a Dose-Ranging Study for Glabellar Lines

IncobotulinumtoxinA Demonstrates Safety and Prolonged Duration of Effect in a Dose-Ranging Study for Glabellar Lines

Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming

Intracellular Delivery of Active Proteins by Polyphosphazene Polymers

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