An effective cell-penetrating antibody delivery platform

Herrmann, Andreas; Nagao, Takaaki; Lahtz, Christoph; Li, Yijia; Yue, Chanyu; Mülfarth, Ronja; Yu, Hua

doi:10.1172/jci.insight.127474

Cited by 22 publications

(21 citation statements)

References 47 publications

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“…Further, we created an acetylated STAT3 peptide by adding an acetyl group to K685 (acet.-STAT3 peptide) ( Supplemental Figure 1 ; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.136176DS1 ), which is expected to specifically interfere with its protein-protein interaction with exportin 7 and dimerization of acetylated STAT3, leading to subsequently inhibition of STAT3 activation (phosphorylation at Y705). Based our previous results showing that conjugating phosphorothioated (PS) DNA oligonucleotides to antibodies enables their cell penetration ( 36 ), we tested whether the same modification can allow effective peptide cell penetration, target binding, and regulation. The acet.-STAT3 peptide was conjugated to either PS-polymer backbone or polymer backbone without phosphorothioated (PO), using a carbon chain linker ( Supplemental Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Our prior work using the same modification to enable the highly efficient cell penetration of antibody suggests that depolarization of cell membrane contributes to antibody cell entry ( 36 ). To test whether alteration in membrane potential also plays a role in internalization of PS-acet.-STAT3 peptide, we induced membrane depolarization with potassium chloride (KCl) in HCT116 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Our prior work with the cell-penetrating antibody suggested a requirement of intracellular target for the retention of PS antibodies ( 36 ). We therefore addressed whether the accumulation of PS-acet.-STAT3 peptide in cells requires intracellular acetylated STAT3.…”

Section: Resultsmentioning

confidence: 99%

“…In the current study, we sought to create an acetylated STAT3 inhibitor to disrupt STAT3 dimerization and activation while overcoming peptide cell penetrability and stability issues. We have also tested cell-penetrating Gp130 and c-Myc peptides, one of which is critical for STAT3 activation and the other a STAT3 downstream effector, by using our newly developed cell-penetrating antibody in vivo delivery platform ( 36 ).…”

Section: Introductionmentioning

confidence: 99%

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Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis

Aftabizadeh¹,

Li²,

Zhao

et al. 2021

JCI Insight

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To date, there are no inhibitors that directly and specifically target activated STAT3 and c-Myc in the clinic. Although peptide-based inhibitors can selectively block activated targets, their clinical usage is limited because of low cell penetration and/or serum stability. Here, we generated cell-penetrating acetylated (acet.) STAT3, c-Myc, and Gp130 targeting peptides by attaching phosphorothioated (PS) polymer backbone to peptides. The cell-penetrating peptides efficiently penetrated cells and inhibited activation of the intended targets and their downstream genes. Locally or systemically treating tumor-bearing mice with PS-acet.-STAT3 peptide at low concentrations effectively blocked STAT3 in vivo, resulting in significant antitumor effects in 2 human xenograft models. Moreover, PS-acet.-STAT3 peptide penetrated and activated splenic CD8 + T cells in vitro. Treating immune-competent mice bearing mouse melanoma with PS-acet.-STAT3 peptide inhibited STAT3 in tumor-infiltrating T cells, downregulating tumor-infiltrating CD4 + T regulatory cells while activating CD8 + T effector cells. Similarly, systemic injections of the cell-penetrating c-Myc and Gp130 peptides prevented pancreatic tumor growth and induced antitumor immune responses. Taken together, we have developed therapeutic peptides that effectively and specifically block challenging cancer targets, resulting in antitumor effects through both direct tumor cell killing and indirectly through antitumor immune responses.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis

Aftabizadeh¹,

Li²,

Zhao

et al. 2021

JCI Insight

Self Cite

View full text Add to dashboard Cite

show abstract

“…Transferrin is also under investigation as a ligand to induce transcytosis across the blood brain barrier, thus enabling cerebral delivery of nanotherapeutics (Ulbrich et al, 2009;Wiley et al, 2013;Clark and Davis, 2015). Furthermore, interaction between complementary DNA strands on liposomes and target cells were shown to improve delivery of the nanoparticles (Li et al, 2019), and grafting single-stranded DNA to antibodies facilitated their intracellular delivery in a sequence-independent fashion (Herrmann et al, 2019).…”

Section: Targeting Nanocarriers To Cancer Cellsmentioning

confidence: 99%

Overcoming Physiological Barriers to Nanoparticle Delivery—Are We There Yet?

Thomas

Weber

2019

Front. Bioeng. Biotechnol.

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The exploitation of nanosized materials for the delivery of therapeutic agents is already a clinical reality and still holds unrealized potential for the treatment of a variety of diseases. This review discusses physiological barriers a nanocarrier must overcome in order to reach its target, with an emphasis on cancer nanomedicine. Stages of delivery include residence in the blood stream, passive accumulation by virtue of the enhanced permeability and retention effect, diffusion within the tumor lesion, cellular uptake, and arrival at the site of action. We also briefly outline strategies for engineering nanoparticles to more efficiently overcome these challenges: Increasing circulation half-life by shielding with hydrophilic polymers, such as PEG, the limitations of PEG and potential alternatives, targeting and controlled activation approaches. Future developments in these areas will allow us to harness the full potential of nanomedicine.

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ACE2 Receptor‐Targeted Inhaled Nanoemulsions Inhibit SARS‐CoV‐2 and Attenuate Inflammatory Responses

Wang,

Luo,

Xie

et al. 2024

Advanced Materials

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Three kinds of coronaviruses are highly pathogenic to humans, and two of them mainly infect humans through Angiotensin‐converting enzyme 2 （ACE2）receptors. Therefore, specifically blocking ACE2 binding at the interface with the receptor‐binding domain is promising to achieve both preventive and therapeutic effects of coronaviruses. Alternatively, drug‐targeted delivery based on ACE2 receptors can further improve the efficacy and safety of inhalation drugs. Here, these two approaches are innovatively combined by designing a nanoemulsion (NE) drug delivery system (termed NE‐AYQ) for inhalation that targets binding to ACE2 receptors. This inhalation‐delivered remdesivir nanoemulsion (termed RDSV‐NE‐AYQ) effectively inhibits the infection of target cells by both wild‐type and mutant viruses. The RDSV‐NE‐AYQ strongly inhibits Severe acute respiratory syndrome coronavirus 2 at two dimensions: they not only block the binding of the virus to host cells at the cell surface but also restrict virus replication intracellularly. Furthermore, in the mouse model of acute lung injury, the inhaled drug delivery system loaded with anti‐inflammatory drugs (TPCA‐1‐NE‐AYQ) can significantly alleviate the lung tissue injury of mice. This smart combination provides a new choice for dealing with possible emergencies in the future and for the rapid development of inhaled drugs for the treatment of respiratory diseases.

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An effective cell-penetrating antibody delivery platform

Cited by 22 publications

References 47 publications

Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis

Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis

Overcoming Physiological Barriers to Nanoparticle Delivery—Are We There Yet?

ACE2 Receptor‐Targeted Inhaled Nanoemulsions Inhibit SARS‐CoV‐2 and Attenuate Inflammatory Responses

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