Design of a new pH‐activatable cell‐penetrating peptide for drug delivery into tumor cells

Zhang, Yun; Li, Li; Chang, Ling‐Sai; Liu, Hui; Song, Jingjing; Liu, Yue; Bao, Hexin; Liu, Beijun; Wang, Rui; Ni, Jingman

doi:10.1111/cbdd.13537

Cited by 18 publications

(11 citation statements)

References 33 publications

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“…The use of well-characterized ligands, like nanobodies, provides an excellent opportunity to compare more than one conjugate to an established “model” (e.g., the unconjugated nanobody). Advances like activatable CPPs could be useful in avoiding off-target accumulation [ 54 , 55 , 56 ], but will need to be evaluated as conjugates in the in vivo setting. In conclusion, CPPs can modify the interactions of targeting ligands with organs and tissues, while maintaining fast clearance.…”

Section: Discussionmentioning

confidence: 99%

CPPs to the Test: Effects on Binding, Uptake and Biodistribution of a Tumor Targeting Nanobody

et al. 2021

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Nanobodies are well-established targeting ligands for molecular imaging and therapy. Their short circulation time enables early imaging and reduces systemic radiation exposure. However, shorter circulation time leads to lower tracer accumulation in the target tissue. Cell-penetrating peptides (CPPs) improve cellular uptake of various cargoes, including nanobodies. CPPs could enhance tissue retention without compromising rapid clearance. However, systematic investigations on how the functionalities of nanobody and CPP combine with each other at the level of 2D and 3D cell cultures and in vivo are lacking. Here, we demonstrate that conjugates of the epidermal growth factor receptor (EGFR)-binding nanobody 7D12 with different CPPs (nonaarginine, penetratin, Tat and hLF) differ with respect to cell binding and induction of endocytosis. For nonaarginine and penetratin we compared the competition of EGF binding and performance of L- and D-peptide stereoisomers, and tested the D-peptide conjugates in tumor cell spheroids and in vivo. The D-peptide conjugates showed better penetration into spheroids than the unconjugated 7D12. Both in vivo and in vitro, the behavior of the agent reflects the combination of both functionalities. Although CPPs cause promising increases in in vitro uptake and 3D penetration, the dominant effect of the CPP in the control of biodistribution warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

CPPs to the Test: Effects on Binding, Uptake and Biodistribution of a Tumor Targeting Nanobody

et al. 2021

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“…The Transportan10 (TP10) based histidine containing pH-sensitive peptides has been developed by other groups. [21][22][23] When choosing the strategy for modifying the TP10 derived third generation peptide NF55, we tested both C-terminal and N-terminal modifications. In our case, the histidine modifications in the C-terminal part of NF55 led to a decrease in the delivery efficiency (ESI Fig.…”

Section: Design Of Ph-sensitive Histidine Containing Nickfect Peptidesmentioning

confidence: 99%

Enhancement of siRNA transfection by the optimization of fatty acid length and histidine content in the CPP

et al. 2019

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Extracellular synthetic nucleic acids, such as siRNAs, are unable to reach their intended targets efficiently.Therefore, delivery methods such as cell-penetrating peptides (CPP), which increase their transport, could enhance the potency of siRNA as therapeutic agents. The CPP NickFect55 (NF55) is an efficient peptide-based delivery vector, which has been previously used to deliver plasmid DNA into cells in vivo.To achieve higher intracellular delivery and bioactivity from the delivered cargo, we designed a series of histidine-containing peptides by optimizing pH-sensitivity, net charge, hydrophobicity, and charge distribution in the sequence of the CPP NF55. In the current work, we have applied a strategy where we have replaced amino acids in the C-terminus of the peptide in order to distribute hydrophobic and hydrophilic amino acids into distinct regions along the alpha-helical projection, including histidine amino acids into the sequence at the N-terminus, and optimizing the N-terminal fatty acid modification to suit the specific peptide sequence. We tested the CPPs based on the transfection efficacy, CPP/siRNA complex stability, and the properties of the CPPs, such as hemolytic activity, buffering capability and cell toxicity. As a result, we have introduced a new peptide with a completely redesigned N-terminus that displays adaptive response to its physical environment. This peptide -NickFect70 (NF70)efficiently condenses siRNA, protects the cargo against degradation and effectively mediates target gene knockdown both in mammalian cell culture and in vivo, in a mouse model. Fig. 4 Membrane activity of nickfect peptides. Hemolytic activity of peptides was measured after 1 h-incubation of murine red blood cells with peptide solutions at 37°C. After incubation released hemoglobin was quantified in the supernatant by measuring absorbance at 540 nm. (a) Cells in PBS pH 7.5 supplemented with 5% glucose at 37°C. as controls RBC in 2× PBS treated with 0.1% Triton X-100 with 5% glucose (100% hemolysis) and mQ with 5% glucose (0% hemolysis) were used. (b) Modeling of endosomolytic activity of CPPs using buffer solutions with different pH. Peptides were used at 0.75 µm concentrations. Hemolytic activity was assessed in PBS buffer at pH 5.5-7.5.

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“…The low pH in the tumor microenvironment compared with normal tissues provides a great opportunity to develop acid‐responsive drug delivery systems 32,33 . Due to the histidine residues being protonated only under low pH conditions, histidine has always been used to construct acid‐activated CPPs or membrane‐lytic peptides 18,34–36 . In addition, increasing the number of histidine residues in CPPs was reported to enhance their cell‐penetrating activity 34,37 .…”

Section: Resultsmentioning

confidence: 99%

Design of acid‐activated cell‐penetrating peptides with nuclear localization capacity for anticancer drug delivery

Huang

Zhu

Jia

et al. 2021

Journal of Peptide Science

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Camptothecin (CPT), a DNA‐toxin drug, exerts anticancer activity by inhibiting topoisomerase I. Targeted delivery of CPT into the cancer cell nucleus is important for enhancing its therapeutic efficiency. In this study, a new type of acid‐activated cell‐penetrating peptide (CPP) with nuclear localization capacity was constructed by conjugating six histidine residues and a hydrophobic peptide sequence, PFVYLI, to the nuclear localization sequence (NLS). Our results indicated that HNLS‐3 displayed significant pH‐dependent cellular uptake efficiency, endosomal escape ability, and nuclear localization activity. More importantly, the HNLS‐3–CPT conjugate showed obviously enhanced cytotoxicity and selectivity compared with CPT. Taken together, our findings provide an effective approach to develop efficient CPPs with both cancer‐ and nucleus‐targeting properties.

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Design of a new pH‐activatable cell‐penetrating peptide for drug delivery into tumor cells

Cited by 18 publications

References 33 publications

CPPs to the Test: Effects on Binding, Uptake and Biodistribution of a Tumor Targeting Nanobody

CPPs to the Test: Effects on Binding, Uptake and Biodistribution of a Tumor Targeting Nanobody

Enhancement of siRNA transfection by the optimization of fatty acid length and histidine content in the CPP

Design of acid‐activated cell‐penetrating peptides with nuclear localization capacity for anticancer drug delivery

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