Activatable cell-penetrating peptides: 15 years of research

Jong, Heleen de; Bonger, Kimberly M.; Löwik, Dennis W. P. M.

doi:10.1039/d0cb00114g

Cited by 43 publications

(55 citation statements)

References 93 publications

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“…The adsorption of CPPs onto cell membranes by electrostatic interactions is the first and crucial step in the process of translocation. Controlling this electrostatic adsorption and activating the CPPs at the target site is a common and effective approach to designing cancer‐targeted CPPs 16 . The low pH in the tumor microenvironment compared with normal tissues provides a great opportunity to develop acid‐responsive drug delivery systems 32,33 .…”

Section: Resultsmentioning

confidence: 99%

“…Recently, cell‐penetrating peptides (CPPs) have received increasing attention as efficient carriers for the intracellular delivery of various types of cargoes, such as small‐molecule drugs, biomolecule and nanoparticles 5,12,13 . To further enhance their clinical application, cancer‐targeted CPPs have been developed leveraging the differences between normal and cancer tissues 5,13–16 . The acidic extracellular microenvironment, a notable hallmark in solid tumors, has been widely utilized to design pH‐responsive CPPs for the precise diagnosis and effective treatment of tumors 12,13,16,17 .…”

Section: Introductionmentioning

confidence: 99%

“…To further enhance their clinical application, cancer‐targeted CPPs have been developed leveraging the differences between normal and cancer tissues 5,13–16 . The acidic extracellular microenvironment, a notable hallmark in solid tumors, has been widely utilized to design pH‐responsive CPPs for the precise diagnosis and effective treatment of tumors 12,13,16,17 . Histidine, a unique amino acid, contains an imidazole group with a pK a of approximately 6.0.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Targeted CPPs may have multiple applications. For instance, these peptides may be used to target drug action into specific cell types in cell cultures [ 35 , 36 ] or in animals [ 10 , 37 ]. Multiple studies aimed at studying cell physiology would benefit from having access to such peptides; for instance studies on yeast mating [ 38 ] or neuroscience [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Selective Moonlighting Cell-Penetrating Peptides

et al. 2021

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Cell penetrating peptides (CPPs) are molecules capable of passing through biological membranes. This capacity has been used to deliver impermeable molecules into cells, such as drugs and DNA probes, among others. However, the internalization of these peptides lacks specificity: CPPs internalize indistinctly on different cell types. Two major approaches have been described to address this problem: I) targeting, in which a receptor-recognizing sequence is added to a CPP, and ii) activation, where a non-active form of the CPP is activated once it interacts with cell target components. These strategies result in multifunctional peptides (i.e., penetrate and target recognition) that increase the CPP’s length, the cost of synthesis and the likelihood to be degraded or become antigenic. In this work we describe the use of machine-learning methods to design short selective CPP; the reduction in size is accomplished by embedding two or more activities within a single CPP domain, hence we referred to these as moonlighting CPPs. We provide experimental evidence that these designed moonlighting peptides penetrate selectively in targeted cells and discuss areas of opportunity to improve in the design of these peptides.

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“…This formulation facilitated the BBB penetration to reach specific cancer cells and increased the survival rate of glioma-bearing animal models [ 149 ]. Two years later, the same group used BBB-penetrating and the activatable cell-penetrating peptide (ACPP) angiopep-2 for the delivery of DTX in glioma-bearing mouse models [ 150 ]. For the construction of the ACPP, a matrix metalloproteinase-2 (MMP-2)-sensitive linker was utilized for the conjugation of EEEEEEEE to R8.…”

Section: Delivery Of Chemotherapeuticsmentioning

confidence: 99%

Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade

et al. 2021

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Cell-penetrating peptides (CPPs), also known as protein transduction domains, are a class of diverse amino acid sequences with the ability to cross cellular membranes. CPPs can deliver several bioactive cargos, including proteins, peptides, nucleic acids and chemotherapeutics, into cells. Ever since their discovery, synthetic and natural CPPs have been utilized in therapeutics delivery, gene editing and cell imaging in fundamental research and clinical experiments. Over the years, CPPs have gained significant attention due to their low cytotoxicity and high transduction efficacy. In the last decade, multiple investigations demonstrated the potential of CPPs as carriers for the delivery of therapeutics to treat various types of cancer. Besides their remarkable efficacy owing to fast and efficient delivery, a crucial benefit of CPP-based cancer treatments is delivering anticancer agents selectively, rather than mediating toxicities toward normal tissues. To obtain a higher therapeutic index and to improve cell and tissue selectivity, CPP-cargo constructions can also be complexed with other agents such as nanocarriers and liposomes to obtain encouraging outcomes. This review summarizes various types of CPPs conjugated to anticancer cargos. Furthermore, we present a brief history of CPP utilization as delivery systems for anticancer agents in the last decade and evaluate several reports on the applications of CPPs in basic research and preclinical studies.

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Activatable cell-penetrating peptides: 15 years of research

Abstract: Since the first report on activatable CPPs (ACPPs) in 2004, various methods of activation have been developed. Here, we provide an overview of the different ACPP strategies known to date and summarize the benefits, drawbacks, and future directions.

Cited by 43 publications

References 93 publications

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

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

Selective Moonlighting Cell-Penetrating Peptides

Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade

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