Cell-penetrating peptides in protein mimicry and cancer therapeutics

Zorko, Matjaž; Jones, Sarah; Langel, Ülo

doi:10.1016/j.addr.2021.114044

Cited by 84 publications

(52 citation statements)

References 250 publications

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“…As explained in many review articles on CPPs, first, it was thought that CPPs can enter unselectively in all types of cells and all tissues. As drug delivery vehicles, it is desired for CPPs to be selective and to deliver cargo into specific types of cells or in specific organelles, particularly when they are designed to carry anticancer drugs into tumor cells (Zorko et al ., 2022). Here we present a design of CPPs targeting the cell nucleus and subnuclear region, as confirmed by confocal scanning system and flow cytometry (Gronewold et al ., 2016).…”

Section: Biophysical Methods and Cppsmentioning

confidence: 99%

“…CPPs are potent carriers of a variety of biological cargoes into different cell types and also promising drug delivery systems (Langel, 2019). In this respect, they were intensively studied, in the last years, particularly for introducing anticancer molecules into tumors (Zorko et al ., 2022). Dozens of peptide-based drugs have been approved for clinical use (Zhang and Eiden, 2019), but among them, CPPs could not be found.…”

Section: Introductionmentioning

confidence: 99%

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Studies of cell-penetrating peptides by biophysical methods

Zorko

Langel

2022

Quart. Rev. Biophys.

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Biophysical studies have a very high impact on the understanding of internalization, molecular mechanisms, interactions, and localization of CPPs and CPP/cargo conjugates in live cells or in vivo. Biophysical studies are often first carried out in test-tube set-ups or in vitro, leading to the complicated in vivo systems. This review describes recent studies of CPP internalization, mechanisms, and localization. The multiple methods in these studies reveal different novel and important aspects and define the rules for CPP mechanisms, hopefully leading to their improved applicability to novel and safe therapies.

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Section: Biophysical Methods and Cppsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Studies of cell-penetrating peptides by biophysical methods

Zorko

Langel

2022

Quart. Rev. Biophys.

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“…Furthermore, CPPs can cross membranes at low concentrations, both in vivo and in vitro, without significant membrane damage. More than 30 CPPs are in clinical trials, but only a few have entered Phase III [60].…”

Section: Cpp-decorated Anticancer Nvsmentioning

confidence: 99%

Peptides to Overcome the Limitations of Current Anticancer and Antimicrobial Nanotherapies

et al. 2022

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Biomedical research devotes a huge effort to the development of efficient non-viral nanovectors (NV) to improve the effectiveness of standard therapies. NVs should be stable, sustainable and biocompatible and enable controlled and targeted delivery of drugs. With the aim to foster the advancements of such devices, this review reports some recent results applicable to treat two types of pathologies, cancer and microbial infections, aiming to provide guidance in the overall design of personalized nanomedicines and highlight the key role played by peptides in this field. Additionally, future challenges and potential perspectives are illustrated, in the hope of accelerating the translational advances of nanomedicine

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“…Cell-penetrating peptides (CPPs), also called “Trojan Horse” peptides, are a class of positively-charged peptides, typically with a size of 5–30 amino acids, such as human immunodeficiency virus (HIV)-1 transactivator of transcription (Tat)-derived peptide and artificial oligoarginine peptides [ 4 ]. Due to their interaction with the negatively-charged plasma membrane, CPPs facilitate the cellular internalization of a variety of cargoes ( e.g., DNA, siRNA, nanoparticles) [ 11 , 12 ], thereby dramatically increasing their in vitro delivery efficiency. However, the lack of specificity for particular cells or tissues, severely hinders the extensive application of CPPs in the systemic delivery of cargoes in vivo [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy

et al. 2022

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Background Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect. However, the elevated tumor interstitial fluid pressure and efficient cytoplasmic release are still two significant obstacles to siRNA delivery. Co-delivery of chemotherapeutic drugs and siRNA represents a potential strategy which may achieve synergistic anticancer effect. Herein, we designed and synthesized a dual pH-responsive peptide (DPRP), which includes three units, a cell-penetrating domain (polyarginine), a polyanionic shielding domain (ehG)n, and an imine linkage between them. Based on the DPRP surface modification, we developed a pH-responsive liposomal system for co-delivering polo-like kinase-1 (PLK-1) specific siRNA and anticancer agent docetaxel (DTX), D-Lsi/DTX, to synergistically exhibit anti-tumor effect. Results In contrast to the results at the physiological pH (7.4), D-Lsi/DTX lead to the enhanced penetration into tumor spheroid, the facilitated cellular uptake, the promoted escape from endosomes/lysosomes, the improved distribution into cytoplasm, and the increased cellular apoptosis under mildly acidic condition (pH 6.5). Moreover, both in vitro and in vivo study indicated that D-Lsi/DTX had a therapeutic advantage over other control liposomes. We provided clear evidence that liposomal system co-delivering siPLK-1 and DTX could significantly downregulate expression of PLK-1 and inhibit tumor growth without detectable toxic side effect, compared with siPLK-1-loaded liposomes, DTX-loaded liposomes, and the combinatorial administration. Conclusion These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment. Graphical Abstract

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Cell-penetrating peptides in protein mimicry and cancer therapeutics

Cited by 84 publications

References 250 publications

Studies of cell-penetrating peptides by biophysical methods

Studies of cell-penetrating peptides by biophysical methods

Peptides to Overcome the Limitations of Current Anticancer and Antimicrobial Nanotherapies

Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy

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