Discovery of novel cell-penetrating and tumor-targeting peptide-drug conjugate (PDC) for programmable delivery of paclitaxel and cancer treatment

Deng, Xin; Mai, Ruiyao; Zhang, Chenyu; Yu, Dianbao; Ren, Yichang; Li, Gang; Cheng, Binbin; Li, Ling; Yu, Zhiqiang; Chen, Jianjun

doi:10.1016/j.ejmech.2020.113050

Cited by 41 publications

(27 citation statements)

References 48 publications

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“…24,25 Peptide-based conjugates possess better biocompatibility, degradability and more convenient preparation processes. [26][27][28] The conjugated D-gal-FFYEE-hyd-DOX designed in this paper is biodegradable and will not cause unnecessary immunogenic reactions. 29,30 Meanwhile, the nanofibers formed by the conjugates sustained stable nanostructures in the water, which could decompose by the stimulation of the specific TME, and release the active drug.…”

Section: Discussionmentioning

confidence: 99%

An Acid-Sensitive Nanofiber Conjugate Based on a Short Aromatic Peptide for Targeted Delivery of Doxorubicin in Liver Cancer

Ju¹,

Guo²,

Xuan³

et al. 2022

IJN

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This study aimed to construct a DOX conjugate with liver tumor targeting and acid sensitivity based on a short aromatic peptide FFYEE, which could amplify the tumor inhibition efficacy of DOX and alleviate tissue toxicity. Methods: A novel DOX-peptide conjugate, D-gal-FFYEE-hyd-DOX, was constructed by linking DOX to the side chain of FFYEE with acid-sensitive hydrazone bond and by modifying the C-terminal of peptide with α-D-galactosamine (D-gal) as targeting ligand. The structure of D-gal-FFYEE-hyd-DOX was characterized by mass spectrometry, infrared spectroscopy (IR), and UV-Vis spectroscopy (UV-Vis). The assembly characteristics of pentapeptide FFYEE and D-gal-FFYEE-hyd-DOX were observed by transmission electron microscope (TEM). In vitro drug release, cytotoxicity, endocytosis, in vivo antitumor experiment and histopathology analysis were investigated. Results: Peptide FFYEE endowed the D-gal-FFYEE-hyd-DOX with self-assembly performance and improved biocompatibility. D-gal-FFYEE-hyd-DOX can self-assemble into nanofibers with a diameter of ~40 nm in neutral aqueous solution and significantly reduced the cytotoxicity of free DOX to L02 cells. In vitro drug release results showed that D-gal-FFYEE-hyd-DOX had acid sensitivity and controlled release characteristics. The cytotoxicity and endocytosis investigations confirmed that D-gal-FFYEE-hyd-DOX enhanced the cellular uptake of DOX and inhibition effect on HepG2 cells. In vivo antitumor experiment indicated that D-gal-FFYEE-hyd-DOX could significantly inhibit the growth of liver tumor in mice and reduce the side effects of DOX. Conclusion:The conjugate D-gal-FFYEE-hyd-DOX with liver tumor targeting and acid sensitivity has the characteristics of strong tumor inhibition and low toxicity, hinting the great clinical application potential for targeted delivery of DOX in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

An Acid-Sensitive Nanofiber Conjugate Based on a Short Aromatic Peptide for Targeted Delivery of Doxorubicin in Liver Cancer

Ju¹,

Guo²,

Xuan³

et al. 2022

IJN

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“…The exact mechanism by which CPP enters the cell is still unclear [ 22 , 70 ]. Although CPP has been proven to be non-toxic under effective penetrating concentration (generally less than 50 μM) [ 54 , 71 – 74 ] at the cellular and animal levels, the effect of CPP on cell function has not been fully evaluated yet. The unclear penetration mechanism will also bring technical barriers to subsequent experiments, such as how to improve penetration efficiency, how to achieve unidirectional transmembrane transport, how to improve stability in the body, and so on.…”

Section: Cpps In Current Clinical Studymentioning

confidence: 99%

“…This limitation impeded many clinical or preclinical studies that require drug delivery to the target site in order to avoid causing systemic damage. In view of this defect of CPPs in drug delivery, there have been studies to correct it by adding tumor-targeted amino acid sequences [ 71 ]. However, there are few specific recognition sites for tumor markers (such as Transferrin, RGD, Lys(3)-bombesin, and NGR) [ 75 , 76 ], and many kinds of tumor sites need more recognition sequences to be discovered.…”

Section: Cpps In Current Clinical Studymentioning

confidence: 99%

“…Traditional CPPs are mostly straight-chain amino acids without steric structure, corresponding to proteolytic instability [ 78 ]. In animal experiments, CPPs had a short plasma half-life [ 21 , 71 ], which became a major drawback in clinical application. However, CPP may be metabolized before being delivered to the target site.…”

Section: Cpps In Current Clinical Studymentioning

confidence: 99%

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Prospect of cell penetrating peptides in stem cell tracking

Zhang

Tong

2021

Stem Cell Res Ther

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Stem cell therapy has shown great efficacy in many diseases. However, the treatment mechanism is still unclear, which is a big obstacle for promoting clinical research. Therefore, it is particularly important to track transplanted stem cells in vivo, find out the distribution and condition of the stem cells, and furthermore reveal the treatment mechanism. Many tracking methods have been developed, including magnetic resonance imaging (MRI), fluorescence imaging, and ultrasound imaging (UI). Among them, MRI and UI techniques have been used in clinical. In stem cell tracking, a major drawback of these technologies is that the imaging signal is not strong enough, mainly due to the low cell penetration efficiency of imaging particles. Cell penetrating peptides (CPPs) have been widely used for cargo delivery due to its high efficacy, good safety properties, and wide delivery of various cargoes. However, there are few reports on the application of CPPs in current stem cell tracking methods. In this review, we systematically introduced the mechanism of CPPs into cell membranes and their advantages in stem cell tracking, discussed the clinical applications and limitations of CPPs, and finally we summarized several commonly used CPPs and their specific applications in stem cell tracking. Although it is not an innovation of tracer materials, CPPs as a powerful tool have broad prospects in stem cell tracking. Graphic abstract

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“…Peptide–drug conjugates (PDCs) are special drug delivery system which comprises a therapeutic peptide, a small molecule drug and a linker. Compared with single drug loaded drug delivery system, PDCs can enhance anti-tumor effect, reduce drug resistance and modified with virous linkers (Deng et al., 2021 ; Zhu et al., 2021 ). Therefore, constructing PTX/PTP-7 co-loaded polymeric nanoparticles could be a creative strategy which can overcome the above shortcomings.…”

Section: Introductionmentioning

confidence: 99%

Legumain/pH dual-responsive lytic peptide–paclitaxel conjugate for synergistic cancer therapy

et al. 2022

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After molecule targeted drug, monoclonal antibody and antibody–drug conjugates (ADCs), peptide–drug conjugates (PDCs) have become the next generation targeted anti-tumor drugs due to its properties of low molecule weight, efficient cell penetration, low immunogenicity, good pharmacokinetic and large-scale synthesis by solid phase synthesis. Herein, we present a lytic peptide PTP7-drug paclitaxel conjugate assembling nanoparticles (named PPP) that can sequentially respond to dual stimuli in the tumor microenvironment, which was designed for passive tumor-targeted delivery and on-demand release of a tumor lytic peptide (PTP-7) as well as a chemotherapeutic agent of paclitaxel (PTX). To achieve this, tumor lytic peptide PTP-7 was connected with polyethylene glycol by a peptide substrate of legumain to serve as hydrophobic segments of nanoparticles to protect the peptide from enzymatic degradation. After that, PTX was connected to the amino group of the polypeptide side chain through an acid-responsive chemical bond (2-propionic-3-methylmaleic anhydride, CDM). Therefore, the nanoparticle (PPP) collapsed when it encountered the weakly acidic tumor microenvironment where PTX molecules fell off, and further triggered the cleavage of the peptide substrate by legumain that is highly expressed in tumor stroma and tumor cell surface. Moreover, PPP presents improved stability, improved drug solubility, prolonged blood circulation and significant inhibition ability on tumor growth, which gives a reasonable strategy to accurately deliver small molecule drugs and active peptides simultaneously to tumor sites.

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Discovery of novel cell-penetrating and tumor-targeting peptide-drug conjugate (PDC) for programmable delivery of paclitaxel and cancer treatment

Cited by 41 publications

References 48 publications

An Acid-Sensitive Nanofiber Conjugate Based on a Short Aromatic Peptide for Targeted Delivery of Doxorubicin in Liver Cancer

An Acid-Sensitive Nanofiber Conjugate Based on a Short Aromatic Peptide for Targeted Delivery of Doxorubicin in Liver Cancer

Prospect of cell penetrating peptides in stem cell tracking

Legumain/pH dual-responsive lytic peptide–paclitaxel conjugate for synergistic cancer therapy

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