Design and application of hybrid cyclic-linear peptide-doxorubicin conjugates as a strategy to overcome doxorubicin resistance and toxicity

Mozaffari, Saghar; Salehi, David; Mahdipoor, Parvin; Beuttler, Richard; Tiwari, Rakesh; Aliabadi, Hamidreza Montazeri; Parang, Keykavous

doi:10.1016/j.ejmech.2021.113836

Cited by 15 publications

(24 citation statements)

References 64 publications

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“…The activity of synthesized conjugate (1, 5, and 10 μM) was evaluated in a comparative study with the noncovalent physical mixture of [WR] 9 (1, 5, and 10 μM) + Dox (5 μM) and Dox alone (5 μM). We have previously reported the synthesis and evaluation of hybrid cyclic linear [R 5 K]W 7 A-Dox conjugate in different cancer cell lines [ 29 ]. The rationale for designing [(WR) 8 WKβA]-Dox conjugate was based on the fact that we found cyclic peptide [WR] 9 composed of alternate R and W was a more potent kinase inhibitor than [WR] 5 and [R 5 K]W 7 against c-Src, Abl, PKCa, Braf, Cdk2/cyclin A1, and that Lck [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

“…[WR] 9 was a superior molecular transporter versus [WR] 5 [ 27 ]. We hypothesized that a Dox conjugate of [(WR) 8 WKβA], a derivative of [WR] 9 , with a large cyclic ring of alternate R and W residues would have a higher antiproliferative activity than [R 5 K]W 7 A-Dox [ 29 ] and [W(RW) 4 ]-Dox [ 23 ], as Dox conjugates of [R 5 K]W 7 and [WR] 5 , respectively.…”

Section: Resultsmentioning

confidence: 99%

“…[(WR) 8 WKβA]-Dox conjugate was able to reduce the SK-OV-3 cell viability by 65%, 59%, and 56% at 10, 5, and 1 µM, respectively, after 72 h compared to Dox, which reduced the viability by 35% at 5 µM after 72 h incubation. Previously in this cell line at 72 h incubation, the cyclic [W(RW) 4 ]−Dox inhibited the cell proliferation by 51% at a concentration of 1 μM [ 23 ], whereas [R 5 K]W 7 A-Dox was able to reduce the cell viability by 29, 39, and 48% at 5, 10, and 25 μM, respectively [ 29 ]. A similar pattern was observed when the physical mixture of [WR] 9 and Dox was used.…”

Section: Resultsmentioning

confidence: 99%

“…At 24 h, the conjugate showed a significant reduction in cell viability by 39, 50, and 64% at 10, 5, and 1 µM, respectively, as shown in Figure 1 D. The antiproliferative activity for [(WR) 8 WKβA]-Dox conjugate was significantly increased after 72 h, with only 8, 8, and 15% Dox-resistant cell survival at 10, 5, and 1 µM, respectively, compared to 85% for control Dox alone. Previously, it was found that [R 5 K]W 7 A-Dox conjugate exhibited minimal cytotoxicity (0–10%) after 72 h at 5 and 10 μM, whereas it was found to significantly reduce the cell viability by almost 80% at 25 μM [ 29 ]. In addition, [WR] 9 + Dox mixture demonstrated significantly higher antiproliferative activity than Dox at 24 and 72 h. However, the activities of the physical mixtures were less than [(WR) 8 WKβA]-Dox conjugate.…”

Section: Resultsmentioning

confidence: 99%

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[(WR)8WKβA]-Doxorubicin Conjugate: A Delivery System to Overcome Multi-Drug Resistance against Doxorubicin

Zoghebi

Aliabadi

Tiwari

et al. 2022

Cells

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Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]9 containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)8WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the corresponding physical mixture of the peptide and Dox to evaluate the effectiveness of synthesized conjugate compared to the parent drug alone. [(WR)8WKβA]-Dox conjugate showed higher antiproliferative activity at 10 µM and 5 µM than Dox alone at 5 μM. The conjugate inhibited the cell viability of ovarian adenocarcinoma (SK-OV-3) by 59% and the triple-negative breast cancer cells MDA-MB-231 and MCF-7 by 71% and 77%, respectively, at a concentration of 5 μM after 72 h of incubation. In contrast, Dox inhibited the proliferation of SK-OV-3, MDA-MB-231, and MCF-7 by 35%, 63%, and 57%, respectively. Furthermore, [(WR)8WKβA]-Dox conjugate (5 µM) inhibited the cell viability of Dox-resistant cells (MES-SA/MX2) by 92%, while the viability of cells incubated with free Dox was only 15% at 5 μM. Confocal microscopy images confirmed the ability of both Dox conjugate and the physical mixture of the peptide with the drug to deliver Dox through an endocytosis-independent pathway, as the uptake was not inhibited in the presence of endocytosis inhibitors. The stability of Dox conjugate was observed at different time intervals using analytical HPLC when the conjugate was incubated with 25% human serum. Half-life (t1/2) for [(WR)8WKβA]-Dox conjugate was (∼6 h), and more than 80% of the conjugate was degraded at 12 h. The release of free Dox was assessed intracellularly using the CCRF-CEM cell line. The experiment demonstrated that approximately 100% of free Dox was released from the conjugate intracellularly within 72 h. These data confirm the ability of the cyclic cell-penetrating peptide containing tryptophan and arginine residues as an efficient tool for delivery of Dox and for overcoming resistance to it.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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[(WR)8WKβA]-Doxorubicin Conjugate: A Delivery System to Overcome Multi-Drug Resistance against Doxorubicin

Zoghebi

Aliabadi

Tiwari

et al. 2022

Cells

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“…A new class of cyclic CPPs containing alternating W and R residues ([WR] n ; n = 4, 5) was previously reported, demonstrating diverse applications in the noncovalent and covalent drug delivery [ 25 , 26 ], improving the cellular uptake of phosphopeptides [ 27 ] and oligonucleotides [ 28 ], generating peptide-capped gold nanoparticles (AuNPs) [ 29 ], silver and selenium nanoparticles [ 30 ], and acting as surfactants and protein stabilizers [ 31 ]. These peptides were used in conjugation with anticancer drugs such as doxorubicin [ 25 , 32 , 33 , 34 ], camptothecin [ 35 ], and curcumin [ 36 ]. These studies concluded that large cyclic peptides containing W and R residues [ 26 , 37 ] could be used as a molecular transporter of compounds.…”

Section: Introductionmentioning

confidence: 99%

Amphiphilic Cell-Penetrating Peptides Containing Natural and Unnatural Amino Acids as Drug Delivery Agents

Salehi

Mozaffari

Zoghebi

et al. 2022

Cells

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A series of cyclic peptides, [(DipR)(WR)4], [(DipR)2(WR)3], [(DipR)3(WR)2], [(DipR)4(WR)], and [DipR]5, and their linear counterparts containing arginine (R) as positively charged residues and tryptophan (W) or diphenylalanine (Dip) as hydrophobic residues, were synthesized and evaluated for their molecular transporter efficiency. The in vitro cytotoxicity of the synthesized peptides was determined in human epithelial ovary adenocarcinoma cells (SK-OV-3), human lymphoblast peripheral blood cells (CCRF-CEM), human embryonic epithelial kidney healthy cells (HEK-293), human epithelial mammary gland adenocarcinoma cells (MDA-MB-468), pig epithelial kidney normal cells (LLC-PK1), and human epithelial fibroblast uterine sarcoma cells (MES-SA). A concentration of 5–10 µM and 3 h incubation were selected in uptake studies. The cellular uptake of a fluorescent-labeled phosphopeptide, stavudine, lamivudine, emtricitabine, and siRNA was determined in the presence of peptides via flow cytometry. Among the peptides, [DipR]5 (10 µM) was found to be the most efficient transporter and significantly improved the uptake of F’-GpYEEI, i.e., by approximately 130-fold after 3 h incubation in CCRF-CEM cells. Confocal microscopy further confirmed the improved delivery of fluorescent-labeled [DipR]5 (F’-[K(DipR)5]) alone and F’-GpYEEI in the presence of [DipR]5 in MDA-MB-231 cells. The uptake of fluorescent-labeled siRNA (F’-siRNA) in the presence of [DipR]5 with N/P ratios of 10 and 20 was found to be 30- and 50-fold higher, respectively, compared with the cells exposed to F’-siRNA alone. The presence of endocytosis inhibitors, i.e., nystatin, chlorpromazine, chloroquine, and methyl β-cyclodextrin, did not completely inhibit the cellular uptake of F’-[K(DipR)5] alone or F’-GpYEEI in the presence of [DipR]5, suggesting that a combination of mechanisms contributes to uptake. Circular dichroism was utilized to determine the secondary structure, while transmission electron microscopy was used to evaluate the particle sizes and morphology of the peptides. The data suggest the remarkable membrane transporter property of [DipR]5 for improving the delivery of various small molecules and cell-impermeable negatively charged molecules (e.g., siRNA and phosphopeptide).

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Galangin alleviated Doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through GSTP1/JNK pathway

Shu,

Chen,

et al. 2024

Phytomedicine

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Design and application of hybrid cyclic-linear peptide-doxorubicin conjugates as a strategy to overcome doxorubicin resistance and toxicity

Cited by 15 publications

References 64 publications

[(WR)8WKβA]-Doxorubicin Conjugate: A Delivery System to Overcome Multi-Drug Resistance against Doxorubicin

[(WR)8WKβA]-Doxorubicin Conjugate: A Delivery System to Overcome Multi-Drug Resistance against Doxorubicin

Amphiphilic Cell-Penetrating Peptides Containing Natural and Unnatural Amino Acids as Drug Delivery Agents

Galangin alleviated Doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through GSTP1/JNK pathway

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