Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin: Evaluation of toxicity and transport mechanisms in the liver

Daga, Martina; Graaf, Inge A. M. de; Argenziano, Monica; Barranco, Ana Sofia Martinez; Loeck, M.; Al-Adwi, Yehya; Cucci, Marie Angèle; Caldera, Fabrizio; Trotta, Francesco; Barrera, Giuseppina; Casini, Angela; Cavalli, Roberta; Pizzimenti, Stefania

doi:10.1016/j.tiv.2020.104800

Cited by 41 publications

(28 citation statements)

References 46 publications

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“…The cellular uptake outcomes illustrated the Coumarin-6 were internalized into the cancer cells effectively, suggesting the uptake of Nisin too. Previous studies indicated that the nanosponges as drug carriers can effectively deliver the biological agents inside the cancer cells [ 33 , 55 ]. The results of MTT and LDH assay illustrated that the cell cytotoxicity and membrane damage in both HT-29 and MCF-7 cancer cells depended on concentration of free Nisin Z and encapsulated with NSs, in particular, Nisin loaded on PMDA-NSs showed better anti-cancer effect against colon (HT-29) cancer that was concordant with other studies outcomes that showed a significant reduction of cell viability in colon [ 56 ], melanoma [ 3 ], and MCF-7 [ 11 ] cancer cells when they were exposed to Nisin-Z, whereas in this study the Nisin Z cytotoxicity effect was remarkably enhanced in complexed with NSs against both cancer cells, which might be related to better entrance of nanosponges into the cells to release Nisin inside the cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Stabilization and Anticancer Enhancing Activity of the Peptide Nisin by Cyclodextrin-Based Nanosponges against Colon and Breast Cancer Cells

et al. 2022

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The great variability of cancer types demands novel drugs with broad spectrum, this is the case of Nisin, a polycyclic antibacterial peptide that recently has been considered for prevention of cancer cells growth. As an accepted food additive, this drug would be very useful for intestinal cancers, but the peptide nature would make easier its degradation by digestion procedures. For that reason, the aim of present study to investigate the protective effect of two different β-cyclodextrin-based nanosponges (carbonyl diimidazole and pyromellitic dianhydride) and their anti-cancer enhancement effect of Nisin-Z encapsulated with against colon cancer cells (HT-29). To extend its possible use, a comparison with breast (MCF-7) cancer cell was carried out. The physicochemical properties, loading efficiency, and release kinetics of Nisin complex with nanosponges were studied. Then, tricin-SDS-PAGE electrophoresis was used to understand the effect of NSs on stability of Nisin-Z in the presence of gastric peptidase pepsin. In addition, the cytotoxicity and cell membrane damage of Nisin Z were evaluated by using the MTT and LDH assay, which was complemented via Annexin-V/ Propidium Iodide (PI) by using flowcytometry. CD-NS are able to complex Nisin-Z with an encapsulation efficiency around 90%. A protective effect of Nisin-Z complexed with CD-NSs was observed in presence of pepsin. An increase in the percentage of apoptotic cells was observed when the cancer cells were exposed to Nisin Z complexed with nanosponges. Interestingly, Nisin Z free and loaded on PMDA/CDI-NSs is more selectively toxic towards HT-29 cells than MCF-7 cancer cells. These results indicated that nanosponges might be good candidates to protect peptides and deliver drugs against intestinal cancers.

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Section: Discussionmentioning

confidence: 99%

Stabilization and Anticancer Enhancing Activity of the Peptide Nisin by Cyclodextrin-Based Nanosponges against Colon and Breast Cancer Cells

et al. 2022

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“…Next to H&E stainings, mostly a Picrosirius Red (PiSR) staining or to a lesser extent, a DAB (3,3 -Diaminobenzidine) staining are performed. A few papers also make use of cryosections for immunofluorescence (IF) [56,57] or Oil Red O (ORO, lipid accumulation) stainings [22,58] and some studies do not even section the slices for the ORO staining [59,60]. Overall, only a few PCLS research papers (<10% of investigated papers) show immunostainings, with HSC markers (e.g., αSMA, Collagen) and Ki67 being the mostly used antigens.…”

Section: Protein Analysismentioning

confidence: 99%

Best Practices and Progress in Precision-Cut Liver Slice Cultures

Dewyse

Reynaert

Grunsven

2021

IJMS

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Thirty-five years ago, precision-cut liver slices (PCLS) were described as a promising tool and were expected to become the standard in vitro model to study liver disease as they tick off all characteristics of a good in vitro model. In contrast to most in vitro models, PCLS retain the complex 3D liver structures found in vivo, including cell–cell and cell–matrix interactions, and therefore should constitute the most reliable tool to model and to investigate pathways underlying chronic liver disease in vitro. Nevertheless, the biggest disadvantage of the model is the initiation of a procedure-induced fibrotic response. In this review, we describe the parameters and potential of PCLS cultures and discuss whether the initially described limitations and pitfalls have been overcome. We summarize the latest advances in PCLS research and critically evaluate PCLS use and progress since its invention in 1985.

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“…No acute cardiotoxic effects were observed in mice after the in vivo administration of doxorubicin-loaded GSH-NS [37]. Recently, the hepatotoxicity of this nanoformulation was investigated either in vitro on human HepG2 cell line or ex vivo on rat precision-cut liver slices (PCLSs), where a good nanosponge safety profile was demonstrated, showing a comparable hepatotoxicity to that of free doxorubicin [52].…”

Section: Discussionmentioning

confidence: 99%

Biological Effect Evaluation of Glutathione-Responsive Cyclodextrin-Based Nanosponges: 2D and 3D Studies

et al. 2020

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This study aims to evaluate the bioeffects of glutathione-responsive β-cyclodextrin-based nanosponges (GSH-NSs) on two- (2D) and three-dimensional (3D) cell cultures. The bioeffects of two types of GSH-NS formulations, with low (GSH-NS B) and high (GSH-NS D) disulfide-bond content, were evaluated on 2D colorectal (HCT116 and HT-29) and prostatic (DU-145 and PC3) cancer cell cultures. In particular, the cellular uptake of GSH-NS was evaluated, as their effects on cell growth, mitochondrial activity, membrane integrity, cell cycle distribution, mRNA expression, and reactive oxygen species production. The effect of GSH-NSs on cell growth was also evaluated on multicellular spheroids (MCS) and a comparison of the GSH-NS cell growth inhibitory activity, in terms of inhibition concentration (IC)50 values, was performed between 2D and 3D cell cultures. A significant decrease in 2D cell growth was observed at high GSH-NS concentrations, with the formulation with a low disulfide-bond content, GSH-NS B, being more cytotoxic than the formulation with a high disulfide-bond content, GSH-NS D. The cell growth decrease induced by GSH-NS was owing to G1 cell cycle arrest. Moreover, a significant down-regulation of mRNA expression of the cyclin genes CDK1, CDK2, and CDK4 and up-regulation of mRNA expression of the cyclin inhibitor genes CDKN1A and CDKN2A were observed. On the other hand, a significant decrease in MCS growth was also observed at high GSH-NS concentrations, but not influenced by the nanosponge disulfide-bond content, with the MCS IC50 values being significantly higher than those obtained on 2D cell cultures. GSH-NSs are suitable nanocarries as they provoke limited cellular effects, as cell cycle arrest only occurred at concentrations significantly higher than those used for drug delivery.

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Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin: Evaluation of toxicity and transport mechanisms in the liver

Cited by 41 publications

References 46 publications

Stabilization and Anticancer Enhancing Activity of the Peptide Nisin by Cyclodextrin-Based Nanosponges against Colon and Breast Cancer Cells

Stabilization and Anticancer Enhancing Activity of the Peptide Nisin by Cyclodextrin-Based Nanosponges against Colon and Breast Cancer Cells

Best Practices and Progress in Precision-Cut Liver Slice Cultures

Biological Effect Evaluation of Glutathione-Responsive Cyclodextrin-Based Nanosponges: 2D and 3D Studies

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