Folate-targeted liposomal nitrooxy-doxorubicin: An effective tool against P-glycoprotein-positive and folate receptor-positive tumors

Gazzano, Elena; Rolando, Barbara; Chegaev, Konstantin; Kopecka, Joanna; Pedrini, Isabella; Saponara, Simona; Sorge, Matteo; Buondonno, Ilaria; Stella, Barbara; Marengo, Alessandro; Valoti, Massimo; Brancaccio, Mara; Fruttero, Roberta; Gasco, Alberto; Berlier, Gloria; Riganti, Chiara

doi:10.1016/j.jconrel.2017.11.042

Cited by 71 publications

(51 citation statements)

References 54 publications

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“…No treatments affected the liver or kidney-related parameters. As expected, doxorubicin-treated animals had increased CPK, CPK-MB, and cTnT, i.e., typical parameters of heart damage [31]. Neither free CURC nor the CURC-loaded SLNs altered the hematochemical parameters versus the untreated animals.…”

Section: Curc-loaded Slns Are Effective and Safe In Preclinical Modelsupporting

confidence: 66%

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Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells

et al. 2020

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Multidrug resistance (MDR) is a critical hindrance to the success of cancer chemotherapy. The main thing responsible for MDR phenotypes are plasma-membranes associated with adenosine triphosphate (ATP) Binding Cassette (ABC) drug efflux transporters, such as the P-glycoprotein (Pgp) transporter that has the broadest spectrum of substrates. Curcumin (CURC) is a Pgp inhibitor, but it is poorly soluble and bioavailable. To overcome these limitations, we validated the efficacy and safety of CURC, loaded in biocompatible solid lipid nanoparticles (SLNs), with or without chitosan coating, with the goal of increasing the stability, homogeneous water dispersibility, and cellular uptake. Both CURC-loaded SLNs were 5–10-fold more effective than free CURC in increasing the intracellular retention and toxicity of doxorubicin in Pgp-expressing triple negative breast cancer (TNBC). The effect was due to the decrease of intracellular reactive oxygen species, consequent inhibition of the Akt/IKKα-β/NF-kB axis, and reduced transcriptional activation of the Pgp promoter by p65/p50 NF-kB. CURC-loaded SLNs also effectively rescued the sensitivity to doxorubicin against drug-resistant TNBC tumors, without signs of systemic toxicity. These results suggest that the combination therapy, based on CURC-loaded SLNs and doxorubicin, is an effective and safe approach to overcome the Pgp-mediated chemoresistance in TNBC.

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Section: Curc-loaded Slns Are Effective and Safe In Preclinical Modelsupporting

confidence: 66%

“…Tumor volumes were monitored daily. Animals were euthanized at day 21 after randomization with zolazepam (0.2 mL/kg) and xylazine (16 mg/kg) [31].…”

Section: Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells

et al. 2020

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“…Since mice have different VγVδ T-cell sets than humans [11], to verify whether NZ could reverse chemo-immune-resistance in preclinical models of osteosarcoma, we used Hu-CD34 + mice, characterized by functional Vγ9δ2 T-lymphocytes [30]. Mice were implanted with cells derived by chemo-immune-resistant 3D U-2OS cultures, treated with doxorubicin at the maximally tolerated dose [35], with or without NZ, at a dosage corresponding to that administered to patients treated with zoledronic acid. Doxorubicin was completely ineffective in reducing tumor growth, while NZ slowed it down.…”

Section: Increasing the Abca1/abcb1 Ratio Reduces The Growth Of Osteomentioning

confidence: 99%

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Belisario

Akman

Godel

et al. 2020

Cells

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The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1 high ABCA1 low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas.

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“…We have made use of the LDH release assay in our previous works on NO photodonors . The LDH assay was also performed here, as it is a sensitive index of irreversible cell damage leading to cell death, and to allow comparisons between the data obtained in the present work and in previous findings to be carried out . Figure shows that the extent of cell death in both irradiated, untreated cells and in irradiated cells that had been treated with compound 2 is two times higher than that of non‐irradiated cells.…”

Section: Resultsmentioning

confidence: 81%

“…[15,27] The LDH www.chemmedchem.org assay was also performed here, as it is as ensitive index of irreversible cell damagel eading to cell death,a nd to allow comparisons between the data obtained in the present work and in previous findings to be carriedo ut. [32] Figure5 shows that the extent of cell death in both irradiated, untreated cells and in irradiated cells that had been treated with compound 2 is two times highert han that of non-irradiated cells. Moreover, the extent of cell deathi ni rradiated cells that had been treated with compound 13 is four times that of not-irradiated cells, whether they were untreated or treated with either compound 2 or 13.R eference 2 did not show any toxicityi nt he dark, unlike 13,w hich was not significantly toxic up to ac oncentration of 5 mm andt hen showede nhanced toxicityw ith increasing concentration (data not shown).…”

Section: Cytotoxicity Of Compounds 2a Nd 13 Against Human Lung Adenocmentioning

confidence: 95%

Tuning the Hydrophobicity of a Mitochondria‐Targeted NO Photodonor

et al. 2018

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A few compounds in which the nitric oxide (NO) photodonor N-[4-nitro-3-(trifluoromethyl)phenyl]propane-1,3-diamine is joined to the mitochondria-targeting alkyltriphenylphosphonium moiety via flexible spacers of variable length were synthesized. The lipophilicity of the products was evaluated by measuring their partition coefficients in n-octanol/water. The obtained values, markedly lower than those calculated, are consistent with the likely collapsed conformation assumed by the compounds in solution, as suggested by molecular dynamics simulations. The capacity of the compounds to release NO under visible light irradiation was evaluated by measuring nitrite production by means of the Griess reaction. The accumulation of compounds in the mitochondria of human lung adenocarcinoma A549 cells was assessed by UPLC-MS. Interestingly, compound 13 [(9-((3-((4-nitro-3-(trifluoromethyl)phenyl)amino)propyl)amino)-9-oxononyl) triphenylphosphonium bromide] displayed both the highest accumulation value and high toxicity toward A549 cells upon irradiation-mediated NO release in mitochondria.

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Folate-targeted liposomal nitrooxy-doxorubicin: An effective tool against P-glycoprotein-positive and folate receptor-positive tumors

Cited by 71 publications

References 54 publications

Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells

Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Tuning the Hydrophobicity of a Mitochondria‐Targeted NO Photodonor

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