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Dextran-Curcumin Nanoparticles as a Methotrexate Delivery Vehicle: A Step Forward in Breast Cancer Combination Therapy.

ABSTRACT: With the aim to effectively deliver methotrexate (MTX) to breast cancer cells, we designed a nanocarrier system (DC) derived from the self-assembly of a dextran-curcumin conjugate prepared via enzyme chemistry with immobilized laccase acting as a solid biocatalyst. Nanoparticles consisted of homogeneously dispersed nanospheres with a mean diameter of 290 nm, as characterized by combined transmission electron microscopy and dynamic light scattering investigations. DC was able to control the MTX release overtime (t1/2 value of 310 min), with cell internalization studies proving its presence inside MCF-7 cytoplasm. Finally, improved MTX efficacy was obtained in viability assays, and attributed to the synergy of curcumin moieties and loaded MTX as underlined by a combination index (CI) < 1.

SUBMITTER: Curcio M

PROVIDER: S-EPMC7169412 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Dextran-Curcumin Nanoparticles as a Methotrexate Delivery Vehicle: A Step Forward in Breast Cancer Combination Therapy.

Curcio Manuela M Cirillo Giuseppe G Tucci Paola P Farfalla Annafranca A Bevacqua Emilia E Vittorio Orazio O Iemma Francesca F Nicoletta Fiore Pasquale FP

Pharmaceuticals (Basel, Switzerland) 20191225 1

With the aim to effectively deliver methotrexate (MTX) to breast cancer cells, we designed a nanocarrier system (DC) derived from the self-assembly of a dextran-curcumin conjugate prepared via enzyme chemistry with immobilized laccase acting as a solid biocatalyst. Nanoparticles consisted of homogeneously dispersed nanospheres with a mean diameter of 290 nm, as characterized by combined transmission electron microscopy and dynamic light scattering investigations. DC was able to control the MTX r ...[more]

PMID: 31881645

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Project description:The main aims in the development of a novel drug delivery vehicle is to efficiently carry therapeutic drugs in the body's circulatory system and successfully deliver them to the targeted site as needed to safely achieve the desired therapeutic effect. In the present study, a passive targeted functionalised nanocarrier was fabricated or wrapped the hollow mesoporous silica nanoparticles with 3-aminopropyl triethoxysilane (APTES) to prepare APTES-coated hollow mesoporous silica nanoparticles (HMSNAP). A nitrogen sorption analysis confirmed that the shape of hysteresis loops is altered, and subsequently the pore volume and pore diameters of GaC-HMSNAP was reduced by around 56 and 37%, respectively, when compared with HMSNAP. The physico-chemical characterisation studies of fabricated HMSNAP, Ga-HMSNAP and GaC-HMSNAP have confirmed their stability. The drug release capacity of the fabricated Ga-HMSNAP and GaC-HMSNAP for delivery of gallium and curcumin was evaluated in the phosphate buffered saline (pH 3.0, 6.0 and 7.4). In an in silico molecular docking study of the gallium-curcumin complex in PDI, calnexin, HSP60, PDK, caspase 9, Akt1 and PTEN were found to be strong binding. In vitro antitumor activity of both Ga-HMSNAP and GaC-HMSNAP treated MCF-7 cells was investigated in a dose and time-dependent manner. The IC50 values of GaC-HMSNAP (25 µM) were significantly reduced when compared with free gallium concentration (40 µM). The mechanism of gallium-mediated apoptosis was analyzed through western blotting and GaC-HMSNAP has increased caspases 9, 6, cleaved caspase 6, PARP, and GSK 3β(S9) in MCF-7 cells. Similarly, GaC-HMSNAP is reduced mitochondrial proteins such as prohibitin1, HSP60, and SOD1. The phosphorylation of oncogenic proteins such as Akt (S473), c-Raf (S249) PDK1 (S241) and induced cell death in MCF-7 cells. Furthermore, the findings revealed that Ga-HMSNAP and GaC-HMSNAP provide a controlled release of loaded gallium, curcumin and their complex. Altogether, our results depicted that GaC-HMNSAP induced cell death through the mitochondrial intrinsic cell death pathway, which could lead to novel therapeutic strategies for breast adenocarcinoma therapy.

Dataset Information

Dextran-Curcumin Nanoparticles as a Methotrexate Delivery Vehicle: A Step Forward in Breast Cancer Combination Therapy.

Publications

Dextran-Curcumin Nanoparticles as a Methotrexate Delivery Vehicle: A Step Forward in Breast Cancer Combination Therapy.

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