Solid lipid nanoparticles co-loaded with doxorubicin and α-tocopherol succinate are effective against drug-resistant cancer cells in monolayer and 3-D spheroid cancer cell models (original) (raw)
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Nanomaterials, 2018
Solid lipid nanoparticles (SLNs) comprise a versatile drug delivery system that has been developed for the treatment of a variety of diseases. The present study will investigate the feasibility of entrapping an active doxorubicin prodrug (a squalenoyl-derivative) in SLNs. The doxorubicin derivative-loaded SLNs are spherically shaped, have a mean diameter of 300-400 nm and show 85% w/w drug entrapment efficiency. The effects on cell growth of loaded SLNs, free doxorubicin and the prodrug have been examined using cytotoxicity and colony-forming assays in both human ovarian cancer line A2780 wild-type and doxorubicin-resistant cells. Further assessments as to the treatment's ability to induce cell death by apoptosis have been carried out by analyzing annexin-V staining and the activation of caspase-3. The in vitro data demonstrate that the delivery of the squalenoyl-doxorubicin derivative by SLNs increases its cytotoxic activity, as well as its apoptosis effect. This effect was particularly evident in doxorubicin-resistant cells.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2013
This work aimed to develop solid lipid nanoparticles (SLNs) loaded with doxorubicin evaluating the influence of docosahexaenoic acid (DHA), a polyunsaturated fatty acid that enhances the activity of anticancer drugs, on drug encapsulation efficiency (EE). The SLN were characterized for size, zeta potential, entrapment efficiency (EE) and drug release. Studies of in vitro antitumor activity and cellular uptake were also conducted. The reduction in particle size (from 127 ± 14 to 94 ± 1 nm) and negative charges were obtained for SLN loaded with DHA and triethanolamine (TEA), amine used to increase the solubility of doxorubicin in melted lipid. The EE was significantly improved from 36 ± 4% to 99 ± 2% for SLN without and with DHA at 0.4%, respectively. The doxorubicin release in a slightly acid medium (pH 5.0) was higher than that observed at physiological pH. The in vitro studies clearly showed the higher cytotoxicity of doxorubicin-DHA-loaded SLN than free doxorubicin + DHA on human lung tumor cell line (A549) and the improved cellular uptake achieved with the drug encapsulation can be an explanation. These findings suggest that DHA-doxorubicin-loaded SLN is a promising alternative for the treatment of cancer.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2018
Combination-based chemotherapies have been the standard treatment for multiple solid tumors since the 1960s. Combined therapies where both agents have toxicity results in dose-limiting effects. α- tocopherol succinate (TS) is an analogue of vitamin E that exhibits antitumor properties in the absence of toxicity. Hence, its combination with a frontline chemotherapy, doxorubicin (DOX) is an alternative to increase antitumor efficacy. Therefore, the aim of this work was to evaluate the antitumor activity of nanostructed lipid carriers (NLC) loaded with TS and DOX. The NLC-TS-DOX were prepared, characterized and radiolabeled with technetium-99m. Cytotoxicity studies were performed in vitro, using two breast cancer cell lines, MDA-MB-231 and 4T1. Biodistribution and antitumor activity were evaluated in 4T1 tumor-bearing mice. The results showed that NLC-TS-DOX had a small diameter (85 nm) and a long blood clearance (Tβ = 1107.71 min) that consequently resulted in a higher tumor uptake co...
Pharmaceutical research, 2014
Purpose To develop a nanostructured lipid carrier (NLC) co-loaded with doxorubicin and docosahexaenoic acid (DHA) and to evaluate its potential to overcome drug resistance and to increase antitumoral effect in MCF-7/Adr cancer cell line. Methods The NLC was prepared by a hot homogenization method and characterized for size, zeta potential, entrapment efficiency (EE) and drug loading (DL). Drug release was evaluated by dialysis in complete DMEM, and NLC aggregation was assayed in the presence of serum. The cytotoxicity of formulations, doxorubicin uptake or penetration were evaluated in MCF-7 and MCF-7/Adr as monolayer or spheroid models. Results The formulation had a size of about 80 nm, negative zeta potential, EE of 99%, DL of 31 mg/g, a controlled drug release in DMEM and no particles aggregation in presence of serum. The NLC loaded with doxorubicin and DHA showed the same activity as free drugs against MCF-7 but a stronger activity against MCF-7/Adr cells. In monolayer model, the doxorubicin uptake as free and encapsulated form was similar in MCF-7 but higher for the encapsulated drug in MCF-7/Adr, suggesting a bypassing of P-glycoprotein bomb efflux. For spheroids, the NLC loaded with doxorubicin and DHA showed a prominent cytotoxicity and a greater penetration of doxorubicin. Conclusions These findings suggest that the co-encapsulation of doxorubicin and DHA in NLC enhances the cytotoxicity and overcomes the doxorubicin resistance in MCF-7/Adr. Figure ᅟ
Biomedicine & Pharmacotherapy, 2020
Doxorubicin (DOX) is widely used in cancer treatment, however, its use is often limited due to its side effects. To avoid these shortcomings, the encapsulation of DOX into nanocarriers has been suggested. Herein, we proposed a novel nanostructured lipid carrier (NLC) formulation loading DOX, docosahexaenoic acid (DHA), and α-tocopherol succinate (TS) for cancer treatment. DHA is an omega-3 fatty acid and TS is a vitamin E derivative. It has been proposed that these compounds can enhance the antitumor activity of chemotherapeutics. Thus, we hypothesized that the combination of DOX, DHA, and TS in NLC (NLC-DHA-DOX-TS) could increase antitumor efficacy and also reduce toxicity. NLC-DHA-DOX-TS was prepared using emulsification-ultrasound. DOX was incorporated after preparing the NLC, which prevented its degradation during manufacture. High DOX encapsulation efficiency was obtained due to the ion-pairing with TS. This ion-pairing increases lipophilicity of DOX and reduces its crystallinity, contributing to its encapsulation in the lipid matrix. Controlled DOX release from the NLC was observed in vitro, with increased drug release at the acidic environment. In vitro cell studies indicated that DOX, DHA, and TS have synergistic effects against 4T1 tumor cells. The in vivo study showed that NLC-DHA-DOX-TS exhibited the greatest antitumor efficacy by reducing tumor growth in 4T1 tumor-bearing mice. In addition, this formulation reduced mice mortality, prevented lung metastasis, and decreased DOX-induced toxicity to the heart and liver, which was demonstrated by hematologic, biochemical, and histologic analyses. These results indicate that NLC-DHA-DOX-TS may be a promising carrier for breast cancer treatment.
BioNanoScience, 2017
Erlotinib (ELT) as a small molecule with poor solubility, poor bioavailability, and instability in gastrointestinal environment, has been considered as a therapeutic agent for Non-Small-Cell Lung Cancer (NSCLC) therapy through oral administration. In the present study, ELT-liposome and ELT-NLCs were successfully prepared and characterized by assessment of the particle size, zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency (EE), and drug loading (DL). DAPI staining and Flow cytometry techniques were employed to probe anticancer activities of the optimal formulations. The obtained results indicated that the average size of optimized ELT-NLCs was 109 ± 2 nm, while the optimal formulation of ELTliposome was 130 ± 4 nm. In addition, the values of EE, DL, and cellular uptake were higher in ELT-NLCs than ELT-liposome. Moreover, the stability of ELT-NLCs and ELT-liposome were not significantly changed (P > 0.05) within storage time. The results of anti-cancer assessment indicated that ELT-NLCs caused more cell viability reduction than ELT-liposome and free ELT. According to the Flow cytometry and DAPI staining results, the exposed A549 cells with ELT-NLCs had more rates of apoptosis than ELT-liposome. The obtained data from this study clearly showed that ELT-NLCs had better anti-cancer activity than ELT-liposome, which may be related to the effective nano particle size, PDI, EE, and DL of ELT-NLCs.
Journal of microencapsulation, 2016
Doxorubicin (DOXO) lauroyl ester and amide were proposed as lipophilic derivatives and entrapped in SLNs. DOXO derivatives-loaded SLNs were spherical shaped, had 200-300 nm mean diameters and showed 80-94% w/w drug entrapment efficiencies. The effect of DOXO derivatives-loaded SLNs and free DOXO on cell growth was examined by MTT and colony-forming assays on four different tumour cell lines: a pancreatic, CFPAC-1, a lung, A549, and two ovarian, A2780 and A2780res (DOXO-resistant). The results obtained with MTT and colony-forming assay show that although DOXO displayed an inhibition of cell proliferation greater or similar to DOXO lauroyl amide-loaded SLNs on all cell types, the effect induced by DOXO lauroyl ester-loaded SLNs was higher and concentration-dependent, and it was the only one maintained at 10(-5 )mM concentration. Only DOXO lauroyl ester-loaded SLNs were able to induce a 40% inhibitory effect on A2780 res cell line up to 10(-4 )mM concentration.
International journal of pharmaceutics, 2012
The objective of this study was to increase the potency of doxorubicin against adriamycin-resistant NCI/ADR-RES cells by concurrent treatment with doxorubicin and MBO-asGCS loaded solid-lipid nanoparticles (SLN). Loading doxorubicin as ion-pair complex with deoxytaurocholate into cationic and neutral SLN was investigated. Fast release and poor entrapment were observed in cationic nanoparticles, which were corrected by entrapping the complex in neutral polyoxyethylene (20) stearyl ether (Brij(®) 78)/VitE-TPGS nanoparticles. Slow doxorubicin release confirmed the influence of charge and electrolytes on the dissociation of ion-pair complexes. To evaluate antitumor activity, NCI/ADR-RES cells were treated with separate SLN: one loaded with doxorubicin and another carrying MBO-asGCS oligonucleotide. The viability of cells treated with 5 μM doxorubicin was reduced to 17.2% whereas viability was reduced to 2.5% for cells treated with both 5 μM doxorubicin SLN and 100 nM MBO-asGCS SLN. This...
Journal of nanoscience and nanotechnology, 2018
This work aims to develop, characterize, and evaluate the anticancer activity of solid lipid nanoparticles (SLN) containing doxorubicin (DOX), an antitumoral from the antracycline class, and sclareol (SC), a lipophilic labdene diterpene (SLN-DOX-SC). The SLN were characterized by Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), Small Angle X-ray Diffraction (SAXS), in vitro release, transmission electron microscopy, and polarized light microscopy. Evaluation of cell viability was performed in two cell cultures: MCF-7 (human breast cancer) and 4T1 (murine breast cancer). The SLN showed a size in the range of 128 nm, negative zeta potential, DOX encapsulation efficiency (EE) of 99%, and drug loading (DL) of 66 mg/g. Characterization of the formulation by DSC, XRD, and SAXS revealed the presence of DOX inside the nanoparticles of SLN and suggested increased expulsion/release of this drug when associated with SC. The release profiles revealed that the SLN-DOX-SC showed ...