Abstract:Itraconazole (ITC), a well-tolerated antifungal drug, exerts multiple anticancer effects which justified its preclinical and clinical investigation as potential anti-cancer agent with reduced side effects. Enhancement of ITC anti-cancer efficacy would bring valuable benefits to patients. We propose herein lipid nanocapsules (LNCs) modified with a subtherapeutic dose of miltefosine (MFS) as a membrane bioactive amphiphilic additive (M-ITC-LNC) for the development of an ITC nanoformulation with enhanced anticanc… Show more
“…For the A549 cell line, the survival rates of the cells treated with siRNA VEGF NPs and ITZ NPs were 80.59% ± 4.32% and 63.25% ± 6.15%, respectively, while that of cells treated with ITZ-siRNA VEGF NPs was 59.58% ± 7.26%. ITZ was reported to induce cancer cell death via apoptosis mainly due to alteration of mitochondria membrane potential, reduction of Bcl-2 expression and increase of caspase-3 activity [ 9 , 35 ]. The greater cytotoxic effect of ITA-loaded NPs as compared to free ITZ against 4T1 cells could be attributed to the small size and rapid uptake of nano-formulations, which facilitates different mechanisms of transport, such as endocytosis or passive transport.…”
Combinations of two different therapeutic modalities of VEGF inhibitors against angiogenesis can cooperatively impede breast cancer tumor growth and enhance therapeutic efficacy. Itraconazole (ITZ) is a conventional antifungal drug with high safety; however, it has been repurposed to be a multi target anti-angiogenesis agent for cancer therapy in recent years. In the present study, composite nanoparticles co-loaded with ITZ and VEGF siRNA were prepared in order to investigate their anti-angiogenesis efficacy and synergistic anticancer effect against breast cancer. The nanoparticles had a suitable particle size (117.9 ± 10.3 nm) and weak positive surface charge (6.69 ± 2.46 mV), as well as good stability and drug release profile in vitro. Moreover, the nanoparticles successfully escaped from endosomes and realized cell apoptosis and cell proliferation inhibition in vitro. In vitro and in vivo experiments showed that the nanoparticles could induce the silencing of VEGF-related expressions as well as anti-angiogenesis efficacy, and the co-loaded ITZ-VEGF siRNA NPs could inhibit tumor growth effectively with low toxicity and side effects. Taken together, the as-prepared delivery vehicles are a simple and safe nano-platform that improves the antitumor efficacy of VEGF siRNA and ITZ, which allows the repositioning of the generic drug ITZ as a great candidate for antitumor therapy.
“…For the A549 cell line, the survival rates of the cells treated with siRNA VEGF NPs and ITZ NPs were 80.59% ± 4.32% and 63.25% ± 6.15%, respectively, while that of cells treated with ITZ-siRNA VEGF NPs was 59.58% ± 7.26%. ITZ was reported to induce cancer cell death via apoptosis mainly due to alteration of mitochondria membrane potential, reduction of Bcl-2 expression and increase of caspase-3 activity [ 9 , 35 ]. The greater cytotoxic effect of ITA-loaded NPs as compared to free ITZ against 4T1 cells could be attributed to the small size and rapid uptake of nano-formulations, which facilitates different mechanisms of transport, such as endocytosis or passive transport.…”
Combinations of two different therapeutic modalities of VEGF inhibitors against angiogenesis can cooperatively impede breast cancer tumor growth and enhance therapeutic efficacy. Itraconazole (ITZ) is a conventional antifungal drug with high safety; however, it has been repurposed to be a multi target anti-angiogenesis agent for cancer therapy in recent years. In the present study, composite nanoparticles co-loaded with ITZ and VEGF siRNA were prepared in order to investigate their anti-angiogenesis efficacy and synergistic anticancer effect against breast cancer. The nanoparticles had a suitable particle size (117.9 ± 10.3 nm) and weak positive surface charge (6.69 ± 2.46 mV), as well as good stability and drug release profile in vitro. Moreover, the nanoparticles successfully escaped from endosomes and realized cell apoptosis and cell proliferation inhibition in vitro. In vitro and in vivo experiments showed that the nanoparticles could induce the silencing of VEGF-related expressions as well as anti-angiogenesis efficacy, and the co-loaded ITZ-VEGF siRNA NPs could inhibit tumor growth effectively with low toxicity and side effects. Taken together, the as-prepared delivery vehicles are a simple and safe nano-platform that improves the antitumor efficacy of VEGF siRNA and ITZ, which allows the repositioning of the generic drug ITZ as a great candidate for antitumor therapy.
“…Their morphological characteristics, particularly in terms of size and shape, were generally similar to those reported in the literature. 50 , 51 Figure 2 ( A and , B ) TEM of TSIIA-PS-LNCs and TSIIA-HA-LNCs, respectively, at magnification 40,000×. ( C ) Release profiles of LNC formulations versus TSIIA suspension at 37°C.…”
Section: Resultsmentioning
confidence: 99%
“…Similar profiles have been reported for the release of diverse drugs, such as praziquantel, itraconazole, and quercetin, from LNCs. 17 , 51 , 52 The sustained-release profiles of lipophilic drugs from LNCs has been attributed to the barrier function of the surrounding aqueous release medium that impedes drug transport owing to the poor aqueous solubility of the drug. 21 Additionally, TSIIA-HA-LNCs showed significant less TSIIA release after 24 hours than TSIIA-PS-LNCs ( p ≤0.01).…”
Section: Resultsmentioning
confidence: 99%
“…Their morphological characteristics, particularly in terms of size and shape, were generally similar to those reported in the literature. 50,51 In Vitro Drug Release Figure 2C shows that complete release of TSIIA (80.57% ±0.52%) from its suspension occurred after 8 hours, while, the tested LNC formulations showed sustained-release profiles with significantly less release after 24 hours than the TSIIA suspension (p≤0.05), indicating drug entrapment inside the LNCs. Similar profiles have been reported for the release of diverse drugs, such as praziquantel, itraconazole, and quercetin, from LNCs.…”
Introduction:Liver fibrosis represents a serious global disease with no approved treatment. Tanshinone IIA (TSIIA) is a phytomedicine with documented activity in treating many hepatic disorders. TSIIA has been reported to have potent anti-inflammatory and antioxidant properties. It can also induce apoptosis for activated hepatic stellate cells, and is thereby considered as a promising herbal remedy for treating fibrotic liver. However, its poor aqueous solubility, short half-life, exposure to the first-pass effect, and low concentration reaching targeted cells constitute the major barriers hindering its effective therapeutic potential. Therefore, this work aimed at enhancing TSIIA systemic bioavailability together with achieving active targeting potential to fibrotic liver via its incorporation into novel modified lipid nanocapsules (LNCs). Methods: Blank and TSIIA-loaded LNCs modified with either hyaluronate sodium or phosphatidyl serine were successfully prepared, optimized, and characterized both in vitro and in vivo.
Results:The developed LNCs showed good colloidal properties (size ≤100 nm and PDI ≤0.2), high drug-entrapment efficiency (>97%) with sustained-release profile for 24 hours, high storage stability up to 6 months, and good in vitro serum stability. After a single intraperitoneal injection, the administered LNCs exhibited a 2.4-fold significant increase in AUC 0-∞ compared with the TSIIA suspension (p≤0.01). Biodistribution-study results proved the liver-targeting ability of the prepared modified LNCs, with a significant ~1.5-fold increase in hepatic accumulation compared with the unmodified formulation (p≤0.05). Moreover, the modified formulations had an improved antifibrotic effect compared with both unmodified LNCs and TSIIA suspension, as evidenced by the results of biochemical and histopathological evaluation.
Conclusion:The modified TSIIA-LNCs could be regarded as promising novel targeted nanomedicines for effective management of liver fibrosis.
“…To evoke drug repurposing and drug combinations, a screening of the most promising drugs with verapamil and ITZ was conducted and identified the combination of ITZ and 5-fluorouracil as the most effective by decreasing cell viability and proliferation ( Correia et al, 2018 ). Recently, EI-Sheridy et al used miltefosine-modified lipid nanocapsules to develop an ITZ nanoformulation, with a relatively small size and high entrapment efficiency, to enhance the chemotherapeutic efficacy of ITZ, regarding inhibition of tumor growth and cellular proliferation ( El-Sheridy et al, 2021 ). Based on the above evidence, ITZ shows promise as an anti-cancer drug in the treatment of patients with TNBC.…”
Triple-negative breast cancer (TNBC) is the aggressive molecular type of breast carcinoma, with a high metastasis/relapse incidence and cancer-related death rate, due to lack of specific therapeutic targets in the clinic. Exploring potential therapeutic targets or developing novel therapeutic strategies are the focus of intense research to improve the survival and life quality of patients with TNBC. The current study focused on drugs targeting the mTOR signaling pathway by investigating the potential utilization of itraconazole (ITZ) combined with rapamycin in the treatment of TNBC. CCK-8, colony formation and transwell assays were conducted to evaluate the effect of ITZ with rapamycin in combination on MDA-MB-231 and BT-549 TNBC cells. Synergistic inhibition was found in terms of proliferation and motility of TNBC cells. However, apoptosis was not enhanced by the combined treatment of ITZ and rapamycin. Flow cytometry analysis showed that ITZ and/or rapamycin arrested cells in G0/G1 phase and prevented G1/S phase transition. Reduced cyclin D1 protein levels were consistent with G0/G1 phase arrest, especially when resulting from the combination of ITZ with rapamycin. In conclusion, the combination of ITZ with rapamycin is a promising therapeutic strategy for patients with TNBC through synergistically arresting cells in the G0/G1 phase of the cell cycle, rather than inducing apoptosis.
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