Administration-dependent efficacy of ferrociphenol lipid nanocapsules for the treatment of intracranial 9L rat gliosarcoma (original) (raw)
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Brain tumour targeting strategies via coated ferrociphenol lipid nanocapsules
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V, 2012
In this study, a new active targeting strategy to favour ferrociphenol (FcdiOH) internalisation into brain tumour cells was developed by the use of lipid nanocapsules (LNCs) coated with a cell-internalising peptide (NFL-TBS.40-63 peptide) that interacts with tubulin-binding sites. In comparison, OX26 murine monoclonal antibodies (OX26-MAb) targeting transferrin receptors were also inserted onto the LNC surface. The incorporation of OX26 or peptide did not influence the in vitro antiproliferative effect of FcdiOH-LNCs on the 9L cells since their IC50 values were found in the same range. In vivo, intracerebral administration of OX26-FcdiOH-LNCs or peptide-FcdiOH-LNCs by convection enhanced delivery did not enhance the animal median survival time in comparison with untreated rats (25 days). Interestingly, intra-carotid treatment with peptide-FcdiOH-LNCs led to an ameliorated survival time of treated rats with the presence of animals surviving until days 35, 40 and 44. Such results were...
Pharmaceutical Research, 2010
Purpose. The goal of the present study was to evaluate the efficacy of a new organometallic drug, ferrociphenol (Fc-diOH), in combination with external radiotherapy in intracerebral 9L glioma model. We tested the hypothesis that the combination of external radiotherapy with Fc-diOH could potentiate the action of this drug. Methods. 9L cells were treated with Fc-diOH-LNCs (from 0.01 to 1µmol/L) and irradiated with external radiotherapy (from 2 to 40 Gy). In vivo assessment was evaluated by the inoculation of 9L cells in Fisher rats. Chemotherapy with Fc-diOH-LNCs (0.36 mg/rat) was administered by means of convection-enhanced delivery (CED), and the treatment was followed by three irradiations of 6 Gy doses (total dose=18 Gy). Results. In vitro evaluations evidenced that a combined treatment with Fc-diOH-LNCs and irradiations showed synergistic antitumor activity on 9L cells. Combining cerebral irradiation with CED of Fc-diOH-LNCs led to a significantly longer survival and the existence of long-term survivors compared to Fc-diOH-LNCs-treated animals (p<0.0001) and to the group treated with blank LNCs+radiotherapy (p=0.0079). Conclusion. The synergistic effect between ferrociphenol-loaded LNCs and radiotherapy was due to a closely oxidative relationship. Upon these considerations, Fc-diOH-LNCs appear to be an efficient radiosensitive anticancer drug delivery system.
Dose effect activity of ferrocifen-loaded lipid nanocapsules on a 9L-glioma model
International Journal of Pharmaceutics, 2009
Ferrociphenol (Fc-diOH) is a new molecule belonging to the fast-growing family of organometallic anticancer drugs. In a previous study, we showed promising in vivo results obtained after the intratumoural subcutaneous administration of the new drug-carrier system Fc-diOH-LNCs on a 9L-glioma model. To further increase the dose of this lipophilic entity, we have created a series of prodrugs of Fc-diOH. The phenol groups were protected by either an acetyl (Fc-diAc) or by the long fatty-acid chain of a palmitate (Fc-diPal). LNCs loaded with Fc-diOH prodrugs have to be activated in situ by enzymatic hydrolysis. We show here that the protection of diphenol groups with palmitoyl results in the loss of Fc-diOH in vitro activity, probably due to a lack of in situ hydrolysis. On the contrary, protection with an acetate group does not affect the strong, in vitro, antiproliferative effect of ferrocifen-loaded-LNCs neither the reduction of tumour volume observed on an ectopic model, confirming that acetate is easily cleaved by cell hydrolases. Moreover, the cytostatic activity of Fc-diOH-LNCs is confirmed on an orthotopic glioma model since the difference in survival time between the infusion of 0.36 mg/rat Fc-diOH-LNCs and blank LNCs is statistically significant. By using LNCs or Labrafac ® to carry the drug, a dose-effect ranging from 0.005 to 2.5 mg of Fc-diOH per animal can be evidenced.
Ferrociphenol lipid nanocapsule delivery by mesenchymal stromal cells in brain tumor therapy
International Journal of Pharmaceutics, 2012
The prognosis of patients with malignant glioma remains extremely poor despite surgery and improvements in radio-and chemo-therapies. Thus, treatment strategies that specifically target these tumors have the potential to greatly improve therapeutic outcomes. "Marrow-isolated adult multilineage inducible" cells (MIAMI cells) are a subpopulation of mesenchymal stromal cells (MSCs) which possess the ability to migrate to brain tumors. We have previously shown that MIAMI cells were able to efficiently incorporate lipid nanocapsules (LNCs) without altering either their stem cell properties or their migration capacity. In this study, we assessed whether the cytotoxic effects of MIAMI cells loaded with LNCs containing an organometallic complex (ferrociphenol or Fc-diOH) could be used to treat brain tumors. The results showed that MIAMI cells internalized Fc-diOH-LNCs and that this internalization did not induce MIAMI cell death. Furthermore, Fc-diOH-LNC-loaded MIAMI cells produced a cytotoxic effect on U87MG glioma cells in vitro. This cytotoxic effect was validated in vivo after intratumoral injection of Fc-diOH-LNC-loaded MIAMI cells in a heterotopic U87MG glioma model in nude mice. These promising results open up a new field of treatment in which cellular vehicles and nanoparticles can be combined to treat brain tumors.
Nanomedicine: Nanotechnology, Biology and Medicine, 2014
In this work, a novel ferrocenyl complex (ansa-FcdiOH) was assessed for brain tumor therapy through stealth lipid nanocapsules (LNCs). 15 Stealth LNCs, prepared according to a one-step process, showed rapid uptake by cancer cells and extended blood circulation time. The 16 ferrocenyl complex was successfully encapsulated into these LNCs measuring 40 nm with a high loading capacity (6.4%). In vitro studies 17 showed a potent anticancer effect of ansa-FcdiOH on 9L cells with a low IC50 value (0.1 μM) associated with an oxidative stress and a dose-18 dependent alteration of the cell cycle. Repeated intravenous injections of stealth ansa-FcdiOH LNCs in ectopic glioma bearing rats induced a 19 significant tumor growth inhibition, supported by a reduced number of proliferative cells in tumors compared to control group. Additionally, 20 no liver damage manifestation was observed in treated animals. These results indicated that stealth ansa-FcdiOH LNCs might be considered 21 as a potential new approach for cancer chemotherapy. 24 25 Q4 29 protocol). 1 Consequently, alternative strategies are needed to 30 tackle this dismal tumor.
International journal of pharmaceutics, 2015
In this work, multifunctional lipid nanocapsules (M-LNC) were designed to combine the activity of the cytotoxic drug paclitaxel (PTX) with the immunostimulant CpG. This nanosystem, consisting of modified lipid nanocapsules coated with a cationic polymeric shell composed of chitosan (CS), was able to allocate the hydrophobic drug PTX in the inner oily core, and to associate onto the surface the genetic material CpG. The CS-coated LNC (CS-LNC), showed a narrow size distribution with an average size of 70nm and a positive zeta potential (+25mV). They encapsulated PTX in a high amount (98%), and, due to the cationic surface charge, were able to adsorb CpG without losing stability. As a preliminary in vitro study, the apoptotic effect on GL261 glioma cells was investigated. The drug-loaded CS-LNC exhibited the ability to interact with glioma cells and induce an important apoptotic effect in comparison with blank systems. Finally, the M-LNC made of CS-LNC loaded with both CpG and PTX were...
Journal of Controlled Release, 2008
Ferrocenyl diphenol tamoxifen derivative (Fc-diOH) is one of the most active molecules of a new class of organometallic drugs, showing in vitro antiproliferative effects on both hormonedependent and independent breast cancer cells. For the first time, Fc-diOH was tested on a 9L glioma model according to two encapsulation strategies: lipid nanocapsules (LNC) and swollen micelles. LNC showed a higher drug loading capacity because of a larger oily core in their structure and were able to be up taken by glioma cells. The large amount of PEG present at the micellar interface prevented interaction with cytoplasm membrane which led to a low level of micelle cell uptake and no biological activity. On the contrary, Fc-diOH cytostatic activity was conserved after its encapsulation in LNC and was very effective on 9L-glioma cells as the IC 50 was about 0.6µM. Interestingly, Fc-diOH-loaded LNC showed low toxicity levels when in contact with healthy cells, conferring a functional specificity of this compound on tumour cells. Finally, Fc-diOH LNC treatment was able to lower significantly both tumour mass and volume evolution after 9L-cell implantation into rats which evidenced for the first time the in vivo efficacy of this new kind of organometallic compound.
Pharmaceutics
Glioblastoma multiforme (GBM) is the most common and malignant type of brain tumor. In fact, tumor recurrence usually appears a few months after surgical resection and chemotherapy, mainly due to many factors that make GBM treatment a real challenge, such as tumor location, heterogeneity, presence of the blood-brain barrier (BBB), and others. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) represent the most promising carriers for therapeutics delivery into the central nervous system (CNS) owing to their inherent ability to cross the BBB. In this review, we present the main challenges in GBM treatment, a description of SLNs and NLCs and their valuable role as drug carriers in GBM treatment, and finally, a detailed description of all modification strategies that aim to change composition of SLNs and NLCs to enhance treatment outcomes. This includes modification of SLNs and NLCs to improve crossing the BBB, reduced GBM cell resistance, target GBM cells select...
Lauroyl-gemcitabine-loaded lipid nanocapsule hydrogel for the treatment of glioblastoma
2016
The local delivery of chemotherapeutic agents is a very promising strategy for the treatment of glioblastoma (GBM). Gemcitabine is a chemotherapeutic agent that has a different mechanism of action compared to alkylating agents and shows excellent radio-sensitizing properties. So, we developed an injectable gel-like nanodelivery system consisting in lipid nanocapsules loaded with anticancer prodrug lauroyl-gemcitabine (GemC 12-LNC) in order to obtain a sustained and local delivery of this drug in the brain. In this study, the GemC 12-LNC has been formulated and characterized and the viscoelastic properties of the hydrogel were evaluated after extrusion from 30 G needles. This system showed a sustained and prolonged in vitro release of the drug over one month. GemC 12 and the GemC 12-LNC have shown increased in vitro cytotoxic activity on U-87 MG glioma cells compared to the parent hydrophilic drug. The GemC 12-LNC hydrogel reduced significantly the size of a subcutaneous human GBM tumor model compared to the drug and short-term tolerability studies showed that this system is suitable for local treatment in the brain. In conclusion, this proof-of-concept study demonstrated the feasibility, safety and efficiency of the injectable GemC 12-LNC hydrogel for the local treatment of GBM.