33 research outputs found

    New lipid nanocapsules for decitabine encapsulation

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    Introduction: Currently decitabine, an antimetabolite agent is approved for acute myeloid leukemia in old patients and is administered via intra-venous (IV) route. It is a harsh treatment characterized by side effects mainly related with the IV administration as pain, risk of infectious, nursing and hospitalization. Oral route may represent a valid alternative route to IV administration because patient convenience and compliance. Due to the quick hydrolyze of the molecule in acidic conditions, decitabine oral bioavailability is very low, it ranges from 3.9 to 14%. The objective of this work was to design and develop a novel formulation to administer the decitabine per os. Material and method: Firstly, decitabine was solubilized in a reverse micelle (RM) formulation based on a mixture of Transcutol® HP and Tween® 80. RM were then incorporated into lipid nanocapsules (LNC-RM) (1).The formulation was then freeze dried and the stability after the freeze drying process was evaluated by comparing the size, the polydispersity index and the zeta potential to the initial values obtained before the freeze drying. The drug paylaod and encapsulation efficiency were determined after an ultracentrifugation to collect the free decitabine and the decitabine loaded in LNC-RM in two different fractions. In vitro release behavior of decitabine from LNC-RM in PBS medium (pH 7.4, 37°C) was evaluated using a dialysis method (Float a Lyzer 100kDa) and compared with the free drug solution. The drug was quantified using LC-MS/MS method. Finally, in vitro permeability study of decitabine-loaded LNC-RM was assessed in a Caco-2 cell model (2). Results and discussion: After freeze drying LNC-RM were stables showing an average size of around 30nm, with a low polydispersity index and a neutral zeta potential. The decitabine payload was 216±57µg/mL, with an encapsulation efficiency of 45±8%. The in vitro release results showed that, after 90min, almost 5% of decitabine was released from the LNC-RM, while the 45% was released from decitabine solution. The apparent permeability was increased when decitabine is encapsulated as compared to the free drug solution in the Caco-2 model after a contact of four hours. Conclusion: Here we presented a new formulation for the oral administration of decitabine. Further studies will be developed to assed the stability of the system in simulated gastro-intestinal media. References: (1) Heurtault B., et al. Pharm Research. 19(6), 2002 (2) Roger E., et al. Eur J Pharm Biopharm. 79(1), 201

    Decitabine encapsulation in nanovector to improve acute myeloid leukemia treatment

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    Acute myeloid leukemia (AML) mainly affects adult patients, and for older ones unfit for intensive chemotherapy only few therapies are available. Hypomethylating agents, as decitabine, is a labeled option but its plasma half-life is short whereas a long cell exposure time improves response rate. Only intravenous administration is available, whereas an oral route is generally preferred by patients. Consequently, to enhance plasma half-life and to develop an oral decitabine formulation, in this work decitabine was encapsulated in nanoparticles. Two different strategies were tested: decitabine loaded into lipid nanocapsules (DAC-LNC), and a decitabine-prodrug synthesis [3’(OH)-5’(OH)-(lauroyl)2-modified DAC] encapsulated into LNC (DAC-(C12)2-LNC). DAC-LNC and DAC-(C12)2-LNC particles were obtained with sizes of 26.5 ± 0.5 nm and 27.45 ± 0.05 nm respectively, and drug payloads of 0.47 ± 0.06 mg/mL and 5.8 ± 0.5 mg/mL (corresponding to 2.3 ± 0.2 mg/mL of decitabine). Both formulations were able to increase in vitro human plasma half-life by protecting decitabine from degradations. Compared to free-decitabine solutions, both nanoparticle formulations were able to preserve decitabine cytotoxicity on an AML cell line (HEL). Moreover, permeability studies across an adenocarcinoma cell model (Caco-2 cells) demonstrated that DAC-LNC improve decitabine’s intestinal permeability whereas DAC-(C12)2-LNC decreased it. However, this drawback could be countered by the enhanced decitabine’s stability in gastrointestinal fluids thanks to DAC-(C12)2-LNC, leading to more available drug for absorption. Globally, both formulation have demonstrated their ability to improve DAC plasma half-life in vitro and their potential for oral administration. In vivo pharmacokinetics evaluations may now confirm interests of such strategies

    Formulation and evaluation of new oxazaphosphorine prodrugs-loaded lipid nanocapsules for cancer treatment

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    Oxazaphosphorines (cyclophosphamide (CPA) and ifosfamide (IFO)) represent an important group of therapeutic molecules due to their substantial antitumor and immunomodulating activities. Unfortunately, despite the benefits brought by these molecules, their clinical use shows limitations, notably in chemotherapy, due to the development of resistance, interpatients variation and toxicities (urinary toxicity, neurotoxicity and nephrotoxicity). To circumvent these problems, new oxazaphosphorine analogs have been synthetized and present an interesting anti-tumor activity alone with reduced toxicity [1]. Pentanoxy moiety has been grafted on C4 position of ifosfamide (P-IFO). Nevertheless, these new analogs are lipophilic and unstable in aqueous medium. To administer it, this paper proposes to formulate this analog into nanocarriers. Lipid nanocapsules form a new generation of nanovector that can encapsulate a number of anticancer agents [2]. In the present research, P-IFO-loaded LNCs were formulated and characterized. A new formulation based on glycerol monooleate (Peceol®) was developed, optimized and then characterized. Batches of P-IFO-LNCs were obtained with a size of 47.2±0.7nm with a narrow size distribution and a drug payload of 8.42±1.05mg/g. The suspension remained stable at 4°C for 14 days in terms of mean particle size, polydispersity index and pH. The drug payload decreased after 7 days but a high rate was still found (5.88±1.01mg/g) up to 14 days. The stealth properties of these nanoparticles were examined in vitro using the complement activation (CH50) test. This test revealed a low consumption of plasma protein in the presence of such P-IFO-LNCs. In vitro cytotoxicity of P-IFO-LNCs was determined in two human cell lines; i.e. rhabdomyosarcoma (RMS-1) and Ewing sarcoma (A673) and showed a similar activity compared to the free form. Finally, in vivo activity testing of P-IFO-LNCs is in progress in a murine model bearing a RMS-1 xenograft after intravenous administration. References [1] Skarbek C, et al., Preactivated Oxazaphosphorines Designed for Isophosphoramide Mustard Delivery as Bulk Form or Nanoassemblies: Synthesis and Proof of Concept. Journal of Medicinal Chemistry. 22;58(2):105-17, 2015. [2] Huynh NT, et al., Lipid nanocapsules: A new platform for nanomedicine. International Journal of Pharmaceutics. 379(2):201–9, 2009. Acknowledgments: The authors are very grateful to the Ligue contre le Cancer, Comité du Maine et Loire and Comité d’Ille et Vilaine which founded this work

    In vitro anti-cancer activity and pharmacokinetic evaluation of curcumin-loaded lipid nanocapsules

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    In the present work, lipid nanocapsules (LNC) for curcumin (CCM) encapsulation have been developed and optimized. The objective was to increase drug cytotoxicity on 9L glioma cells and drug bioavailability following intravenous administration (IV). Using the phase inversion technique, we obtained 50 nm LNC loaded with CCM (4 and 6 mg/mL) and, due to the hydrophobic nature of the drug, the encapsulation efficiency was very high, being around 90%. Following 48 h of incubation with 9L cells, CCM-loaded LNC were able to reduce the viability of glioma cells resulting in significant twofold lower IC50 in comparison with the free drug solution. Moreover, CCM-loaded LNC induced both the apoptosis of 9L cells and a strong release of ATP. This suggests a cellular uptake of the LNC and an enhanced anti-proliferative effect. In order to evaluate any alteration in the pharmacokinetic behavior of the encapsulated drug, CCM-loaded LNC were injected IV into healthy rats, at a dose of 10 mg/kg. CCM pharmacokinetic studies were carried out quantifying the CCM concentration from the blood of rats, receiving either CCM-loaded LNC or free CCM solution as a control. The results demonstrated that loaded LNC exhibited a significantly higher AUC, C and t in comparison with the control, while the clearance was strongly reduced. Globally, these results encouraged the use of CCM-loaded LNC to enhance the in vivo therapeutic activity of the drug after systemic administration

    Modeling nigrostriatal degeneration in organotypic cultures, a new ex vivo model of Parkinson’s disease

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    Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder afflicting 2% of the population older than 65 years worldwide. Recently, brain organotypic slices have been used to model neurodegenerative disorders, including PD. They conserve brain three-dimensional architecture, synaptic connectivity and its microenvironment. This model has allowed researchers a simple and rapid method to observe cellular interactions and mechanisms. In the present study, we developed an organotypic PD model from rat brains that includes all the areas involved in the nigrostriatal pathway in a single slice preparation, without using neurotoxins to induce the dopaminergic lesion. The mechanical transection of the nigrostriatal pathway obtained during slice preparation induced PD-like histopathology. Progressive nigrostriatal degeneration was monitored combining innovative approaches, such as diffusion tensor magnetic resonance imaging (DT-RMI) to follow fiber degeneration and mass spectrometry to quantify striatal dopamine content, together with bright-field and fluorescence microscopy imaging. A substantia nigra dopaminergic cell number decrease was observed by immunohistochemistry against rat tyrosine hydroxylase (TH) reaching 80% after 2 days in culture associated with a 30% decrease of striatal TH-positive fiber density, a 15% loss of striatal dopamine content quantified by mass spectrometry and a 70% reduction of nigrostriatal fiber fractional anisotropy quantified by DT-RMI. In addition, a significant decline of medium spiny neuron density was observed from days 7 to 16. These sagittal organotypic slices could be used to study the early stage of PD, namely dopaminergic degeneration, and the late stage of the pathology with dopaminergic and GABAergic neuron loss. This novel model might improve the understanding of PD and may represent a promising tool to refine the evaluation of new therapeutic approaches

    Stealth nanocarriers based sterosomes using PEG post-insertion process

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    Sterosomes (STEs), a new and promising non-phospholipidic liposome platform based on palmitic acid (PA) and cholesterol (Chol) mixtures, need to have polyethylene glycol (PEG) chains grafted to their surface in order to obtain long-circulating nanocarriers in the blood stream. A post-insertion method was chosen to achieve this modification. The post-insertion process of PEG-modified distearoylphosphoethanolamine (DSPE-PEG) was monitored using the zeta potential value of STEs. Various conditions including PEG chain length and the DSPE-PEG/PA-Chol ratio, were explored. Zeta potential of STEs changed from about -40mV for non-modified STEs to values close to 0 mV by the end of the process, i.e. for PEG-modified STEs. The kinetics of DSPE-PEG insertion and the stability of the resulting PEG-modified STEs were not considerably influenced, within the investigated range, by changes in PEG chain lengths and in DSPE-PEG/PA-Chol proportion. The post-insertion of PEG chains reduced in vitro complement activation as well as in vitro macrophage uptake compared to the non-modified STEs. Moreover, longer blood circulation time in mice was established for PEG-modified STEs intravenously injected compared to non-modified STEs. These results establish that post-insertion process of PEG chains to STEs is a promising strategy for developing long-term circulating drug delivery nanocarriers

    Development and in vitro evaluation of a novel lipid nanocapsule formulation of etoposide.

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    Small cell lung cancer (SCLC) is the most aggressive carcinoma in thoracic oncology, unfortunately, despite chemotherapy, relapse is constant. The effect of etoposide, a major drug used against SCLC, can potentially be enhanced after its encapsulation in nanocarriers. The aim of this study was to use the technology of lipid nanocapsules (LNCs) to obtain nanocarriers with drug loadings compatible with clinical use and with an industrial process. Solubility studies with different co-solvent were first performed, then several process were developed to obtain LNCs. LNCs were then characterized (size, zeta potential, and drug loading). The best formulation called Ω-LNCs had a size of 54.1±2.0 nm and a zeta potential of -5.8±3.5 mV and a etoposide drug loading of 5.7±0.3mg/g. The characteristics of this formulation were maintained after freeze drying and after a 15× scale-up. Release studies in a media mimicking plasma composition showed that 40% of the drug was released from the LNCs after 48 h. Moreover the activity of etoposide after encapsulation was enhanced on H209 cells, IC50 was 100 μM and 2.5 μM for etoposide and etoposide LNCs respectively. Unfortunately the formulation failed to be more cytotoxic than etoposide alone on H69AR cells that are resistant to etoposide. This study showed that is was possible to obtain a new etoposide nanocarrier without the use of organic solvent, that the process is suitable for scale-up and freeze drying and finally that etoposide activity is maintained which is very promising for future treatment of SCLC
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