Molybdenum cluster loaded PLGA nanoparticles: An innovative theranostic approach for the treatment of ovarian cancer

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Molybdenum cluster loaded PLGA nanoparticles as efficient tools against epithelial ovarian cancer

International audienceIn this study, poly (lactic-co-glycolic) acid nanoparticles loading inorganic molybdenum octahedral cluster were used for photodynamic therapy (PDT) of ovarian cancer. Three cluster compounds, ((CH)N)[{MoBr}Br], Cs[{MoBr}Br] and Cs[{MoI}(OOCF)] denoted TMB, CMB and CMIF were studied following their incorporation in nanoparticles by a nanoprecipitation method. All resulting nanoparticles exhibited physico-chemical characteristics such as size and zeta potential compatible with cellular uptake. All cluster compounds tested were shown to produce singlet oxygen in vitro once released from their nanoparticulate system. Confocal images showed an internalisation of cluster loaded nanoparticles (CNPs) in A2780 ovarian cancer cell line, more efficient with CMIF compared to CMB or TMB loaded nanoparticles. In vitro cellular viability studies conducted on A2780 cell line treated with non activated CNPs did not show any sign of toxicity for concentrations up to 15 µM. Following photo-activation, CNPs were able to generate singlet oxygen resulting in a decrease of the cellular viability, compared to non-activated conditions. Nevertheless, no significant differences between IC with or without photo-activation were observed with TMB and CMB CNPs while for CMIF loaded nanoparticles, the photo-activation led to a significant decrease of cellular viability compared to the non activated condition and this decrease was independant of the P/C ratio. The strong photo-toxicity obtained for CMIF loaded nanoparticles with a P/C ratio of 2.5, as shown with half maximal inhibitory concentration (IC) value near 1.8 µM suggests that PLGA nanoparticles seem to be efficient delivery systems intended for tumor management and that CMIF can be further investigated as photosensitizer for PDT of ovarian cancer

PLGA nanoparticles embedding molybdenum cluster salts: Influence of chemical composition on physico-chemical properties, encapsulation efficiencies, colloidal stabilities and in vitro release

International audienceWe present a screening of poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles embedding a series of inorganic molybdenum octahedral clusters intended for photodynamic therapy (PDT) of cancer. Three cluster compounds from 2 cluster units, [{Mo6Br8}Br6]2− and [{Mo6I8}(OOC2F5)6]2− were studied. [{Mo6Br8}Br6]2−cluster units are found in the soluble ternary salt Cs2[{Mo6Br8}Br6] (CMB) prepared by solid state chemistry at high temperature. In solution Cs+ cations are replaced by tetrabutyl ammonium cations (C4H9)4N+) to form the salt ((C4H9)4N)2[{Mo6Br8}Br6] (TBA2). [{Mo6I8}(OOC2F5)6]2− was prepared combining solid state and solution chemistries; it is paired with Cs+ cations to form Cs2[{Mo6I8}(OOC2F5)6] (CMIF). All tested cluster-based salts could efficiently be incorporated in PLGA nanoparticles as seen with encapsulation efficiencies always higher than 60%. Cluster loaded nanoparticles (CNPs) freshly prepared by solvent displacement method showed spherical shapes, zeta potential values between −20 and −47 mV, polydispersity index in the range 0.123–0.167 and sizes in the range 75–150 nm according to the cluster compound and the polymer-to-cluster mass ratio (P/C), suggesting a good cellular uptake. CNPs colloidal stability was maintened for 3 months when they were stored refrigerated and protected from light but the chemical stability was shorter, i.e. 4 weeks, 1 week and 1 day for CMIF, TBA2 and CMB, respectively, CMIF penta-fluoropropionate apical ligands being less rapidly substituted by hydroxyles groups than TBA2 and CMB halogen apical ligands. FT-IR analysis revealed the lack of strong chemical interaction between cluster compounds and polymer within the nanoparticles. An interesting quick cluster in vitro release driven by diffusion outside the nanoparticles porous matrix was observed for all cluster compounds when P/C ratio was ≤2.5 and only a higher P/C ratio not studied in this work (i.e. >5) could significantly affect the release of the encapsulated cluster compound. Photophysical properties of cluster compounds were preserved following PLGA incorporation. This work presents PLGA nanoparticles as a stable and efficient cluster compound delivery systems for further in vitro and vivo evaluations in cancer models

Macrophage-Specific Targeting of Isoniazid Through Mannosylated Gelatin Microspheres

Active targeting of drug molecules can be achieved by effective attachment of suitable ligands to the surface of carriers. The present work was attempted to prepare mannosylated gelatin microspheres (m-GMs) so as to achieve targeted delivery of isoniazid (INH) to alveolar macrophages (AMs) and maintain its therapeutic concentration for prolonged period of time. Microspheres were prepared by emulsification solvent extraction method and evaluated for physicochemical characteristics, drug release, ex vivo drug uptake by AMs and pharmacokinetic characteristics. Fourier transform infrared spectroscopy and nuclear magnetic resonance spectral analysis confirmed that mannosylation took place through Schiff base formation between aldehyde and amino groups of mannose and gelatin, respectively. Prepared microspheres offered suitable physicochemical characteristics for their delivery to AMs. Their average size was about 4 μm and drug entrapment efficiency of 56% was achieved with them. Ex vivo uptake results indicated that in comparison to plain microspheres, m-GMs were selectively uptaken and were found to be associated with phago-lysosomal vesicles of AMs. Pharmacokinetic studies showed the formulation could maintain the therapeutic concentration of INH for prolonged period of time even with a reduced clinical dose. m-GMs were found to be stable in broncheo-alveolar lavage fluid. The study concluded that ligand decorated carriers could be a potential strategy to improve the therapeutic properties of INH