Oily core/amphiphilic polymer shell nanocapsules change the intracellular fate of doxorubicin in breast cancer cells.

The aim of this work was to develop and test the in vitro biological activity of nanocapsules loaded with a doxorubicin (DOX) free base dissolved in a core of castor oil shelled by poly(methyl vinyl ether-co-maleic anhydride) conjugated to n-octadecylamine residues. This system was stable and monodisperse, with a hydrodynamic diameter of about 300 nm. These nanocapsules changed the intracellular distribution of DOX, from the nuclei to the cytoplasm, and exhibited higher toxicity towards cancer cells - 4T1 and MCF-7 - and significantly lower toxicity towards normal cells - NIH-3T3 and MCF-10A - in vitro. In conclusion, these nanocapsules are suitable DOX carriers, which remain to be studied in in vivo tumor models.

Decoration of a Poly(methyl vinyl ether-co-maleic anhydride)-Shelled Selol Nanocapsule with Folic Acid Increases Its Activity Against Different Cancer Cell Lines In Vitro.

Due to the low therapeutic index of different chemotherapeutic drugs used for cancer treatment, the development of new anticancer drugs remains an intense field of research. A recently developed mixture of selenitetriacylglycerides, selol, was shown to be active against different cancer cells in vitro. As this compound is highly hydrophobic, it was encapsulated, in a previous study, into poly(methyl vinyl ether-co-maleic anhydride)-shelled nanocapsules in order to improve its dispersibility in aqueous media. Following this line of research, the present report aimed at enhancing the In Vitro activity of the selol nanocapsules against cancerous cells by decorating their surface with folic acid. It is known that several cancer cells overexpress folate receptors. Stable folic acid-decorated selol nanocapsules (SNP-FA) were obtained, which showed to be spherical, with a hydro-dynamic diameter of 364 nm, and zeta potential of -24 mV. In comparison to non-decorated selol nanocapsules, SNP-FA presented higher activity against 4T1, MCF-7 and HeLa cells. Moreover, the decoration of the nanocapsules did not alter their toxicity towards fibroblasts, NIH-3T3 cells. These results show that the decoration with folic acid increased the toxicity of selol nanocapsules to cancer cells. These nanocapsules, besides enabling to disperse selol in an aqueous medium, increased the toxicity of this drug In Vitro, and may be useful to treat cancer in vivo, potentially increasing the specificity of selol towards cancer cells.

Self-nanoemulsifying drug-delivery systems improve oral absorption and antischistosomal activity of epiisopiloturine.

AIM: To develop a self-nanoemulsifying drug-delivery system (SNEDDS) able to improve oral absorption of epiisopiloturine (EPI), and test the antischistosomal activity in a mice model. RESULTS: SNEDDS had a nanoscopic size and was able to enhance EPI bioavailability after oral administration, and SNEDDS-EPI (40 mg.kg-1) improved the in vivo antischistosomal activity of EPI, demonstrating that SNEDDS was able to improve the pharmacokinetics of EPI, and to maintain the pharmacodynamic activity against Schistosoma mansoni in vivo. CONCLUSION: Taken together, these results indicate that SNEDDS-EPI is efficient in reducing worm burden in comparison to treatment with the free version of EPI. [Formula: see text].

Nanocapsules for the co-delivery of selol and doxorubicin to breast adenocarcinoma 4T1 cells in vitro.

Nanocapsules (NCS-DOX) with an oily core of selol and a shell of poly(methyl vinyl ether-co-maleic anhydride) covalently conjugated to doxorubicin were developed. These nanocapsules are spherical, with an average hydrodynamic diameter of about 170 nm, and with negative zeta potential. NCS-DOX effectively co-delivered the selol and the doxorubicin into 4T1 cells and changed the intracellular distribution of DOX from the nuclei to the mitochondria. Moreover, a significantly increased cytotoxicity against 4T1 cells was observed, which is suggestive of additive or synergic effect of selol and doxorubicin. In conclusion, PVM/MA nanocapsules are suitable platforms to co-deliver drugs into cancer cells.

Exploring the pH Sensitivity of Poly(allylamine) Phosphate Supramolecular Nanocarriers for Intracellular siRNA Delivery.

Silencing RNA (siRNA) technologies emerge as a promising therapeutic tool for the treatment of multiple diseases. An ideal nanocarrier (NC) for siRNAs should be stable at physiological pH and release siRNAs in acidic endosomal pH, fulfilling siRNA delivery only inside cells. Here, we show a novel application of polyamine phosphate NCs (PANs) based on their capacity to load negatively charged nucleic acids and their pH stability. PANs are fabricated by complexation of phosphate anions from phosphate buffer solution (PB) with the amine groups of poly(allylamine) hydrochloride as carriers for siRNAs. PANs are stable in a narrow pH interval, from 7 to 9, and disassemble at pH's higher than 9 and lower than 6. siRNAs are encapsulated by complexation with poly(allylamine) hydrochloride before or after PAN formation. PANs with encapsulated siRNAs are stable in cell media. Once internalized in cells following endocytic pathways, PANs disassemble at the low endosomal pH and release the siRNAs into the cytoplasm. Confocal laser scanning microscopy (CLSM) images of Rhodamine Green labeled PANs (RG-PANs) with encapsulated Cy3-labeled siRNA in A549 cells show that siRNAs are released from the PANs. Colocalization experiments with labeled endosomes and either labeled siRNAs prove the translocation of siRNAs into the cytosol. As a proof of concept, it is shown that PANs with encapsulated green fluorescence protein (GFP) siRNAs silence GFP in A549 cells expressing this protein. Silencing efficacy was evaluated by flow cytometry, CLSM, and Western blot assays. These results open the way for the use of poly(allylamine) phosphate nanocarriers for the intracellular delivery of genetic materials.

Photodynamic Therapy treatment of onychomycosis with Aluminium-Phthalocyanine Chloride nanoemulsions: A proof of concept clinical trial.

The conventional treatment of onychomycosis, a common fungal infection, consists in the use of local and systemic drugs for 4-6 months. This long protocol is often ineffective due to patient compliance, and usually promotes important collateral effects such as liver and kidney failure. As the alternative, Photodynamic Therapy (PDT) has been used as a noninvasive alternative local treatment for onychomycosis due to the reduction of systemic side effects, fact indicates their use for patients undergoing other systemic treatments. In the present article, we evaluated the effectiveness, as well as the safety of PDT mediated by Aluminium-Phthalocyanine Chloride, entrapped in nanoemulsions, as a drug carrier, to treat onychomycosis in a proof of concept clinical trial. To the date, this is the first published clinical trial that uses PDT mediated by nanomedicines to treat onychomycosis. As main results, we can highlight the safety of the clinical protocol and the antifungal effectiveness similar to the conventional treatments. We observed the (1) clinical cure of 60% of treated lesions; (2) the absence of local and systemic adverse effects; (3) from these clinically healed lesions, 40% were negative for fungal infection in laboratorial exams; and (4) nails that presented negative fungal culture were kept without fungal infection for at least four weeks. The innovation of this approach is the absence of collateral effects, due to the local therapeutically treatment, and the possibility to repeat the treatment without inducing fungal resistance, a fact that indicates this approach as a possible alternative protocol for onychomycosis management.

Aluminium-phthalocyanine chloride nanoemulsions for anticancer photodynamic therapy: Development and in vitro activity against monolayers and spheroids of human mammary adenocarcinoma MCF-7 cells.

BACKGROUND: Photodynamic therapy (PDT) combines light, molecular oxygen and a photosensitizer to induce oxidative stress in target cells. Certain hydrophobic photosensitizers, such as aluminium-phthalocyanine chloride (AlPc), have significant potential for antitumor PDT applications. However, hydrophobic molecules often require drug-delivery systems, such as nanostructures, to improve their pharmacokinetic properties and to prevent aggregation, which has a quenching effect on the photoemission properties in aqueous media. As a result, this work aims to develop and test the efficacy of an AlPc in the form of a nanoemulsion to enable its use in anticancer PDT. RESULTS: The nanoemulsion was developed using castor oil and Cremophor ELP®, and a monodisperse population of nanodroplets with a hydrodynamic diameter of approximately 25 nm was obtained. While free AlPc failed to show significant activity against human breast adenocarcinoma MCF-7 cells in an in vitro PDT assay, the AlPc in the nanoemulsion showed intense photodynamic activity. Photoactivated AlPc exhibited a 50 % cytotoxicity concentration (CC50) of 6.0 nM when applied to MCF-7 cell monolayers and exerted a powerful cytotoxic effect on MCF-7 cell spheroids. CONCLUSION: Through the use of spontaneous emulsification, a stable AlPc nanoemulsion was developed that exhibits strong in vitro photodynamic activity on cancer cells.