RESUMO
Seriniquinone (SQ) was initially described by our group as an antimelanoma drug candidate and now also as an antifungal drug candidate. Despite its promising in vitro effects, SQ translation has been hindered by poor water-solubility. In this paper, we described the challenging nanoformulation process of SQ, which culminated in the selection of a phosphatidylcholine-based lamellar phase (PLP1). Liposomes and nanostructured lipid carriers were also evaluated but failed to encapsulate the compound. SQ-loaded PLP1 (PLP1-SQ) was characterized for the presence of sedimented or non-dissolved SQ, rheological and thermal behavior, and irritation potential with hen's egg test on the chorioallantoic membrane (HET-CAM). PLP1 influence on transepidermal water loss (TEWL) and skin penetration of SQ was assessed in a porcine ear skin model, while biological activity was evaluated against melanoma cell lines (SK-MEL-28 and SK-MEL-147) and C. albicans SC5314. Despite the presence of few particles of non-dissolved SQ (observed under the microscope 2 days after formulation obtainment), PLP1 tripled SQ retention in viable skin layers compared to SQ solution at 12 h. This effect did not seem to relate to formulation-induced changes on the barrier function, as no increases in TEWL were observed. No sign of vascular toxicity in the HET-CAM model was observed after cutaneous treatment with PLP1. SQ activity was maintained on melanoma cells after 48 h-treatment (IC50 values of 0.59-0.98 µM) whereas the minimum inhibitory concentration (MIC) against C. albicans after 24 h-treatment was 32-fold higher. These results suggest that a safe formulation for SQ topical administration was developed, enabling further in vivo studies.
Assuntos
Melanoma , Micoses , Neoplasias Cutâneas , Animais , Feminino , Suínos , Galinhas , Melanoma/metabolismo , Pele/metabolismo , Neoplasias Cutâneas/metabolismo , Candida albicans , Água/farmacologiaRESUMO
In this study, the addition of monoolein to phosphatidylcholine (PC), tricaprylin, and propylene glycol (PG) mixtures was studied to produce fluid precursor formulations (FIPs) that could transform into hexagonal phase (resistant to aqueous dilution) in vitro and in vivo. The overall goal was to obtain FIPs that could incorporate chemopreventive drugs for subcutaneous administration in the mammary tissue to inhibit the development and/or recurrence of breast cancer. Increasing PG content reduced FIP viscosity up to ~ 2.5-fold, while increases in PC (over monoolein) increased the formation of emulsified systems. The hexagonal phase was observed at 20% of water and higher, with the minimum amount of water necessary for this formation increasing with PG content. The selected FIP formed a depot in vivo after ~ 24 h of administration; its structure was compatible with the hexagonal phase and it remained in the mammary tissue for at least 30 days, prolonging the permanence of a fluorescent probe. In vitro, the release of the synthetic retinoid fenretinide was slow, with ~ 9% of the drug released in 72 h. Consistent with this slow release, fenretinide IC50 in breast cancer cells was ~ 100-fold higher in the selected FIP compared to its solution. The FIP reduced cell migration and presented higher cytotoxicity towards tumor compared to non-tumor cells. Given the limited number of options for pharmacological prevention of breast cancer development and recurrences, this formulation could potentially find applicability to reduce the frequency of administration and improve local concentrations of chemopreventive drugs.
Assuntos
Neoplasias da Mama , Fenretinida , Neoplasias da Mama/tratamento farmacológico , Liberação Controlada de Fármacos , Feminino , Corantes Fluorescentes , Humanos , Fosfatidilcolinas , Propilenoglicol/química , Água/químicaRESUMO
Nanoemulsions modified with chitosan (NE-Q) or hyaluronic acid (NE-HA), developed for intraductal administration of piplartine (piperlongumine) and local breast cancer treatment, were evaluated for cytotoxic effects in vitro in 2D and 3D breast cancer models and in vivo in a chemically induced carcinogenesis model. Droplet size was lower than 100 nm, and zeta potential varied from +17.9 to -25.5 mV for NE-Q and NE-HA, respectively. Piplartine nanoencapsulation reduced its IC50 up to 3.6-fold in T-47D and MCF-7 monolayers without differences between NE-Q and NE-HA, and up to 6.6-fold in cancer spheroids. Cytotoxicity improvement may result from a more efficient NE-mediated delivery, as suggested by stronger fluorescent staining of cells and spheroids. In 1-methyl-1-nitrosourea -induced breast cancer models, intraductal administration of piplartine-loaded NE-HA inhibited breast tumor development and histological alterations. These results support the potential applicability of piplartine-loaded NE-HA for intraductal treatment of breast cancer.
Assuntos
Neoplasias da Mama , Quitosana , Nanopartículas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quitosana/farmacologia , Feminino , Humanos , Ácido Hialurônico/farmacologia , PiperidonasRESUMO
The high incidence and costs of chronic wounds in the elderly have motivated the search for innovations to improve product performance and the healing process while reducing costs. In this study, bioadhesive nanostructured lipid carriers (NLC) were developed for the co-encapsulation of compounds with antioxidant (α-tocopherol and quercetin) and antimicrobial (tea tree oil) activity for management of wounds. The NLC was produced with shea butter and argan oil, and modified with sodium alginate or chitosan to confer bioadhesive properties. Spherical nanoparticles of ~307-330 nm and zeta potential varying from -21.2 to +11.8 mV were obtained. Thermal analysis demonstrated that the lipid matrix reduced tea tree oil thermal loss (~1.8-fold). Regardless of the type of polysaccharide employed, the NLCs promoted cutaneous localization of antioxidants in damaged (subjected to incision) skin, with a ~74 to 180-fold higher delivery into the skin compared to percutaneous delivery. This result is consistent with the similar bioadhesive properties of chitosan or sodium alginate-modified NLC. Nanoencapsulation of tea tree oil did not preclude its antimicrobial effects against susceptible and resistant strains of S. aureus and P. aeruginosa, while co-encapsulation of antioxidants increased the NLC-induced fibroblasts migration, supporting their potential usefulness for management of wounds.
Assuntos
Alginatos/química , Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Quitosana/química , Portadores de Fármacos , Lipídeos/química , Nanopartículas , Cicatrização/efeitos dos fármacos , Animais , Anti-Infecciosos/química , Antioxidantes/química , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Composição de Medicamentos , Fibroblastos/efeitos dos fármacos , Humanos , Lipídeos/isolamento & purificação , Óleos de Plantas/química , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Quercetina/química , Quercetina/farmacologia , Sapotaceae/química , Pele/efeitos dos fármacos , Pele/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Óleo de Melaleuca/química , Óleo de Melaleuca/farmacologia , alfa-Tocoferol/química , alfa-Tocoferol/farmacologiaRESUMO
As a new strategy for treatment of ductal carcinoma in situ, biocompatible and bioadhesive nanoemulsions for intraductal administration of the cytotoxic agent piplartine (piperlongumine) were optimized in this study. To confer bioadhesive properties, the nanoemulsion was modified with chitosan or hyaluronic acid. Tricaprylin was selected as the nanoemulsion non-polar phase due to its ability to dissolve larger drug amounts compared to isopropyl myristate and monocaprylin. Use of phosphatidylcholine as sole surfactant did not result in a homogeneous nanoemulsion, while its association with polysorbate 80 and glycerol (in a surfactant blend) led to the formation of nanoemulsions with droplet size of 76.5⯱â¯1.2â¯nm. Heating the aqueous phase to 50⯰C enabled sonication time reduction from 20 to 10â¯min. Inclusion of either chitosan or hyaluronic acid resulted in nanoemulsions with similar in vitro bioadhesive potential, and comparable ability to prolong mammary tissue retention (to 120â¯h) in vivo without causing undesirable histological alterations. Piplartine was stable in both nanoemulsions for 60â¯days; however, the size of loaded NE-HA was maintained at a similar range for longer periods of time, suggesting that this nanoemulsion may be a stronger candidate for intraductal delivery.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Dioxolanos/administração & dosagem , Glândulas Mamárias Animais/metabolismo , Nanopartículas/administração & dosagem , Piperidonas/administração & dosagem , Adesividade , Animais , Antineoplásicos Fitogênicos/química , Galinhas , Quitosana/administração & dosagem , Quitosana/química , Membrana Corioalantoide/efeitos dos fármacos , Dioxolanos/química , Vias de Administração de Medicamentos , Emulsões , Feminino , Glicerol/administração & dosagem , Glicerol/química , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Nanopartículas/química , Fosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/química , Piperidonas/química , Polissorbatos/administração & dosagem , Polissorbatos/química , Ratos Wistar , Pele/química , SuínosRESUMO
In spite of the high incidence of breast cancer worldwide, there are few strategies for its chemoprevention, and they have limited adherence mainly due to their serious adverse effects. As a new approach for local breast cancer chemoprevention, we developed and optimized microemulsions for topical delivery of celecoxib to the breast skin, and evaluated their combination with microneedles to improve drug penetration for localization in the mammary tissue. Microemulsions containing water at 15% (ME-15), 29% (ME-29) and 60% (ME-60) were obtained and characterized. They were isotropic, displayed Newtonian behavior and particle size smaller than 100â¯nm. ME-15 and ME-29 increased transepidermal water loss (TEWL) compared to ME-60, and displayed stronger vascular toxicity, evidenced by hemorrhage and lysis in HET-CAM assays. ME-60 was more efficacious at increasing celecoxib cutaneous and percutaneous delivery (1.3-4-fold). Increasing the number of microneedle roller applications from 1 to 8 increased the number of skin punctures and TEWL; its association with ME-60 promoted no further increase in TEWL, but improved (1.6-4-fold) celecoxib cutaneous and percutaneous delivery. Microemulsion incorporation reduced celecoxib IC50 in MCF-7 cells (3.3-fold), suggesting that presence of formulation components in the mammary tissue might improve drug cytotoxicity.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Celecoxib/administração & dosagem , Sistemas de Liberação de Medicamentos , Absorção Cutânea , Administração Cutânea , Animais , Celecoxib/farmacocinética , Celecoxib/farmacologia , Química Farmacêutica/métodos , Quimioprevenção/métodos , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Inibidores de Ciclo-Oxigenase 2/farmacologia , Emulsões , Feminino , Humanos , Concentração Inibidora 50 , Células MCF-7 , Agulhas , Tamanho da Partícula , SuínosRESUMO
Considering that breast cancer usually begins in the lining of the ducts, local drug administration into the ducts could target cancers and pre-tumor lesions locally while reducing systemic adverse effects. In this study, a cationic bioadhesive nanoemulsion was developed for intraductal administration of C6 ceramide, a sphingolipid that mediates apoptotic and non-apoptotic cell death. Bioadhesive properties were obtained by surface modification with chitosan. The optimized nanoemulsion displayed size of 46.3 nm and positive charge, properties that were not affected by ceramide encapsulation (0.4%, w/w). C6 ceramide concentration necessary to reduce MCF-7 cells viability to 50% (EC50) decreased by 4.5-fold with its nanoencapsulation compared to its solution; a further decrease (2.6-fold) was observed when tributyrin (a pro-drug of butyric acid) was part of the oil phase of the nanocarrier, a phenomenon attributed to synergism. The unloaded nanocarrier was considered safe, as indicated by a score <0.1 in HET-CAM models, by the high survival rates of Galleria mellonella larvae exposed to concentrations ≤500 mg/mL, and absence of histological changes when intraductally administered in rats. Intraductal administration of the nanoemulsion prolonged drug localization for more than 120 h in the mammary tissue compared to its solution. These results support the advantage of the optimized nanoemulsion to enable mammary tissue localization of C6 ceramide.