Polyvinyl Alcohol (PVA)-Based Nanoniosome for Enhanced in vitro Delivery and Anticancer Activity of Thymol

Introduction: There is an unmet need to develop potent therapeutics against cancer with minimal side effects and systemic toxicity. Thymol (TH) is an herbal medicine with anti-cancer properties that has been investigated scientifically. This study shows that TH induces apoptosis in cancerous cell lines such as MCF-7, AGS, and HepG2. Furthermore, this study reveals that TH can be encapsulated in a Polyvinyl alcohol (PVA)-coated niosome (Nio-TH/PVA) to enhance its stability and enable its controlled release as a model drug in the cancerous region. Materials and Methods: TH-loaded niosome (Nio-TH) was fabricated and optimized using Box–Behnken method and the size, polydispersity index (PDI) and entrapment efficiency (EE) were characterized by employing DLS, TEM and SEM, respectively. Additionally, in vitro drug release and kinetic studies were performed. Cytotoxicity, antiproliferative activity, and the mechanism were assessed by MTT assay, quantitative real-time PCR, flow cytometry, cell cycle, caspase activity evaluation, reactive oxygen species investigation, and cell migration assays. Results: This study demonstrated the exceptional stability of Nio-TH/PVA at 4 °C for two months and its pH-dependent release profile. It also showed its high toxicity on cancerous cell lines and high compatibility with HFF cells. It revealed the modulation of Caspase-3/Caspase-9, MMP-2/MMP-9 and Cyclin D/ Cyclin E genes by Nio-TH/PVA on the studied cell lines. It confirmed the induction of apoptosis by Nio-TH/PVA in flow cytometry, caspase activity, ROS level, and DAPI staining assays. It also verified the inhibition of metastasis by Nio-TH/PVA in migration assays. Conclusion: Overall, the results of this study revealed that Nio-TH/PVA may effectively transport hydrophobic drugs to cancer cells with a controlled-release profile to induce apoptosis while exhibiting no detectable side effects due to their biocompatibility with normal cells

Folate-Targeted Curcumin-Loaded Niosomes for Site-Specific Delivery in Breast Cancer Treatment: In Silico and In Vitro Study

As the most common cancer in women, efforts have been made to develop novel nanomedicine-based therapeutics for breast cancer. In the present study, the in silico curcumin (Cur) properties were investigated, and we found some important drawbacks of Cur. To enhance cancer therapeutics of Cur, three different nonionic surfactants (span 20, 60, and 80) were used to prepare various Cur-loaded niosomes (Nio-Cur). Then, fabricated Nio-Cur were decorated with folic acid (FA) and polyethylene glycol (PEG) for breast cancer suppression. For PEG-FA@Nio-Cur, the gene expression levels of Bax and p53 were higher compared to free drug and Nio-Cur. With PEG-FA-decorated Nio-Cur, levels of Bcl2 were lower than the free drug and Nio-Cur. When MCF7 and 4T1 cell uptake tests of PEG-FA@Nio-Cur and Nio-Cur were investigated, the results showed that the PEG-FA-modified niosomes exhibited the most preponderant endocytosis. In vitro experiments demonstrate that PEG-FA@Nio-Cur is a promising strategy for the delivery of Cur in breast cancer therapy. Breast cancer cells absorbed the prepared nanoformulations and exhibited sustained drug release characteristics

Ligand-functionalized nanoparticles for targeted therapy of melanoma in situ

Diretores de Tese : Dra. Patrícia Rijo ; Dra. Catarina Reis ; Dr. Jesús MolpeceresEl melanoma cutáneo es un tipo de cáncer con origen en los melanocitos que se vuelven malignos. El tratamiento del melanoma cutáneo ha evolucionado mucho en los últimos treinta años, sin embargo, no ha conseguido incrementar significativamente la supervivencia de los pacientes con cáncer avanzado. Además, el tratamiento presenta muchas limitaciones, como una reducida especificidad, efectos secundarios graves y multi-resistencia a los fármacos. De hecho, un paso importante para el éxito del tratamiento del melanoma es su detección precoz. En el caso de que no haya metástasis, el cáncer puede ser extirpado por cirugía, pero hay casos en que el riesgo de la intervención, así como el elevado riesgo de recurrencia, obligan a un tratamiento adyuvante. Actualmente, sólo está aprobado un tratamiento adyuvante, con interferón alfa, para estos casos. De este modo, el principal objetivo de esta tesis es el estudio de alternativas para tratamientos adyuvantes, más eficientes y menos agresivos, del melanoma cutáneo. En este contexto, se han estudiado dos estrategias para aplicación de sistemas de nanopartículas. La primera estrategia consiste en el desarrollo de nanopartículas de oro, cubiertas con polímeros naturales y péptidos, con absorción en la región del infrarojo próximo, para terapia fototérmica. La segunda estrategia incluye el desarrollo de nanopartículas hibridas, para encapsulación de compuestos antitumorales, cubiertas con polímeros naturales y péptidos, capaces de una acción química local en el tumor. Conjuntamente, hemos investigado el comportamiento físico-químico y la estabilidad de las nanopartículas para cada aplicación. Reconociendo la importancia de un tratamiento eficaz y específico, ambas las estrategias se basan en un direccionamiento específico hacia las células de melanoma, que sobre-expresan múltiples receptores en su superficie. Por fin, se utilizaron modelos animales de melanoma humano para evaluación de la eficacia de las dos formulaciones propuestas. En conclusión, es posible desarrollar nanosistemas que comprenden diferentes estrategias terapéuticas, basadas en núcleos con estructuras distintas y funcionalización de superficies con múltiples ligandos, para una aplicación amplia y exitosa en los cánceres heterogéneos, tales como el melanoma cutáneo.Cutaneous melanoma occurs on the skin and is the most common type of melanoma. Treatment of cutaneous melanoma has improved over the last thirty years; however, without demonstrating a significant increase on survival of patients with advanced disease. Indeed, conventional treatment generally shows several limitations, such as reduced target specificity, severe adverse effects and multiple drug resistance. In fact, an important step for the success of melanoma treatment is its early detection. In cases where there are no metastases, this cancer can be removed by surgery, but in some cases the risk of intervention has to be measured, as well as the high risk of recurrence, which impose the use of an adjuvant treatment. Currently, there is only one adjuvant treatment approved, with interferon alpha, in these cases. Therefore, the main objective of this thesis was the study of alternatives as adjuvant treatments, more efficient and less aggressive, for cutaneous melanoma. In this context, two strategies have been studied for application of nanoparticles systems. The first strategy is focused on the development of gold nanoparticles, coated with natural polymers and peptides, with absorption at the near infrared range, for photothermal therapy. The second strategy includes the development of hybrid nanoparticles, for encapsulation of anti-tumor compounds, coated with natural polymers and peptides, capable of a local chemotherapy at the tumor site. Overall, the physico-chemical behavior and stability of both nanoparticles for each application were investigated. Recognizing the importance of an efficient and specific treatment, both strategies were based on a specific targeting to melanoma cells, which overexpressed multiple receptors at their surface. At last, animal models for human melanoma were used for evaluation of the efficiency of both proposed strategies. In conclusion, it is possible to develop nanosystems comprising different therapeutic strategies, based on distinct core structures and surface functionalization with multiple targeting ligands, for a broad and potential application in heterogeneous cancers, such as cutaneous melanoma