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- Development of gold core silica shell nanospheres for cancer therapyPublication . Guimarães, Rafaela da Silva; Correia, Ilídio Joaquim Sobreira; Moreira, André Ferreira; Rodrigues, Ana Carolina FélixCurrently, cancer is major public health problem, presenting an increasing incidence and mortality rate that affects the worldwide population. Among the treatments used in the clinic, chemotherapy is the most commonly used anticancer therapy, despite its low therapeutic efficacy. This scenario can be explained by rapid degradation, reduced solubility, and selectivity of chemotherapeutic drugs to cancer cells. Additionally, cancer cells can develop resistance to multiple drugs, which highlights the necessity to develop novel and more effective anti-cancer approaches. Combinatorial therapies based on the simultaneous administration of multiple drugs can lead to synergistic effects, which consequently increase the therapeutic efficiency of chemotherapy. However, chemotherapeutic drugs present limitations that impair their intravenous administration. Thus, despite the need to found novel drug combinations with high therapeutic potential, it is crucial to develop delivery systems capable of increasing the drugs’ therapeutic selectivity and efficacy while simultaneously decreasing their systemic toxicity. Among the drug delivery systems that have been developed so far, gold core silica shell (AuMSS) nanoparticles present excellent physicochemical and biological properties that allow their simultaneous application in chemotherapy and bioimaging. Thus, the research work developed during the second year of my master’s degree aimed to design a dual drug combination based on Doxorubicin (DOX) and Acridine orange (AO) to be encapsulated in AuMSS nanospheres. Moreover, a novel AuMSS surface modification using 3-(Triethoxysilyl)propyl isocyanate-Poly(ethylene glycol)-4- Methoxybenzamide (TPANIS) was developed to improve nanoparticles’ blood circulation time and specificity to cancer cells. The 4-Methoxybenzamide or Anisamide (ANIS) was selected due to its specificity for sigma receptors that are overexpressed in the cancer cells’ membranes. On the other hand, PEG was selected due to its amphiphilic nature and high solubility, that lead to a reduce protein adsorption on nanoparticles’ surface, and consequently increase its blood circulation time. The obtained results demonstrated that the DOX:AO drug combination can mediate a synergistic therapeutic effect in both HeLa and MCF-7 cells, particularly at the 2:1, 1:1, and 1:2 ratios. Otherwise, AuMSS nanoparticles’ functionalization with the TPANIS promoted a slight increase in the nanoparticles’ size and stability. The successful incorporation of the polymers on nanoparticles surface was also confirmed by thermogravimetric analysis (TGA) and by Fourier Transform Infrared Spectroscopy (FTIR). Additionally, both the DOX and AO were successfully encapsulated on the AuMSS-TPANIS nanospheres. In in vitro studies, nanoparticles demonstrated to be biocompatible when in contact with healthy cells (fibroblasts) and cancer cells (HeLa and MCF-7) up to the maximum tested concentration of 200 µg/mL. Moreover, the AuMSS nanospheres' functionalization with TPANIS significantly increased their internalization by MCF-7 cells. This selectivity towards MCF-7 (overexpressing sigma receptors) also resulted in an enhanced cytotoxic effect against this cell line. In summary, the presented results confirm the successful functionalization of AuMSS nanoparticles with PEG and ANIS. Additionally, the therapeutic potential of the DOX:AO drug combination as well as the targeting capacity of AuMSS-TPANIS nanospheres were also demonstrated. Such supports the application of AuMSS-TPANIS nanoparticles for cancer-targeted chemotherapy based on the DOX:AO drug combination.
- Overview of stimuli-responsive mesoporous organosilica nanocarriers for drug deliveryPublication . Guimarães, Rafaela; Rodrigues, Ana Carolina Félix; Moreira, André F.; Correia, I.J.The application of nanomaterials is regarded nowadays as a highly promising approach for overcoming the limitations of the currently available cancer treatments, contributing for the creation of more effective, precise, and safer therapies. In the last years, organosilica nanoparticles arisen as alternatives to the most common mesoporous silica nanoparticles. The organosilica nanoparticles combine the advantages of the mesoporous silica, such as structural stability and mesoporous structure, with the increased biocompatibility and biodegradability of organic materials. Therefore, the variety of organic bridges that can be incorporated into the silica matrix allowed the development of new and exciting compositions, properties, and functions for improving the therapeutic effectiveness of the anticancer nanomedicines. In this review, the strategies that have been explored to create stimuli-responsive organosilica-based drug delivery systems are highlighted, describing the practical approaches and mechanisms controlling the drug release. Additionally, the organosilica nanoparticles surface modifications aimed for increasing the blood circulation time and the tumor targeting are also described.
- Combinatorial delivery of doxorubicin and acridine orange by gold core silica shell nanospheres functionalized with poly(ethylene glycol) and 4- methoxybenzamide for cancer targeted therapyPublication . Guimarães, Rafaela; Rodrigues, Ana Carolina Félix; Fernandes, Natanael; Diogo, Duarte de Melo; Ferreira, Paula; Correia, I.J.; Moreira, André F.Combinatorial therapies based on the simultaneous administration of multiple drugs can lead to synergistic effects, increasing the efficacy of the cancer therapy. However, it is crucial to develop new delivery systems that can increase the drugs' therapeutic selectivity and efficacy. Gold core silica shell (AuMSS) nanoparticles present physicochemical properties that allow their simultaneous application as drug delivery and imaging agents. Herein, poly(ethylene glycol) was modified with 4-methoxybenzamide and 3- (triethoxysilyl)propyl isocyanate (TPANIS) to create a novel surface functionalization capable of improving the colloidal stability and specificity of AuMSS nanospheres towards cancer cells. Moreover, a dual drug combination based on Doxorubicin (DOX) and Acridine orange (AO) was characterized and administered using the AuMSS-TPANIS nanospheres. The obtained results show that the DOX:AO drug combination can mediate a synergistic therapeutic effect in both HeLa and MCF-7 cells, particularly at the 2:1, 1:1, and 1:2 ratios. Otherwise, the TPANIS functionalization increased the AuMSS nanospheres colloidal stability and selectivity towards MCF-7 cancer cells (overexpressing sigma receptors). Such also resulted in an enhanced cytotoxic effect against MCF-7 cells when administering the DOX:AO drug combination with the AuMSSTPANIS nanospheres. Overall, the obtained results confirm the therapeutic potential of the DOX:AO drug combination as well as the targeting capacity of AuMSS-TPANIS, supporting its application in the cancer targeted combinatorial chemotherapy.