Browsing by Author "Rodrigues, Ana Carolina Félix"
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- Cell‐Derived Vesicles for Nanoparticles' Coating: Biomimetic Approaches for Enhanced Blood Circulation and Cancer TherapyPublication . Rodrigues, Ana Carolina Félix; Fernandes, Natanael; Diogo, Duarte de Melo; Correia, I.J.; Moreira, André F.Cancer nanomedicines are designed to encapsulate different therapeuticagents, prevent their premature release, and deliver them specifically tocancer cells, due to their ability to preferentially accumulate in tumor tissue.However, after intravenous administration, nanoparticles immediatelyinteract with biological components that facilitate their recognition by theimmune system, being rapidly removed from circulation. Reports show thatless than 1% of the administered nanoparticles effectively reach the tumorsite. This suboptimal pharmacokinetic profile is pointed out as one of themain factors for the nanoparticles’ suboptimal therapeutic effectiveness andpoor translation to the clinic. Therefore, an extended blood circulation timemay be crucial to increase the nanoparticles’ chances of being accumulated inthe tumor and promote a site-specific delivery of therapeutic agents. For thatpurpose, the understanding of the forces that govern the nanoparticles’interaction with biological components and the impact of the physicochemicalproperties on the in vivo fate will allow the development of novel and moreeffective nanomedicines. Therefore, in this review, the nano–bio interactionsare summarized. Moreover, the application of cell-derived vesicles forextending the blood circulation time and tumor accumulation is reviewed,focusing on the advantages and shortcomings of each cell source.
- 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.
- Desenvolvimento e funcionalização de nanopartículas de ouro com revestimento de sílica para aplicação na terapia do cancroPublication . Rodrigues, Ana Carolina Félix; Correia, Ilídio Joaquim Sobreira; Moreira, André FerreiraCancer is one of the leading causes of death in the world and its incidence has been increasing over the years. On the other side, the currently available treatments, such as surgery, radiotherapy, and chemotherapy, are characterized by presenting a low efficacy and non-specific toxicity. Particularly, the chemotherapeutic agents are poorly soluble, rapidly degraded or removed from blood circulation and present low selectivity towards the cancer cells. Therefore, there is a huge demand for novel and more effective anti-cancer therapeutics. The recent breakthroughs in nanotechnology paved the way for a new era of anti-cancer medicines. Nanoparticles can be produced with different materials and organizations, among them, the gold-core silica shell (Au-MSS) nanoparticles present advantageous physicochemical and biological properties that make them a promising nanoplatform for cancer therapy. Nevertheless, the successful application of Au-MSS nanoparticles as an effective cancer nanomedicine is hindered by the uncontrolled release of the therapeutic payloads, limited blood circulation time and unfavorable pharmacokinetics. This dissertation work plan aimed at designing and developing a novel Au-MSS surface modification with biofunctional polymers for overcoming the uncontrolled drug release profile, limited nanoparticles’ blood circulation time and ultimately potentiate the therapeutic effect. For that purpose, two different methodologies, electrostatic interaction or chemical linkage, were explored and optimized to functionalize Au-MSS, displaying a rod-like shape, with D-a tocopherol polyethylene glycol 1000 succinate (TPGS) and branched polyethyleneimine (PEI). TPGS was selected based on its amphiphilic nature that can act as solubilizer and consequently increase the particles’ colloidal stability. On the other side, PEI due to its cationic nature will be attracted to the negatively charged mesoporous silica surface blocking the particle’ pores and consequently the drug release. Additionally, the rod-like shape of Au-MSS allows the combination of drug delivery with photothermal therapy. The produced Au-MSS nanorods display a uniform morphology and a well-defined gold nucleus and silica shell. Further, the particles’ surface charge was dependent on the synthesis methodology. The particles modified by electrostatic interactions (Au-MSS/TPGS-PEI) were negative (-16.9 and -5.1 mV) whereas the formulations produced by chemical linkage (Au-MSS/TPGS/PEI) resulted in positively charged nanoparticles (+30.9 and +6.8 mV). The successful incorporation of the polymers was confirmed by Fourier Transformed Infrared spectroscopy and thermogravimetric analysis. Moreover, the Au-MSS functionalization did not affect the particles photothermal capacity. However, the Au-MSS/TPGS/PEI nanorods displayed a decreased drug encapsulation efficiency. In vitro assays demonstrated the biocompatibility of Au-MSS and Au-MSS/TPGS-PEI up to concentrations of 200 µg/mL, however, the positively charged formulations only remained biocompatible until 100 and 125 µg/mL. Overall, the results presented in this thesis confirm the successful modification of Au-MSS nanorods with TPGS and PEI. Additionally, it was also demonstrated the potential of Au-MSS formulations for being applied in cancer therapy, where they can act simultaneously as photothermal, drug delivery and bioimaging agents.
- Development of gold-core silica shell nanospheres coated with poly-2-ethyl-oxazoline and β-cyclodextrin aimed for cancer therapyPublication . Reis, Ana Catarina Almeida; Rodrigues, Ana Carolina Félix; Moreira, André; Jacinto, Telma A.; Ferreira, Paula; Correia, I.J.Cancer is one of the major world public health problems and the currently available treatments are nonspecific and ineffective. This reality highlights the importance of developing novel therapeutic approaches. In this field, multifunctional nanomedicines have the potential to revolutionize the currently available treatments. These unique nanodevices can simultaneously act as therapeutic and imaging agents allowing the real-time monitoring of the nanoparticles biodistribution and the treatment outcome. Among the different nanoparticles, the gold-core silica shell (AuMSS) nanoparticles advantageous physicochemical and biological properties make them promising nanoplatforms for cancer therapy. Nevertheless, their successful application as an effective cancer nanomedicine is limited by the unfavorable pharmacokinetics and uncontrolled release of the therapeutic payloads. Herein, a new polymeric coating for AuMSS nanospheres was developed by combining different ratios (25/75, 50/50 and 75/25) of two materials, Poly-2-ethyl-2-oxazoline (PEOZ) and β-cyclodextrin (β-CD). The surface functionalization of AuMSS nanospheres led to a size increase and to the neutralization of the surface charge. On the other side, the nanoparticles biological performance was improved. The coated AuMSS nanospheres showed an increased cytocompatibility and internalization rate by the HeLa cancer cells. Overall, the obtained data confirm the successful modification of the AuMSS nanospheres with PEOZ and β-CD as well as their promising properties for being applied in cancer therapy.
- Development of multifunctional gold core silica shell nanomedicines for chemo/photothermal therapy of cancerPublication . Rodrigues, Ana Carolina Félix; Correia, Ilídio Joaquim Sobreira; Moreira, André FerreiraCancer remains one of the most diagnosed and deadliest diseases worldwide. The currently available cancer treatments, such as surgery, chemotherapy, and radiotherapy present low therapeutic efficacies and selectivity toward cancer cells, inducing several side effects. Particularly, the chemotherapeutic agents are characterized by high non-specific toxicity, and low solubility, being rapidly degraded or eliminated from blood circulation. Therefore, there is an urgent and increased need to develop new anti-cancer approaches with greater therapeutic efficacy, selectivity, and safety. In past years, nanoparticles’ application in medicine triggered a new era of cancer research, from diagnostic to therapeutic. These nanosystems can encapsulate drugs, prevent their premature degradation, and promote the drug's specific delivery to the target site. In addition, researchers have also developed nanosystems capable of mediating a photothermal effect in response to near-infrared (NIR; 700-1100 nm) light, as well as, promoting a tumor-specific delivery of the chemotherapeutic agents. In fact, photothermal therapy (PTT) mediated by nanomaterials has been explored as a standalone or combinatorial therapy, focusing on the hyperthermia of the tumor tissue, and avoiding damage in healthy tissues. PTT take advantage of the nanomaterials’ physicochemical properties, which confer them an intrinsic capacity to accumulate at the tumor site, by taking advantage of the defective vasculature of the tumor (e.g., the enhanced permeability and retention (EPR) effect and/or vascular bursts). Thus, under NIR irradiation of the tumor tissue, the accumulated’ nanoparticles can induce a localized hyperthermia which in turn can sensitize cancer cells to other therapeutic approaches (e.g., chemotherapy) or induce several cellular damages that can ultimately lead to cancer cells’ apoptosis or necrosis. Among the different nanostructures developed so far, gold-core mesoporous silica shell (AuMSS) nanorods have been widely explored for cancer therapy application due to their unique physical and chemical properties, that support their simultaneous application as imaging (e.g., computed tomography) and therapeutic agents (e.g., drug delivery and PTT). The anisotropic morphology of the gold core confers to AuMSS nanorods an inherent capacity to present high absorption in the NIR region, and consequently mediate a photothermal effect. Additionally, the inclusion of a mesoporous silica shell provides a biocompatible, inert, and large surface area that can be easily functionalized; tubular pores that improve the particle's ability to encapsulate and deliver bioactive molecules; protection and stabilization of the gold core from photodegradation when exposed to energetic radiations (e.g., NIR light). Despite all the efforts and several studies showing the huge potential of nanomedicines to act as drug delivery platforms and induce cancer cells death both in vitro and in vivo, the treatment of human tumors with this technology has led to modest improvements. In fact, only 0.7% of the injected nanoparticles dose effectively reaches the tumor site, hindering their real therapeutic potential. Thus, this suboptimal pharmacokinetic profile is pointed out as one of the main factors for the reduced therapeutic effectiveness of nanomedicines and their poor translation to clinical practice. Systemic administration is the main route of nanomedicines’ administration in cancer therapy applications. However, upon intravenous administration nanoparticles are highly susceptible to the adsorption of plasma proteins on their surface. Such protein corona can induce several modifications in the nanomedicines' initial physicochemical properties (e.g., immunogenicity, aggregation state, hydrodynamic size, surface chemistry), that will impact their blood retention, bioavailability, tumor accumulation, and even their biosafety. Therefore, there is a consensus that the first step to increase the nanoparticles’ accumulation in the tumor tissue should encompass the optimization of the nanoparticles’ pharmacokinetics, starting with the blood circulation time, which is crucial to increase the chances of their accumulation in the tumor tissue and exert their therapeutic effect. In recent years, different strategies have been developed to improve nanoparticles’ circulation time, mainly by the optimization of their physicochemical properties and/or functionalization with hydrophilic polymers or biomimetic coatings. In fact, due to the non-immunogenicity, biocompatibility, and biodegradability of hydrophilic polymers, they can resist to non-specific protein adsorption and cell adhesion, which significantly attenuates immune system recognition, improving the pharmacokinetic profile. Particularly, biomimetic coatings based on cell-derived vesicles are an emerging concept to improve the nanomaterials’ biological performance. These cell-derived vesicles inherit the unique features of the source cells, such as biocompatibility, long circulation time, homologous targeting, and immune evasion, showing a high potential to create novel and more effective cancer therapies. In this way, the main goal of this Doctoral thesis work plan was to develop and validate the potential of AuMSS nanorods functionalized with polymeric and biomimetic coatings to improve their applicability in chemo-photothermal combinatorial therapy of cancer. This Doctoral thesis includes an introduction section (Chapter 2) where the AuMSS nanorods general properties and application in cancer therapy are discussed. Moreover, an overview of nanoparticles' role in cancer therapy, particularly the impact of physicochemical properties and surface functionalization in nanoparticles’ blood circulation and tumor accumulation. Furthermore, this thesis includes two chapters presenting the research work developed during this doctorate. In the first study (Chapter 3), branched polyethylenimine (PEI) and hyaluronic acid (HA) were combined, for the first time, to functionalize AuMSS nanorods and create a tumor-targeted chemo-photothermal nanomedicine. AuMSS nanorods were produced using the “seed-mediated growth” and Stöber’s modified methods to obtain the gold nanorod core and mesoporous silica shell, respectively. The functionalization of the AuMSS nanorods' surface was achieved through the chemical linkage of PEI (modified with 3-(triethoxysilyl)propyl isocyanate) followed by electrostatic adsorption of HA. The inclusion of PEI and HA on the AuMSS surface promoted a controlled and sustained release of the chemotherapeutic agent – acridine orange (AO). HA functionalization promoted a neutralization of AuMSS surface charge (from 44 to -10 mV) and consequently improved the AuMSS’ biocompatibility by decreasing the blood hemolysis to safe levels. The in vitro assays demonstrated that the HA functionalization increased the nanoparticles’ internalization by cervical cancer cells. Additionally, the combinatorial treatment (i.e., chemotherapy and PTT) mediated by AuMSS/PEI/HA_AO nanorods presented an enhanced effect when compared to single PTT or chemotherapy regiments, leading to the almost complete elimination of the cancer cells (95%). In the second study (Chapter 4), PEI and Red blood cells (RBC)-derived membranes were combined for the first time to functionalize AuMSS nanorods. The RBC-derived membranes were further loaded with AO to allow the combined chemo-photothermal therapy of cervical cancer cells. PEI was chemically modified with 3-(triethoxysilyl)propyl isocyanate, to enable its grafting on the AuMSS nanorods, followed by the entrapment on RBC-derived membranes. PEI/RBC-derived membranes promoted a neutralization of AuMSS surface charge (-26 to -16 mV) and consequently improved the AuMSS nanorods’ colloidal stability and biocompatibility. Also, the AuMSS/PEI/RBC nanorods induced a photo-induced heat variation (ΔT ≈30°C) under NIR irradiation (808 nm, 1.7 W/cm2, 10 min). The in vitro uptake studies revealed that PEI/RBC-derived membranes’ functionalization improved the nanoparticles’ cellular internalization. Furthermore, the combinatorial chemo-PTT mediated by AuMSS/PEI/RBC_AO nanorods eliminated cervical cancer cells, in contrast to less efficient standalone therapies. Overall, the results obtained herein demonstrated that AuMSS nanorods functionalization with hydrophilic polymers (PEI and HA) or biomimetic coating (RBC-derived membranes) improved nanoparticles’ surface charge and colloidal stability, yielding nanomedicines with enhanced biological properties and therapeutic performance. Furthermore, these results support the therapeutic potential of AuMSS nanorods as multifunctional nanomedicines in cancer therapy and highlight that their therapeutic potential can be improved by combining different therapeutic approaches (i.e., chemotherapy and PTT). Altogether, these results reinforce the great potential of AuMSS nanorods, encouraging their continuous study and optimization. This will allow the development of increasingly precise and personalized anticancer therapies, in order to accelerate the translation of AuMSS nanorods into clinical practice, and thus be able to effectively contribute to the treatment of cancer and the reduction of the mortality rate associated with this disease.
- Development of poly-2-ethyl-2-oxazoline coated gold-core silica shell nanorods for cancer chemo-photothermal therapyPublication . Moreira, André; Rodrigues, Ana Carolina Félix; Reis, Ana Catarina Almeida; Costa, Elisabete C.; Ferreira, Paula; Correia, Ilídio Joaquim SobreiraAim: Develop a new poly-2-ethyl-2-oxazoline (PEOZ)-based coating for doxorubicin-loaded gold-core mesoporous silica shell (AuMSS) nanorods application in cancer chemo-photothermal therapy. Methods: PEOZ functionalized AuMSS nanorods were obtained through the chemical grafting on AuMSS of a PEOZ silane derivative. Results: The PEOZ chemical grafting on the surface of AuMSS nanorods allowed the neutralization of nanodevices’ surface charge, from -30 to -15 mV, which improved nanoparticles’ biocompatibility, namely by decreasing the blood hemolysis to negligible levels. In vitro antitumoral studies revealed that the combined treatment mediated by the PEOZ-coated AuMSS nanorods result in a synergistic effect, allowing the complete eradication of cervical cancer cells. Conclusion: The application of the PEOZ coating improves the AuMSS nanorods performance as a multifunctional combinatorial therapy for cervical cancer.
- Functionalization of AuMSS nanorods towards more effective cancer therapiesPublication . Rodrigues, Ana Carolina Félix; Jacinto, Telma A.; Moreira, André; Costa, Elisabete C.; Miguel, Sónia P.; Correia, I.J.The application of nanoparticles as selective drug delivery platforms arises as one the most promising therapeutic strategies in the biomedical field. Such systems can encapsulate drugs, prevent its premature degradation, transport and promote the drugs specific delivery to the target site. Among the different nanostructures, gold-core mesoporous silica shell (AuMSS) nanorods have been one of the most explored due to their unique physical and chemical properties. The mesoporous silica biocompatibility, high surface area that can be easily functionalized, tubular pores that can store the drugs, conjugated with the intrinsic capacity of gold nanorod to absorb near-infrared radiation, allows the combination of hyperthermia (i.e., photothermal effect) with drug delivery, making them a nanoplatforms with a huge potential for cancer therapy. Nevertheless, the successful application of AuMSS nanoparticles as an effective cancer nanomedicine is hindered by the uncontrolled release of the therapeutic payloads, limited blood circulation time and unfavorable pharmacokinetics. In this review, an overview of the modifications performed to improve the AuMSS nanorods application in nanomedicine is provided, highlighting the practical approaches that enhanced the AuMSS nanorods targeting, responsiveness to different stimuli, and blood circulation time. Further, the basics of AuMSS nanorods synthesis procedures, general properties, and its application in cancer therapy are also described.
- Gold-core silica shell nanoparticles application in imaging and therapy: A reviewPublication . Moreira, André; Rodrigues, Ana Carolina Félix; Reis, Ana Catarina Almeida; Costa, Elisabete C.; Correia, Ilídio Joaquim SobreiraNanomaterials have assumed a prominent role in biomedical field during the past years. Particularly, the gold-core silica shell nanoparticles present unique physical and chemical properties that make nanodevices appealing for theragnostic applications. The gold core characteristic X-ray attenuation, surface enhanced raman scattering and tunable absorption in the near-infrared region supports the applicability of these systems in X-ray, photoacoustic and thermal imaging as well as in photothermal and photodynamic based therapies. Additionally, the inclusion of the silica shell stabilizes the gold core, protecting it from premature degradation and aggregation, and also provides additional cargo capacity for therapeutic molecules. Further, both silica and gold are described as biocompatible, inert and nontoxic materials. In this review, an overview of the gold core-silica shell nanoparticles applications in nanomedicine is provided, highlighting the different particle shapes and their application in bioimaging and therapy. Further, the basics of the gold core-silica shell nanoparticles synthesis procedures, general properties, and biosafety are also described.
- HA/PEI-coated acridine orange-loaded gold-core silica shell nanorods for cancer-targeted photothermal and chemotherapyPublication . Rodrigues, Ana Carolina Félix; Fernandes, Natanael; Diogo, Duarte de Melo; Ferreira, Paula; Correia, I.J.; Moreira, AndréAims: To develop a tumor-targeted chemo-photothermal nanomedicine through the functionalization of acridine orange (AO)-loaded gold-core mesoporous silica shell (AuMSS) nanorods with polyethylenimine (PEI) and hyaluronic acid (HA). Methods: Functionalization of the AuMSS nanorods was achieved through the chemical linkage of PEI followed by electrostatic adsorption of HA. Results: HA functionalization improved AuMSS' cytocompatibility by decreasing blood hemolysis, and PEI-HA inclusion promoted a controlled and sustained AO release. In vitro assays revealed that HA functionalization increased the internalization of nanoparticles by human negroid cervix epithelioid carcinoma cancer (HeLa) cells, and the combinatorial treatment mediated by AuMSS/PEI/HA_AO nanorods presented an enhanced effect, with >95% of cellular death. Conclusion: AuMSS/PEI/HA_AO formulations can act as tumor-targeted chemo-photothermal nanomedicines for the combinatorial therapy of cervical cancer.
- Hyaluronic acid and vitamin E polyethylene glycol succinate functionalized gold-core silica shell nanorods for cancer targeted photothermal therapyPublication . Jacinto, Telma A.; Rodrigues, Ana Carolina Félix; Moreira, André F.; Miguel, Sónia P.; Costa, Elisabete; Ferreira, Paula; Correia, I.J.Gold-core mesoporous silica shell (AuMSS) nanorods unique physicochemical properties makes them versatile and promising nanomedicines for cancer photothermal therapy. Nevertheless, these nanomaterials present a reduced half-life in the blood and poor specificity towards the tumor tissue. Herein, d-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and Hyaluronic Acid (HA) were combined for the first time to improve the AuMSS nanorods biological performance. The obtained results revealed that AuMSS surface functionalization induced the surface charge neutralization, from -28 ± 10 mV to −3 ± 5 mV and −10 ± 4 mV for AuMSS-TPGS-HA (1:1) and (4:1) formulations, without impacting on nanomaterials’ photothermal capacity. Moreover, the AuMSS functionalization improved the nanomaterials hemocompatibility and selectivity towards the cancer cells, particularly in the AuMSS-TPGS-HA (4:1) formulation. Furthermore, both formulations were able to mediate an on-demand photothermal effect, that induced the HeLa cancer cells death, confirming its potential for being applied as targeted multifunctional theragnostic nanomedicines.
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