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- Microneedle-based delivery devices for cancer therapy: a reviewPublication . Moreira, André; Rodrigues, Ana Carolina Félix; Jacinto, Telma A.; Miguel, Sónia; Costa, Elisabete; Correia, I.J.Macroscale delivery systems that can be locally implanted on the tumor tissue as well as avoid all the complications associated to the systemic delivery of therapeutics have captured researchers' attention, in recent years. Particularly, the microneedle-based devices can be used to efficiently deliver both small and macro-molecules, like chemotherapeutics, proteins, and genetic material, along with nanoparticle-based anticancer therapies. Such capacity prompted the application of microneedle devices for the development of new anticancer vaccines that can permeate the tumor tissue and simultaneously improve the effectiveness of therapeutic agents. Based on the promising results demonstrated by the microneedle systems in the local administration of anticancer therapeutics, this review summarizes the different microneedle formulations developed up to now aimed for application on cancer therapy (mphasizing those produced with polymers). Additionally, the microneedles' general properties, type of therapeutic approach and its main advantages are also highlighted.
- Optimization of the GSH-Mediated Formation of Mesoporous Silica-Coated Gold Nanoclusters for NIR Light-Triggered Photothermal ApplicationsPublication . Fernandes, Natanael; Rodrigues, Ana Carolina Félix; Diogo, Duarte de Melo; Correia, I.J.; Moreira, AndréCancer light-triggered hyperthermia mediated by nanomaterials aims to eliminate cancer cells by inducing localized temperature increases to values superior to 42 C, upon irradiation with a laser. Among the different nanomaterials with photothermal capacity, the gold-based nanoparticles have been widely studied due to their structural plasticity and advantageous physicochemical properties. Herein, a novel and straightforward methodology was developed to produce gold nanoclusters coated with mesoporous silica (AuMSS), using glutathione (GSH) to mediate the formation of the gold clusters. The obtained results revealed that GSH is capable of triggering and control the aggregation of gold nanospheres, which enhanced the absorption of radiation in the NIR region of the spectra. Moreover, the produced AuMSS nanoclusters mediated a maximum temperature increase of 20 C and were able to encapsulate a drug model (acridine orange). In addition, these AuMSS nanoclusters were also biocompatible with both healthy (fibroblasts) and carcinogenic (cervical cancer) cells, at a maximum tested concentration of 200 g/mL. Nevertheless, the AuMSS nanoclusters’ NIR light-triggered heat generation successfully reduced the viability of cervical cancer cells by about 80%. This confirms the potential of the AuMSS nanoclusters to be applied in cancer therapy, namely as theragnostic agents.
- Red blood cell membrane-camouflaged gold-core silica shell nanorods for cancer drug delivery and photothermal therapyPublication . Rodrigues, Ana Carolina F.; Correia, I.J.; Moreira, André F.Gold core mesoporous silica shell (AuMSS) nanorods are multifunctional nanomedicines that can act simultaneously as photothermal, drug delivery, and bioimaging agents. Nevertheless, it is reported that once administrated, nanoparticles can be coated with blood proteins, forming a protein corona, that directly impacts on nanomedicines’ circulation time, biodistribution, and therapeutic performance. Therefore, it become crucial to develop novel alternatives to improve nanoparticles’ half-life in the bloodstream. In this work, Polyethylenimine (PEI) and Red blood cells (RBC)-derived membranes were combined for the first time to functionalize AuMSS nanorods and simultaneously load acridine orange (AO). The obtained results revealed that the RBC 41 derived membranes promoted the neutralization of the AuMSS’ surface charge and consequently improved the colloidal stability and biocompatibility of the nanocarriers. Indeed, the in vitro data revealed that PEI/RBC-derived membranes’ functionalization also improved the nanoparticles’ cellular internalization and was capable of mitigating the hemolytic effects of AuMSS and AuMSS/PEI nanorods. In turn, the combinatorial chemo-photothermal therapy mediated by AuMSS/PEI/RBC_AO nanorods was able to completely eliminate HeLa cells, contrasting with the less efficient standalone therapies. Such data reinforce the potential of AuMSS nanomaterials to act simultaneously as photothermal and chemotherapeutic agents.
- 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.
- IR780 loaded gelatin‐PEG coated gold core silica shell nanorods for cancer‐targeted photothermal/photodynamic therapyPublication . Gonçalves, Ariana; Rodrigues, Ana Carolina Félix; Fernandes, Natanael; Diogo, Duarte de Melo; Ferreira, Paula; Moreira, André F.; Correia, I.J.Gold core silica shell (AuMSS) nanorods present excellent physicochemical proper-ties that allow their application as photothermal and drug delivery agents. Herein,AuMSS nanorods were dual‐functionalized with Polyethylene glycol methyl ether(PEG‐CH3) and Gelatin (GEL) to enhance both the colloidal stability and uptake byHeLa cancer cells. Additionally, the AuMSS nanorods were combined for the firsttime with IR780 (a heptamethine cyanine molecule) and its photothermal and pho-todynamic capacities were determined. The obtained results reveal that the en-capsulation of IR780 (65 μg per AuMSS mg) increases the photothermal conversionefficiency of AuMSS nanorods by 10%, and this enhanced heat generation wasmaintained even after three irradiation cycles with a NIR (808 nm) laser. Moreover,the IR780‐loaded AuMSS/T‐PEG‐CH3/T‐GEL presented≈2‐times higher uptake inHeLa cells, when compared to the non‐coated counterparts, and successfullymediated the light‐triggered generation of reactive oxygen species. Overall, thecombination of photodynamic and photothermal therapy mediated by IR780‐loadedAuMSS/T‐PEG‐CH3/T‐GEL nanorods effectively promoted the ablation of HeLacancer cells.
- Inorganic-based drug delivery systems for cancer therapyPublication . Rodrigues, Ana Carolina Félix; Alves, Cátia; Lima-Sousa, Rita; Moreira, André F.; Diogo, Duarte de Melo; Correia, I.J.The aging of the worldwide population has associated an increased incidence and prevalence of several pathologies, such as cancer, skin lesions, and neurological disorders. To improve the therapeutic outcome, researchers have been involved in the development of new disruptive therapeutic products that provide personalized and more efficient healthcare solutions. Among them, inorganic nanoparticles such as those made of gold, silica, or graphene-based materials have been used by researchers and clinicians for cancer therapy. Inorganic nanoparticles present unique size- and shape-dependent physicochemical and optical properties that in conjugation with high loading capacities prompted their application as therapeutics, drug delivery vehicles, and imaging agents. Additionally, these structures can also be conjugated with targeting moieties or stealthing agents to further improve their accumulation in the tumor tissue and, consequently, enhance their therapeutic effect. Herein, the advances attained in the application of inorganic nanoparticles in tumor targeting, imaging, photothermal therapy, and delivery of bioactive molecules, such as drugs (e.g., doxorubicin), genetic material (e.g., DNA, siRNA), and immunotherapy mediators are discussed as well as its limitations and toxicity issues.
- 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.
- 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.
- Strategies to improve the photothermal capacity of gold-based nanomedicinesPublication . Gonçalves, Ariana S.C.; Rodrigues, Ana Carolina Félix; Moreira, André F.; Correia, I.J.The plasmonic photothermal properties of gold nanoparticles have been widely explored in the biomedical field to mediate a photothermal effect in response to the irradiation with an external light source. Particularly, in cancer therapy, the physicochemical properties of gold-based nanomaterials allow them to efficiently accumulate in the tumor tissue and then mediate the light-triggered thermal destruction of cancer cells with high spatial-temporal control. Nevertheless, the gold nanomaterials can be produced with different shapes, sizes, and organizations such as nanospheres, nanorods, nanocages, nanoshells, and nanoclusters. These gold nanostructures will present different plasmonic photothermal properties that can impact cancer thermal ablation. This review analyses the application of gold-based nanomaterials in cancer photothermal therapy, emphasizing the main parameters that affect its light-to-heat conversion efficiency and consequently the photothermal potential. The different shapes/organizations (clusters, shells, rods, stars, cages) of gold nanomaterials and the parameters that can be fine-tuned to improve the photothermal capacity are presented. Moreover, the gold nanostructures combination with other materials (e.g. silica, graphene, and iron oxide) or small molecules (e.g. indocyanine green and IR780) to improve the nanomaterials photothermal capacity is also overviewed.
- In situ formation of alginic acid‐gold nanohybrids for application in cancer photothermal therapyPublication . Figueiredo, André Q.; Rodrigues, Ana Carolina Félix; Fernandes, Natanael; Correia, I.J.; Moreira, André F.Gold-based nanoparticles present excellent optical properties that propelled their widespread application in biomedicine, from bioimaging to photothermal applications. Nevertheless, commonly employed manufacturing methods for gold-based nanoparticles require long periods and laborious protocols that reduce cost-effectiveness and scalability. Herein, a novel methodology was used for producing gold-alginic acid nanohybrids (Au-Alg-NH) with photothermal capabilities. This was accomplished by promoting the in situ reduction and nucleation of gold ions throughout a matrix of alginic acid by using ascorbic acid. The results obtained reveal that the Au-Alg-NHs present a uniform size distribution and a spike-like shape. Moreover, the nanomaterials were capable to mediate a temperature increase of ≈11°C in response to the irradiation with a near-infrared region (NIR) laser (808 nm, 1.7 W cm−2). The in vitro assays showed that Au-Alg-NHs were able to perform a NIR light-triggered ablation of cancer cells (MCF-7), being observed a reduction in the cell viability to ≈27%. Therefore, the results demonstrate that this novel methodology holds the potential for producing Au-Alg-NH with photothermal capacity and higher translatability to the clinical practice, namely for cancer therapy.
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