Adriele Prina-Mello | Trinity College Dublin (original) (raw)

Papers by Adriele Prina-Mello

The poor clinical translation of oncological nanomedicine products is one of the greatest challen... more The poor clinical translation of oncological nanomedicine products is one of the greatest challenges faced by research today. The use of reductionist in vitro models of human cancer and non-predictive animal models is generally considered as one of the main causes of such very low translation rate. The integration of three-dimensional (3D) tumour spheroids in the early stages of the preclinical screening pipeline could significantly facilitate the translation of nanomedicine candidates into clinical practice, by allowing for a more reliable prediction of their efficacy and safety in humans. To lead a successful integration of 3D spheroids, protocols that satisfy issues of ease-of-use, reproducibility and compatibility with conventional and high-throughput assays, without losing the advantages offered by two-dimensional (2D) cell systems, are still needed. To address such need, protocols for the formation and characterisation of scaffold-free 3D tumour spheroids of human adenocarcino...

Nanomaterials, 2020

Magnetic hyperthermia involves the use of iron oxide nanoparticles to generate heat in tumours fo... more Magnetic hyperthermia involves the use of iron oxide nanoparticles to generate heat in tumours following stimulation with alternating magnetic fields. In recent times, this treatment has undergone numerous clinical trials in various solid malignancies and subsequently achieved clinical approval to treat glioblastoma and prostate cancer in 2011 and 2018, respectively. However, despite recent clinical advances, many questions remain with regard to the underlying mechanisms involved in this therapy. One such query is whether intracellular or extracellular nanoparticles are necessary for treatment efficacy. Herein, we compare the effects of intracellular and extracellular magnetic hyperthermia in BxPC-3 cells to determine the differences in efficacy between both. Extracellular magnetic hyperthermia at temperatures between 40–42.5 °C could induce significant levels of necrosis in these cells, whereas intracellular magnetic hyperthermia resulted in no change in viability. This led to a di...

Unraveling the Safety Profile of Nanoscale Particles and Materials - From Biomedical to Environmental Applications, 2018

Current Opinion in Pharmacology, 2021

Nanotechnology in medicine-nanomedicine-is extensively employed to diagnose, treat, and prevent p... more Nanotechnology in medicine-nanomedicine-is extensively employed to diagnose, treat, and prevent pulmonary diseases. Over the last few years, this brave new world has made remarkable progress, offering opportunities to address historical clinical challenges in pulmonary diseases including multidrug resistance, adverse side effects of conventional therapeutic agents, novel imaging, and earlier disease detection. Nanomedicine is also being applied to tackle the new emerging infectious diseases, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), influenza A virus subtype H1N1 (A/H1N1), and more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review we provide both a historical overview of the application of nanomedicine to respiratory diseases and more recent cutting-edge approaches such as nanoparticle-mediated combination therapies, novel double-targeted nondrug delivery system for targeting, stimuli-responsive nanoparticles, and theranostic imaging in the diagnosis and treatment of pulmonary diseases.

Nanomaterials, 2020

Carbon-based nanomaterials (C-BNM) have recently attracted an increased attention as the material... more Carbon-based nanomaterials (C-BNM) have recently attracted an increased attention as the materials with potential applications in industry and medicine. Bioresistance and proinflammatory potential of C-BNM is the main obstacle for their medicinal application which was documented in vivo and in vitro. However, there are still limited data especially on graphene derivatives such as graphene platelets (GP). In this work, we compared multi-walled carbon nanotubes (MWCNT) and two different types of pristine GP in their potential to activate inflammasome NLRP3 (The nod-like receptor family pyrin domain containing 3) in vitro. Our study is focused on exposure of THP-1/THP1-null cells and peripheral blood monocytes to C-BNM as representative models of canonical and alternative pathways, respectively. Although all nanomaterials were extensively accumulated in the cytoplasm, increasing doses of all C-BNM did not lead to cell death. We observed direct activation of NLRP3 via destabilization of...

Advanced Science, 2019

tics, and theranostic agents. [1] Interest in cancer nanomedicines has gained significant momentu... more tics, and theranostic agents. [1] Interest in cancer nanomedicines has gained significant momentum in both the public eye as well as the scientific community. Horizon is the biggest supporter of innovative technology in the European Union with a seven-year budget plan of €80 billion. Nanotechnology is proving to be at the heart of this funding. [2] In the United States, the National Nanotechnology Initiative has provided at least €1.2 billion annually since 2013. [3] Despite this funding, there is growing necessity to improve translation as there are many pitfalls in current preclinical assessment. [4] Immunotoxic effects related to cancer nanomedicines are major clinical roadblocks that must be carefully considered to improve translation in the future. [5] Nanoparticles aim to reduce immunotoxicities associated with conventional drugs but can also indirectly induce many immunotoxic effects of their own. Their unique physiochemical characteristics (PCC), such as size and large surface area, make them susceptible to undesirable interactions when administered intravenously that can hinder their development as potential cancer nanomedicines. Due to common pitfalls in this area of assessment, and speed at which this technology is growing, immunotoxicity is not fully understood. [6] There is growing demand to improve current preclinical assessment in order to reduce the amount of failures and Although interest and funding in nanotechnology for oncological applications is thriving, translating these novel therapeutics through the earliest stages of preclinical assessment remains challenging. Upon intravenous administration, nanomaterials interact with constituents of the blood inducing a wide range of associated immunotoxic effects. The literature on the immunological interactions of nanomaterials is vast and complicated. A small change in a particular characteristic of a nanomaterial (e.g., size, shape, or charge) can have a significant effect on its immunological profile in vivo, and poor selection of specific assays for establishing these undesirable effects can overlook this issue until the latest stages of preclinical assessment. This work describes the current literature on unintentional immunological effects associated with promising cancer nanomaterials (liposomes, dendrimers, mesoporous silica, iron oxide, gold, and quantum dots) and puts focus on what is missing in current preclinical evaluations. Opportunities for avoiding or limiting immunotoxicity through efficient preclinical assessment are discussed, with an emphasis placed on current regulatory views and requirements. Careful consideration of these issues will ensure a more efficient preclinical assessment of cancer nanomedicines, enabling a smoother clinical translation with less failures in the future.

Nanomedicine (London, England), 2018

The use of nanotechnology in medical products has been demonstrated at laboratory scale, and many... more The use of nanotechnology in medical products has been demonstrated at laboratory scale, and many resulting nanomedicines are in the translational phase toward clinical applications, with global market trends indicating strong growth of the sector in the coming years. The translation of nanomedicines toward the clinic and subsequent commercialization may require the development of new or adaptation of existing standards to ensure the quality, safety and efficacy of such products. This work addresses some identified needs, and illustrates the shortcomings of currently used standardized methods when applied to medical-nanoparticles to assess particle size, drug loading, drug release and in vitro safety. Alternative physicochemical, and in vitro toxicology methods, with the potential to qualify as future standards supporting the evaluation of nanomedicine are provided.

Scientific reports, Jan 12, 2018

Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved ... more Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. Recent studies have shown that nanomaterials can trigger protein citrullination, which might constitute a common pathogenic link to disease development. Here we demonstrated auto-antibody production in serum of nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples. The observed systemic responses in mice exposed to nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furt...

Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology, Jan 7, 2016

With the growing numbers of nanomaterials (NMs), there is a great demand for rapid and reliable w... more With the growing numbers of nanomaterials (NMs), there is a great demand for rapid and reliable ways of testing NM safety-preferably using in vitro approaches, to avoid the ethical dilemmas associated with animal research. Data are needed for developing intelligent testing strategies for risk assessment of NMs, based on grouping and read-across approaches. The adoption of high throughput screening (HTS) and high content analysis (HCA) for NM toxicity testing allows the testing of numerous materials at different concentrations and on different types of cells, reduces the effect of inter-experimental variation, and makes substantial savings in time and cost. HTS/HCA approaches facilitate the classification of key biological indicators of NM-cell interactions. Validation of in vitro HTS tests is required, taking account of relevance to in vivo results. HTS/HCA approaches are needed to assess dose- and time-dependent toxicity, allowing prediction of in vivo adverse effects. Several HTS/...

Theranostics, 2015

In a report from 2008, The International Agency for Research on Cancer predicted a tripled cancer... more In a report from 2008, The International Agency for Research on Cancer predicted a tripled cancer incidence from 1975, projecting a possible 13-17 million cancer deaths worldwide by 2030. While new treatments are evolving and reaching approval for different cancer types, the main prevention of cancer mortality is through early diagnosis, detection and treatment of malignant cell growth. The last decades have seen a development of new imaging techniques now in widespread clinical use. The development of nano-imaging through fluorescent imaging and magnetic resonance imaging (MRI) has the potential to detect and diagnose cancer at an earlier stage than with current imaging methods. The characteristic properties of nanoparticles result in their theranostic potential allowing for simultaneous detection of and treatment of the disease. This review provides state of the art of the nanotechnological applications for cancer therapy. Furthermore, it advances a novel concept of personalized nanomedical theranostic therapy using iron oxide magnetic nanoparticles in conjunction with MRI imaging. Regulatory and industrial perspectives are also included to outline future perspectives in nanotechnological cancer research.

Breast Cancer Research, 2015

Introduction: Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia.... more Introduction: Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death. Methods: The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice. Results: All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H = 15.4 kA/m, f = 435 kHz). We could show a gradual inter-and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced. Conclusion: The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally.

Journal of Nanobiotechnology, 2015

Background: Different superparamagnetic iron oxide nanoparticles have been tested for their poten... more Background: Different superparamagnetic iron oxide nanoparticles have been tested for their potential use in cancer treatment, as they enter into cells with high effectiveness, do not induce cytotoxicity, and are retained for relatively long periods of time inside the cells. We have analyzed the interaction, internalization and biocompatibility of dimercaptosuccinic acid-coated superparamagnetic iron oxide nanoparticles with an average diameter of 15 nm and negative surface charge in MCF-7 breast cancer cells. Results: Cells were incubated with dimercaptosuccinic acid-coated superparamagnetic iron oxide nanoparticles for different time intervals, ranging from 0.5 to 72 h. These nanoparticles showed efficient internalization and relatively slow clearance. Time-dependent uptake studies demonstrated the maximum accumulation of dimercaptosuccinic acid-coated superparamagnetic iron oxide nanoparticles after 24 h of incubation, and afterwards they were slowly removed from cells. Superparamagnetic iron oxide nanoparticles were internalized by energy dependent endocytosis and localized in endosomes. Transmission electron microscopy studies showed macropinocytosis uptake and clathrin-mediated internalization depending on the nanoparticles aggregate size. MCF-7 cells accumulated these nanoparticles without any significant effect on cell morphology, cytoskeleton organization, cell cycle distribution, reactive oxygen species generation and cell viability, showing a similar behavior to untreated control cells. Conclusions: All these findings indicate that dimercaptosuccinic acid-coated superparamagnetic iron oxide nanoparticles have excellent properties in terms of efficiency and biocompatibility for application to target breast cancer cells.

Nanomedicine: Nanotechnology, Biology and Medicine, 2015

Bismuth Ferrite (BFO) nanoparticles (BFO-NP) display interesting optical (nonlinear response) and... more Bismuth Ferrite (BFO) nanoparticles (BFO-NP) display interesting optical (nonlinear response) and magnetic properties which make them amenable for bio-oriented applications as intra-and extra membrane contrast agents. Due to the relatively recent availability of this material in well dispersed nanometric form, its biocompatibility was not known to date. In this study, we present a thorough assessment of the effects of in vitro exposure of human adenocarcinoma (A549), lung squamous carcinoma (NCI-H520), and acute monocytic leukemia (THP-1) cell lines to uncoated and poly(ethylene glycol)-coated BFO-NP in the form of cytotoxicity, haemolytic response and biocompatibility. Our results support the attractiveness of the functional-BFO towards biomedical applications focused on advanced diagnostic imaging.

Journal of Visualized Experiments, 2014

In this visualized experiment, protocol details are provided for in vitro labeling of human embry... more In this visualized experiment, protocol details are provided for in vitro labeling of human embryonic stem cells (hESC) with second harmonic generation nanoparticles (HNPs). The latter are a new family of probes recently introduced for labeling biological samples for multi-photon imaging. HNPs are capable of doubling the frequency of excitation light by the nonlinear optical process of second harmonic generation with no restriction on the excitation wavelength. Multi-photon based methodologies for hESC differentiation into cardiac clusters (maintained as long term air-liquid cultures) are presented in detail. In particular, evidence on how to maximize the intense second harmonic (SH) emission of isolated HNPs during 3D monitoring of beating cardiac tissue in 3D is shown. The analysis of the resulting images to retrieve 3D displacement patterns is also detailed.

RSC Advances, 2014

Clinically, overexpression of human epidermal growth factor receptor 2 (ErbB2) is considered to b... more Clinically, overexpression of human epidermal growth factor receptor 2 (ErbB2) is considered to be an important hallmark for a number of solitary and metastatic cancers, and has been approved as a drug treatment target for ErbB2-positive cancers. Additionally, the soluble cleaved form of ErbB2 protein (sErbB2), found in blood, has been shown to be a valuable marker for tumour diagnosis in ErbB2-positive breast cancer. Although a variety of clinical diagnostic approaches have been developed to establish ErbB2 load, they each have their own pitfalls. Nanotechnology has offered some promising breakthrough solutions towards imaging and quantifying ErbB2 at the molecular level and holds the possibility of improving the sensitivity and reliability of ErbB2 detection for clinical purposes. Here we review the currently available methods of ErbB2 detection and quantification in biological samples, followed by analysis and evaluation of those nanotechnological approaches which have demonstrated most potential to improve clinical diagnostic practises.

Proceedings of the 7th International Conference on Body Area Networks, 2012

This paper proposes and evaluates Neuronal TDMA, a TDMAbased signaling protocol framework for mol... more This paper proposes and evaluates Neuronal TDMA, a TDMAbased signaling protocol framework for molecular communication, which utilizes neurons as a primary component to build in-body sensor-actuator networks (IBSANs). Neuronal TDMA leverages an evolutionary multiobjective optimization algorithm (EMOA) that optimizes the signaling schedule for nanomachines in IBSANs. The proposed EMOA uses a population of solution candidates, each of which represents a particular signaling schedule, and evolves them via several operators such as selection, crossover, mutation and offspring size adjustment. The evolution process is performed to seek Pareto-optimal signaling schedules subject to given constraints. Simulation results verify that the proposed EMOA efficiently obtains quality solutions. It outperforms several conventional EMOAs.

European Journal of Nanomedicine, 2013

Lung cancer is a major and increasing global health problem. While there have been significant ad... more Lung cancer is a major and increasing global health problem. While there have been significant advances in the understanding of lung cancer biology, still no current therapy exists to reduce the inevitable and lethal progression of this disease. Silver nanowires (AgNWs) are promising candidates for a wide range of biomedical applications and the treatment of life-threatening diseases due to their unique physico-chemical and biochemical properties. However, the safety of this nanomaterial and its use as a biomedical tool are still under debate. This study evaluates the in vitro internalisation, cytotoxicity and influence on the cell cycle of AgNWs in lung adenocarcinoma (A549) cells and lung normal fibroblasts (MRC-5 cells). Our results demonstrate that AgNWs could be internalised effectively into A549 and MRC-5 cells without inducing detectable cytotoxicity, thus providing preliminary evidence on the future potential of AgNWs as biocompatible drug delivery platforms applicable in lu...

Scientific Reports, 2013

Single-walled carbon nanotubes (SWCNTs) have been widely explored as potential technologies for i... more Single-walled carbon nanotubes (SWCNTs) have been widely explored as potential technologies for information systems and medical applications. The impact of SWCNTs on human health is of prime concern, if SWCNTs have a future in the manufacturing industry. This study proposes a novel, inflammation-independent paradigm of toxicity for SWCNTs, identifying the protein citrullination process as early-stage indicator of inflammatory responses of macrophages (THP-1) and of subtle phenotypic damages of lung epithelial (A549) cells following exposure to chemically-treated SWCNTs. Our results showed that, while most of the cellular responses of A549 cells exposed to SWCNTs are different to those of similarly treated THP-1 cells, the protein citrullination process is triggered in a dose-and time-dependent manner in both cell lines, with thresholds comparable between inflammatory (THP-1) and non-inflammatory (A549) cell types. The cellular mechanism proposed herein could have a high impact in predicting the current risk associated with environmental exposure to SWCNTs.

Toxicological Sciences, 2012

Suspicion has been raised that high aspect ratio nanoparticles or nanofibers might possess asbest... more Suspicion has been raised that high aspect ratio nanoparticles or nanofibers might possess asbestos-like pathogenicity. The pleural space is a specific target for disease in individuals exposed to asbestos and by implication of nanofibers. Pleural effects of fibers depends on fiber length, but the key threshold length beyond which adverse effects occur has never been identified till now because all asbestos and vitreous fiber samples are heterogeneously distributed in their length. Nanotechnology advantageously allows for highly defined length distribution of synthetically engineered fibers that enable for in-depth investigation of this threshold length. We utilized the ability to prepare silver nanofibers of five defined length classes to demonstrate a threshold fiber length for acute pleural inflammation. Nickel nanofibers and carbon nanotubes were then used to strengthen the relationship between fiber length and pleural inflammation. A method of intrapleural injection of nanofibers in female C57Bl/6 strain mice was used to deliver the fiber dose, and we then assessed the acute pleural inflammatory response. Chest wall sections were examined by light and scanning electron microscopy to identify areas of lesion; furthermore, cellnanowires interaction on the mesothelial surface of the parietal pleura in vivo was investigated. Our results showed a clear threshold effect, demonstrating that fibers beyond 4 µm in length are pathogenic to the pleura. The identification of the threshold length for nanofiber-induced pathogenicity in the pleura has important implications for understanding the structure-toxicity relationship for asbestos-induced mesothelioma and consequent risk assessment with the aim to contribute to the engineering of synthetic nanofibers by the adoption of a benign-by-design approach.

Nanotoxicology, 2011

The use of fibre-shaped nanomaterials in commercial applications has met with concern that they c... more The use of fibre-shaped nanomaterials in commercial applications has met with concern that they could cause health effects similar to those seen with pathogenic fibres such as certain forms of asbestos. Of the attributes which form the fibre pathogenicity paradigm, fibre length is thought to be a critical factor in determining fibre toxicity. We have previously shown that carbon nanotubes display such length-dependent pathogenicity but it remains unclear if other forms of fibrous nanomaterials conform to the fibre pathogenicity paradigm. As such, our aim is to determine the generality of this hypothesis by asking whether a radically different form of fibrous nanomaterial, nickel nanowires, show length-dependent pathogenicity. Our results indicate that nickel nanowires synthesised to be predominantly long (>20 mm) show the ability to elicit strong inflammation in the mouse peritoneal model in a dose-dependent manner; inflammation or fibrosis was not seen with the short (<5 mm) nanowires. This length-dependent response was also seen after lung aspiration and within a macrophage in vitro model adding further weight to the contention that fibre length is an important driver of hazard potential. This may have important implications when considering the hazard posed by fibrous nanomaterials and their regulation in workplaces.

Nanomaterials, 2020

Unraveling the Safety Profile of Nanoscale Particles and Materials - From Biomedical to Environmental Applications, 2018

Current Opinion in Pharmacology, 2021

Nanomaterials, 2020

Advanced Science, 2019

Nanomedicine (London, England), 2018

Scientific reports, Jan 12, 2018

Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology, Jan 7, 2016

Theranostics, 2015

Breast Cancer Research, 2015

Journal of Nanobiotechnology, 2015

Nanomedicine: Nanotechnology, Biology and Medicine, 2015

Journal of Visualized Experiments, 2014

RSC Advances, 2014

Proceedings of the 7th International Conference on Body Area Networks, 2012

European Journal of Nanomedicine, 2013

Scientific Reports, 2013

Toxicological Sciences, 2012

Nanotoxicology, 2011