Publications in the Year: 2015

Book Chapter

Larguinho, M, Figueiredo S, Cordeiro A, Carlos FF, Cordeiro M, Pedrosa P, Baptista PV.  2015.  Nanoparticles for Diagnostics and Imaging. Frontiers in Nanomedicine. (Maria Luisa Bondì Bondì, Chiara Botto, Erika Amore, Eds.).:3-46.: Bentham Science Abstractsample.pdf

Nanoparticles possess unique optical and physic-chemical properties that may potentiate applications in biomedicine, in particular in diagnostics, therapy and imaging. Advances on biomolecular diagnostics strategies have greatly focused on single molecule detection and characterization of DNA, RNA or proteins through improved nanoparticle-based platforms. Nanoparticles improve analytical capability when compared to traditional techniques with high resolution and medium-high throughput. Also, particular interest has been directed at SNP detection, gene expression profiles and biomarker characterization through colorimetric, spectrometric or electrochemical strategies.
Molecular imaging has also benefited from the introduction of nanoparticles in standard techniques towards non-invasive imaging procedures that can be used to highlight regions of interest, allowing the characterization of biological processes at the cellular and/or molecular level. Several imaging modalities are associated with low sensitivity, an issue that can be tackled by the use of probes, e.g. contrast agents for X-ray and magnetic resonance imaging, radiolabelled molecules for nuclear medicine. Furthermore, nanoparticles can be used as vehicles that deliver specifically these contrast agents, leading to overcome the limitations of conventional modalities.
This chapter will discuss the use of nanoparticles in biomolecular recognition and imaging applications, focusing those already being translated into clinical settings. Current knowledge will be addressed as well as its evolution towards the future of nanoparticle-based biomedical applications.

Pedrosa, P, Baptista PV.  2015.  Gold and silver nanoparticles for diagnostics of infection. Nanotechnology in Diagnosis, Treatment and Prophylaxis of Infectious Diseases. (Mahendra Rai, Kateryna Kon, Eds.).:1-18.: Elsevier Abstract

Nanotechnology in Diagnosis, Treatment and Prophylaxis of Infectious Diseases delivers comprehensive coverage of the application of nanotechnology to pressing problems in infectious disease.
This text equips readers with cutting-edge knowledge of promising developments and future prospects in nanotechnology, paying special attention to microbes that are now resistant to conventional antibiotics, a concerning problem in modern medicine.
Readers will find a thorough discussion of this new approach to infectious disease treatment, including the reasons nanotechnology presents a promising avenue for the diagnosis, treatment, and prophylaxis of infectious diseases.

Franco, R, Pedrosa P, Carlos FF, Veigas B, Baptista PV.  2015.  Gold Nanoparticles for DNA/RNA-Based Diagnostics. Handbook of Nanoparticles. :1-25., Berlin: Springer Abstract

The remarkable physicochemical properties of gold nanoparticles (AuNPs) have prompted development
in exploring biomolecular interactions with AuNPs-containing systems, pursuing biomedical applications
in diagnostics. Among these applications, AuNPs have been remarkably useful for the development of
DNA/RNA detection and characterization systems for diagnostics, including systems suitable for point of
need. Here, emphasis will be on available molecular detection schemes of relevant pathogens and their
molecular characterization, genomic sequences associated with medical conditions (including cancer),
mutation and polymorphism identification, and the quantification of gene expression.

Journal Article

Larguinho, M, Canto R, Cordeiro M, Pedrosa P, Fortuna A, Vinhas R, Baptista PV.  2015.  Gold nanoprobe-based non-crosslinking hybridization for molecular diagnostics. Expert Review of Molecular Diagnostics. 15:1355-1368., Number 10 Abstract

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Mendo, AS, Figueiredo S, Roma-Rodrigues C, Videira PA, Ma Z, Diniz M, Larguinho M, Costa P, Lima JC, Pombeiro AJL, Baptista PV, Fernandes AR.  2015.  Characterization of antiproliferative potential and biological targets of a copper compound containing 4'-phenyl terpyridine. JBIC Journal of Biological Inorganic Chemistry. 2(6):935-948. AbstractWebsite

Several copper complexes have been assessed as anti-tumor agents against cancer cells. In this work, a copper compound [Cu(H2O){OS(CH3)2}L](NO3)2 incorporating the ligand 4'-phenyl-terpyridine antiproliferative activity against human colorectal, hepatocellular carcinomas and breast adenocarcinoma cell lines was determined, demonstrating high cytotoxicity. The compound is able to induce apoptosis and a slight delay in cancer cell cycle progression, probably by its interaction with DNA and induction of double-strand pDNA cleavage, which is enhanced by oxidative mechanisms. Moreover, proteomic studies indicate that the compound induces alterations in proteins involved in cytoskeleton maintenance, cell cycle progression and apoptosis, corroborating its antiproliferative potential.

Veigas, B, Pedrosa P, Carlos FF, Mancio-Silva L, Grosso AR, Fortunato E, Mota MM, Baptista PV.  2015.  One nanoprobe, two pathogens: gold nanoprobes multiplexing for point-of-care. Journal of Nanobiotechnology. 13 Abstract

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Conde, J, Ambrosone A, Hernandez Y, Tian F, McCully M, Berry CC, Baptista PV, T C.  2015.   15 years on siRNA delivery: Beyond the State-of-the-Art on inorganic nanoparticles for RNAi therapeutics. NANO TODAY. In Press Abstract

RNAi has always captivated scientists due to its tremendous power to modulate the phenotype of living organisms. This natural and powerful biological mechanism can now be harnessed to down-regulate specific gene expression in diseased cells; opening up endless opportunities. Since most of the conventional siRNA delivery methods are limited by a narrow therapeutic index and significant side and off-target effects, we are now in the dawn of a new age in gene therapy driven by nanotechnology vehicles for RNAi therapeutics. Here, we outlook the "do's and dont's" of the inorganic RNAi nanomaterials developed in the last 15 years and the different strategies employed are compared and scrutinized, offering important suggestions for the next 15.

Conde, J, Tian F, Hernandez Y, Bao C, Baptista PV, Cui D, Stoeger T, de la Fuente JM.  2015.  RNAi-based glyconanoparticles trigger apoptotic pathways for in vitro and in vivo enhanced cancer-cell killing. Nanoscale. 7:9083-9091., Number 19 Abstract

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Veigas, B, Fortunato E, Baptista PV.  2015.  Field Effect Sensors for Nucleic Acid Detection: Recent Advances and Future Perspectives. Sensors. 15:10380-10398., Number 5 Abstract

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Child, HW, Hernandez Y, Conde J, Mullin M, Baptista PV, de la Fuente JM, Berry CC.  2015.  Gold nanoparticle-siRNA mediated oncogene knockdown at RNA and protein level, with associated gene effects. NANOMEDICINE. 10(16):2513-2525. AbstractWebsite

Aims: RNAi is a powerful tool for gene silencing that can be used to reduce undesirable overexpression of oncogenes as a novel form of cancer treatment. However, when using RNAi as a therapeutic tool there is potential for associated gene effects. This study aimed to utilize gold nanoparticles to deliver siRNA into HeLa cells. Results: Knockdown of the c-myc oncogene by RNAi, at the RNA, protein and cell proliferation level was achieved, while also identifying associated gene responses. Discussion: The gold nanoparticles used in this study present an excellent delivery platform for siRNA, but do note associated gene changes. Conclusion: The study highlights the need to more widely assess the cell physiological response to RNAi treatment, rather than focus on the immediate RNA levels.

Bernacka-Wojcik, I, Aguas H, Carlos FF, Lopes P, Wojcik PJ, Costa MN, Veigas B, Igreja R, Fortunato E, Baptista PV, Martins R.  2015.  Single Nucleotide Polymorphism Detection Using Gold Nanoprobes and Bio-Microfluidic Platform With Embedded Micro lenses. Biotechnology and Bioengineering. 112:1210-1219., Number 6 Abstract

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Veigas, B, Fortunato E, Baptista PV.  2015.  Mobile based gold nanoprobe TB diagnostics for point-of-need.. Methods in molecular biology (Clifton, N.J.). 1256:41-56. Abstract

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Martins, P, Marques M, Coito L, Pombeiro A, Baptista PV, Fernandes AR.  2015.  Organometallic Compounds in Cancer Therapy: Past Lessons and Future Directions. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY. 9(14) AbstractWebsite

Over the past few years, modern medicinal chemistry has evolved towards providing us new and alternative chemotherapeutic compounds with high cytotoxicity towards tumor cells, alongside with reduced side effects in cancer patients. Organometallic compounds and their unique physic-chemical properties typically used in homogenous catalysis are now being translated as potential candidates for medical purposes. Their structural diversity, ligand exchange, redox and catalytic properties make them promising drug candidates for cancer therapy. Over the last decade this area has witnessed a steady growth and a few organometallic compounds have in fact already entered clinical trials, emphasizing its increasing importance and clinical relevance. Here we intend to stress out the different applications of organometallic compounds in medicine with emphasis on cancer therapy, as well as address setbacks regarding formulation issues, systemic toxicity and off-target effects. Advantages over classical coordination metal complexes, their nanovectorisation and specific molecular targets are also discussed.

Pedrosa, P, Vinhas R, Fernandes A, Baptista PV.  2015.  Gold Nanotheranostics: Proof-of-Concept or Clinical Tool? Nanomaterials. 5(4):1853-1879. AbstractWebsite

Nanoparticles have been making their way in biomedical applications and personalized medicine, allowing for the coupling of diagnostics and therapeutics into a single nanomaterial—nanotheranostics. Gold nanoparticles, in particular, have unique features that make them excellent nanomaterials for theranostics, enabling the integration of targeting, imaging and therapeutics in a single platform, with proven applicability in the management of heterogeneous diseases, such as cancer. In this review, we focus on gold nanoparticle-based theranostics at the lab bench, through pre-clinical and clinical stages. With few products facing clinical trials, much remains to be done to effectively assess the real benefits of nanotheranostics at the clinical level. Hence, we also discuss the efforts currently being made to translate nanotheranostics into the market, as well as their commercial impact.

McCully, M, Hernandez Y, Conde J, Baptista PV, de la Fuente JM, Hursthouse A, St D.  2015.  The significance of the balance between intracellular glutathione and polyethylene glycol (PEG) for successful siRNA release from gold nanoparticles. Nano Research. AbstractWebsite

The therapeutic promise of small interfering RNAs (siRNAs) for specific gene silencing is dependent on the
successful delivery of functional siRNAs to the cell cytoplasm. Their conjugation to an established delivery
platform, such as gold nanoparticles, offers a huge potential for treating diseases and advancing our
understanding of cellular processes. The success or failure is dependent on both the uptake of the nanoparticlesinto the cells and subsequent intracellular release of the functional siRNA. In this paper, utilising gold nanoparticle siRNA-mediated delivery against C-MYC, we aimed to determine if we could achieve knockdown in a cancer cell line with low levels of intracellular glutathione, and determine the influence, if any, of polyethylene glycol (PEG) ligand density on knockdown, with a view to determine the optimal nanoparticle
design to achieve C-MYC knockdown. We demonstrate that, regardless of the PEG density, knockdown in cells with relatively low glutathione levels can be achieved, and also the possible effect of steric hindrance in terms of PEG on the availability of the siRNA for cleavage in the intracellular environment. Gold nanoparticle uptake was demonstrated via transmission electron microscopy and mass spectroscopy, whilst knockdown was determined at the protein and physiological levels (cells in S-phase) by in-cell westerns and BrdU incorporation, respectively.

McCully, M, Hernandez Y, Conde J, Baptista PV, de la Fuente JM, Hursthouse A, Stirling D, Berry CC.  2015.  Significance of the balance between intracellular glutathione and polyethylene glycol for successful release of small interfering RNA from gold nanoparticles. Nano Research. 8:3281-3292., Number 10 Abstract

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Vinhas, R, Correia C, Ribeiro P, Lourenco A, Sousa A, Fernandes A, Baptista P.  2015.  GOLD NANOPROBES IN THE DIAGNOSTIC OF CHRONIC MYELOID LEUKEMIA: DETECTION OF THE E14A2 BCR-ABL TRANSCRIPT DIRECTLY IN RNA SAMPLES. Leukemia Research. 39:S90. Abstract

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Martins, P, Jesus J, Santos S, Raposo LR, Roma-Rodrigues C, Baptista PV, Fernandes A.  2015.  Heterocyclic Anticancer Compounds: Recent Advances and the Paradigm Shift towards the Use of Nanomedicine’s Tool Box. Molecules. (20):16852-16891. AbstractWebsite

The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. Apart from the already marketed drugs, there are many other being investigated for their promising activity against several malignancies. In particular, anticancer research has been capitalizing on the intrinsic versatility and dynamic core scaffold of these compounds. Nevertheless, as for any other promising anticancer drugs, heterocyclic compounds do not come without shortcomings. In this review, we provide for a concise overview of heterocyclic active compounds and families and their main applications in medicine. We shall focus on those suitable for cancer therapy while simultaneously addressing main biochemical modes of action, biological targets, structure-activity relationships as well as intrinsic limitation issues in the use of these compounds. Finally, considering the advent of nanotechnology for effective selective targeting of drugs, we shall discuss fundamental aspects and considerations on nanovectorization of such compounds that may improve pharmacokinetic/pharmacodynamic properties of heterocycles.

Larguinho, M, Santos S, Almeida J, Baptista PV.  2015.  DNA adduct identification using gold-aptamer nanoprobes. Iet Nanobiotechnology. 9:95-101., Number 2 Abstract

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Vinhas, R, Cordeiro M, Carlos F, Mendo S, Fernandes A, Figueiredo S, Baptista P.  2015.  Gold nanoparticle-based theranostics: disease diagnostics and treatment using a single nanomaterial. Journal of Nanobiosensors in Disease Diagnosis. (4):11-23. AbstractWebsite

Nanotheranostics takes advantage of nanotechnology-based systems in order to diagnose and treat a specific disease. This approach is particularly relevant for personalized medicine, allowing the detection of a disease at an early stage, to direct a suitable therapy toward the target tissue based on the molecular profile of the altered phenotype, subsequently facilitating disease monitoring and following treatment. A tailored strategy also enables to reduce the off-target effects associated with universal treatments and improve the safety profile of a given treatment. The unique optical properties of gold nanoparticles, their ease of surface modification, and high surface-to-volume ratio have made them central players in this area. By combining imaging, targeting, and therapeutic agents in a single vehicle, these nanoconjugates are (ought to be) an important tool in the clinics. In this review, the multifunctionality of gold nanoparticles as theranostics agents will be highlighted, as well as the requirements before the translation of these nanoplatforms into routine clinical practice.

Veigas, B, Portugal C, Valerio R, Fortunato E, Crespo JG, Baptista PV.  2015.  Scalable approach for the production of functional DNA based gold nanoprobes. Journal of Membrane Science. 492:528-535. Abstract

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Restani, RB, Conde J, Pires RF, Martins P, Fernandes AR, Baptista PV, Bonifacio VDB.  2015.  POxylated Polyurea Dendrimers: Smart Core-Shell Vectors with IC50 Lowering Capacity. MACROMOLECULAR BIOSCIENCE. 15(8):1045–1051. AbstractWebsite

The design and preparation of highly efficient drug delivery platforms using green methodologies is at the forefront of nanotherapeutics research. POxylated polyurea dendrimers are efficiently synthesized using a supercritical-assisted polymerization in carbon dioxide. These fluorescent, pH-responsive and water-soluble core-shell smart nanocarriers show low toxicity in terms of cell viability and absence of glutathione depletion, two of the major side effect limitations of current vectors. The materials are also found to act as good transfection agents, through a mechanism involving an endosomal pathway, being able to reduce 100-fold the IC50 of paclitaxel.