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McCully, M, Conde J, V. Baptista P, Mullin M, Dalby MJ, Berry CC.  2018.  Nanoparticle-antagomiR based targeting of miR-31 to induce osterix and osteocalcin expression in mesenchymal stem cells, 2018/02/14. PLOS ONE. 13(2):e0192562-.: Public Library of Science AbstractWebsite

Mesenchymal stem cells are multipotent adult stem cells capable of generating bone, cartilage and fat, and are thus currently being exploited for regenerative medicine. When considering osteogenesis, developments have been made with regards to chemical induction (e.g. differentiation media) and physical induction (e.g. material stiffness, nanotopography), targeting established early transcription factors or regulators such as runx2 or bone morphogenic proteins and promoting increased numbers of cells committing to osteo-specific differentiation. Recent research highlighted the involvement of microRNAs in lineage commitment and terminal differentiation. Herein, gold nanoparticles that confer stability to short single stranded RNAs were used to deliver MiR-31 antagomiRs to both pre-osteoblastic cells and primary human MSCs in vitro. Results showed that blocking miR-31 led to an increase in osterix protein in both cell types at day 7, with an increase in osteocalcin at day 21, suggesting MSC osteogenesis. In addition, it was noted that antagomiR sequence direction was important, with the 5 prime reading direction proving more effective than the 3 prime. This study highlights the potential that miRNA antagomiR-tagged nanoparticles offer as novel therapeutics in regenerative medicine.

Ribeiro, APC, Anbu S, Alegria ECBA, Fernandes AR, Baptista PV, Mendes R, Matias AS, Mendes M, Guedes da Silva MFC, Pombeiro AJL.  2018.  Evaluation of cell toxicity and DNA and protein binding of green synthesized silver nanoparticles, 2018. 101:137-144. AbstractWebsite
Alves, PU, Vinhas R, Fernandes AR, Birol SZ, Trabzon L, Bernacka-Wojcik I, Igreja R, Lopes P, Baptista PV, Águas H, Fortunato E, Martins R.  2018.  Multifunctional microfluidic chip for optical nanoprobe based RNA detection – application to Chronic Myeloid Leukemia, 2018. 8(1):381. AbstractWebsite

Many diseases have their treatment options narrowed and end up being fatal if detected during later stages. As a consequence, point-of-care devices have an increasing importance for routine screening applications in the health sector due to their portability, fast analyses and decreased cost. For that purpose, a multifunctional chip was developed and tested using gold nanoprobes to perform RNA optical detection inside a microfluidic chip without the need of molecular amplification steps. As a proof-of-concept, this device was used for the rapid detection of chronic myeloid leukemia, a hemato-oncological disease that would benefit from early stage diagnostics and screening tests. The chip passively mixed target RNA from samples, gold nanoprobes and saline solution to infer a result from their final colorimetric properties. An optical fiber network was used to evaluate its transmitted spectra inside the chip. Trials provided accurate output results within 3 min, yielding signal-to-noise ratios up to 9 dB. When compared to actual state-of-art screening techniques of chronic myeloid leukemia, these results were, at microscale, at least 10 times faster than the reported detection methods for chronic myeloid leukemia. Concerning point-of-care applications, this work paves the way for other new and more complex versions of optical based genosensors.

Cordeiro, M, Otrelo-Cardoso AR, Svergun DI, Konarev PV, Lima JC, Santos-Silva T, Baptista PV.  2018.  Optical and Structural Characterization of a Chronic Myeloid Leukemia DNA Biosensor, 2018. ACS Chemical BiologyACS Chemical Biology. : American Chemical Society AbstractWebsite
Daniela, P, Margarida F, Gabriela M, Catarina R‐R, V. BP, R. FA, Sónia B, Luísa CA, M. ACA, M. FL, S. BP.  2018.  Synthesis, Cytotoxicity Evaluation in Human Cell Lines and in Vitro DNA Interaction of a Hetero‐Arylidene‐9(10H)‐Anthrone, 2018. European Journal of Organic ChemistryEuropean Journal of Organic Chemistry. 2018(4):545-549.: Wiley-Blackwell AbstractWebsite

A new and never before reported hetero?arylidene?9(10H)?anthrone structure (4) was unexpectedly isolated on reaction of 1,2?dimethyl?3?ethylimidazolium iodide (2) and 9?anthracenecarboxaldehyde (3) under basic conditions. Its structure was unequivocally confirmed by X?ray crystallography. No cytotoxicity in human healthy fibroblasts and in two different cancer cell lines was observed, indicating its applicability in biological systems. Compound 4 interacts with CT?DNA by intercalation between the adjacent base pairs of DNA with a high binding affinity [Kb = 2.0?(±0.20)???105 m?1], which is 10?? higher than that described for doxorubicin [Kb = 3.2?(±0.23)???104 m?1]. Furthermore, compound 4 quenches the fluorescence emission of a GelRed?CT?DNA system with a quenching constant (KSV) of 3.3?(±0.3)???103 m?1 calculated by the Stern?Volmer equation.

Vinhas, R, Mendes R, Fernandes AR, Baptista PV.  2017.  Nanoparticles—Emerging Potential for Managing Leukemia and Lymphoma, 2017. 5:79. AbstractWebsite

Nanotechnology has become a powerful approach to improve the way we diagnose and treat cancer. In particular, nanoparticles possess unique features for enhanced sensitivity and selectivity for earlier detection of circulating cancer biomarkers. In vivo, nanoparticles enhance the therapeutic efficacy of anticancer agents when compared to conventional chemotherapy, improving vectorization and delivery, and helping to overcome drug resistance. Nanomedicine has been mostly focused on solid cancers due to take advantage from the enhanced permeability and retention (EPR) effect experienced by tissues in the close vicinity of tumors, which enhance nanomedicine’s accumulation and, consequently, improve efficacy. Nanomedicines for leukemia and lymphoma, where EPR effect is not a factor, are addressed differently from solid tumors. Nevertheless, nanoparticles have provided innovative approaches to simple and non-invasive methodologies for diagnosis and treatment in liquid tumors. In this review, we consider the state of the art on different types of nanoconstructs for the management of liquid tumors, from pre-clinical studies to clinical trials. We also discuss the advantages of nanoplatforms for theranostics and the central role played by nanoparticles in this combined strategy.

Cordeiro, M, Carvalho L, Silva J, Saúde L, Fernandes AR, Baptista. PV.  2017.  Gold nanobeacons for tracking gene silencing in Zebrafish. Nanomaterials. AbstractWebsite

The use of gold nanoparticles for effective gene silencing has demonstrated its potential as a tool for gene expression experiments and for the treatment of several diseases. Here, we used a gold nanobeacon designed to specifically silence the enhanced green fluorescence protein (EGFP) mRNA in embryos of a fli-EGFP transgenic zebrafish line, while simultaneously allowing the tracking and localization of the silencing events via the beacon’s emission. Fluorescence imaging measurements demonstrated a decrease of the EGFP emission with a concomitant increase in the fluorescence of the Au-nanobeacon. Furthermore, microinjection of the Au-nanobeacon led to a negligible difference in mortality and malformations in comparison to the free oligonucleotide, indicating that this system is a biocompatible platform for the administration of gene silencing moieties. Together, these data illustrate the potential of Au-nanobeacons as tools for in vivo zebrafish gene modulation with low toxicity which may be used towards any gene of interest.

Mendes, R, Fernandes AR, Baptista PV.  2017.  Gold Nanoparticle Approach to the Selective Delivery of Gene Silencing in Cancer—The Case for Combined Delivery? Genes. 3(8):94. AbstractWebsite

Gene therapy arises as a great promise for cancer therapeutics due to its potential to silence genes involved in tumor development. In fact, there are some pivotal gene drivers that suffer critical alterations leading to cell transformation and ultimately to tumor growth. In this vein, gene silencing has been proposed as an active tool to selectively silence these molecular triggers of cancer, thus improving treatment. However, naked nucleic acid (DNA/RNA) sequences are reported to have a short lifetime in the body, promptly degraded by circulating enzymes, which in turn speed up elimination and decrease the therapeutic potential of these drugs. The use of nanoparticles for the effective delivery of these silencers to the specific target locations has allowed researchers to overcome this issue. Particularly, gold nanoparticles (AuNPs) have been used as attractive vehicles for the target-specific delivery of gene-silencing moieties, alone or in combination with other drugs. We shall discuss current trends in AuNP-based delivery of gene-silencing tools, considering the promising road ahead without overlooking existing concerns for their translation to clinics

Vinhas, R, Fernandes A, Baptista PV.  2017.  Gold Nanoparticles for BCR-ABL1 Gene Silencing: Improving Tyrosine Kinase Inhibitor Efficacy in Chronic Myeloid Leukemia. Molecular Therapy Nucleic Acids. 7:408-416. AbstractWebsite

Introduction of tyrosine kinase inhibitors for chronic myeloid leukemia treatment is associated with a 63% probability of maintaining a complete cytogenetic response, meaning that over 30% patients require an alternative methodology to overcome resistance, tolerance, or side effects. Considering the potential of nanotechnology in cancer treatment and the benefits of a combined therapy with imatinib, a nanoconjugate was designed to achieve BCR-ABL1 gene silencing. Gold nanoparticles were functionalized with a single-stranded DNA oligonucleotide that selectively targets the e14a2 BCR-ABL1 transcript expressed by K562 cells. This gold (Au)-nanoconjugate showed great efficacy in gene silencing that induced a significant increase in cell death. Variation of BCL-2 and BAX protein expression, an increase of caspase-3 activity, and apoptotic bodies in cells treated with the nanoconjugate demonstrate its aptitude for inducing apoptosis on K562 BCR-ABL1-expressing cells. Moreover, the combination of the silencing Au-nanoconjugate with imatinib prompted a decrease of imatinib IC50. This Au-nanoconjugate was also capable of inducing the loss of viability of imatinib-resistant K562 cells. This strategy shows that combination of Au-nanoconjugate and imatinib make K562 cells more vulnerable to chemotherapy and that the Au-nanoconjugate alone may overcome imatinib-resistance mechanisms, thus providing an effective treatment for chronic myeloid leukemia patients who exhibit drug tolerance.

Fernandes, AR, Jesus J, Martins P, Figueiredo S, Rosa D, Martins L, Corvo ML, Carvalheiro MC, Costa PM, Baptista PV.  2017.  Multifunctional gold-nanoparticles: A nanovectorization tool for the targeted delivery of novel chemotherapeutic agents. Journal Control Release. 245:52-61. AbstractWebsite

Due to their small size and unique properties, multifunctional nanoparticles arise as versatile delivery systems easily grafted with a vast array of functional moieties, such as anticancer cytotoxic chemotherapeutics and targeting agents. Here, we formulated a multifunctional gold-nanoparticle (AuNP) system composed of a monoclonal antibody against epidermal growth factor receptor (EGFR) (anti-EGFR D-11) for active targeting and a Co(II) coordination compound [CoCl(H2O)(phendione)2][BF4] (phendione =1.10-phenanthroline-5.6-dione) (TS265) with proven antiproliferative activity towards cancer cells (designated as TargetNanoTS265). The efficacy of this nanoformulation, and the non-targeted counterpart (NanoTS265), were evaluated in vitro using cancer cell models and in vivo using mice xenografts. Compared to the free compound, both nanoformulations (TargetNanoTS265 and NanoTS265) efficiently delivered the cytotoxic cargo in a controlled selective manner due to the active targeting, boosting tumor cytotoxicity. Treatment of HCT116-derived xenographs tumors with TargetNanoTS265 led to 93% tumor reduction. This simple conceptual nanoformulation demonstrates the potential of nanovectorization of chemotherapeutics via simple assembly onto AuNPs of BSA/HAS-drug conjugates that may easily be expanded to suit other cargo of novel compounds that require optimized controlled delivery to cancer target.

Mendes, R, Pedrosa P, Lima JC, Fernandes AR, Baptista PV.  2017.  Photothermal enhancement of chemotherapy in breast cancer by visible irradiation of Gold Nanoparticles. Scientific Reports. (7):10872. AbstractWebsite

Photothermal Therapy (PTT) impact in cancer therapy has been increasing due to the enhanced
photothermal capabilities of a new generation of nanoscale photothermal agents. Among these
nanoscale agents, gold nanoshells and nanorods have demonstrated optimal properties for translation
of near infra-red radiation into heat at the site of interest. However, smaller spherical gold nanoparticles
(AuNPs) are easier to produce, less toxic and show improved photoconversion capability that may proft
from the irradiation in the visible via standard surgical green lasers. Here we show the efcient lightto-heat
conversion of spherical 14nm AuNPs irradiated in the visible region (at the surface plasmons
resonance peak) and its application to selectively obliterate cancer cells. Using breast cancer as model,
we show a synergistic interaction between heat (photoconversion at 530nm) and cytotoxic action by
doxorubicin with clear advantages to those of the individual therapy approaches.

Pedrosa, P, Heuer-Jungemann A, Kanaras AG, Fernandes AR, Baptista PV.  2017.  Potentiating angiogenesis arrest in vivo via laser irradiation of peptide functionalised gold nanoparticles. Journal of Nanobiotechnology. 85(15) AbstractWebsite

Anti-angiogenic therapy has great potential for cancer therapy with several FDA approved formulations but there are considerable side effects upon the normal blood vessels that decrease the potential application of such therapeutics. Chicken chorioallantoic membrane (CAM) has been used as a model to study angiogenesis in vivo. Using a CAM model, it had been previously shown that spherical gold nanoparticles functionalised with an anti-angiogenic peptide can humper neo-angiogenesis.

Our results show that gold nanoparticles conjugated with an anti-angiogenic peptide can be combined with visible laser irradiation to enhance angiogenesis arrest in vivo. We show that a green laser coupled to gold nanoparticles can achieve high localized temperatures able to precisely cauterize blood vessels. This combined therapy acts via VEGFR pathway inhibition, leading to a fourfold reduction in FLT-1 expression.

The proposed phototherapy extends the use of visible lasers in clinics, combining it with chemotherapy to potentiate cancer treatment. This approach allows the reduction of dose of anti-angiogenic peptide, thus reducing possible side effects, while destroying blood vessels supply critical for tumour progression.

Roma-Rodrigues, C, Raposo L, Cabral R, Paradinha F, Baptista PV, Fernandes AR.  2017.  Tumor microenvironment modulation via gold nanoparticles targeting malicious exosomes: implications in cancer diagnostics and Therapy. Int. J. Mol. Sci.. 18(1):162. AbstractWebsite

Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes’ release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs) make them suitable vehicles to pursuit this goal. AuNPs’ properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs’ role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression.

Cordeiro, M, Giestes L, Lima JC, Baptista P.  2016.  BioCode gold-nanobeacon for the detection of fusion transcripts causing chronic myeloid leukemia. Journal of Nanobiotechnology. 38(14) AbstractWebsite

Gold-nanobeacons (Au-nanobeacons) have proven to be versatile systems for molecular diagnostics and therapeutic actuators. Here, we present the development and characterization of two gold nanobeacons combined with Förster resonance energy transfer (FRET) based spectral codification for dual mode sequence discrimination. This is the combination of two powerful technologies onto a single nanosystem.

We proved this concept to detect the most common fusion sequences associated with the development of chronic myeloid leukemia, e13a2 and e14a2. The detection is based on spectral shift of the donor signal to the acceptor, which allows for corroboration of the hybridization event. The Au-nanobeacon acts as scaffold for detection of the target in a homogenous format whose output capability (i.e. additional layer of information) is potentiated via the spectral codification strategy.

The spectral coded Au-nanobeacons permit the detection of each of the pathogenic fusion sequences, with high specificity towards partial complementary sequences. The proposed BioCode Au-nanobeacon concept provides for a nanoplatform for molecular recognition suitable for cancer diagnostics.

Vinhas, R, Correia C, Ribeiro P, Lourenço A, Botelho A, Fernandes AR, Baptista PV.  2016.  Colorimetric assessment of BCR-ABL1 transcripts in clinical samples via gold nanoprobes. Anal Bioanal Chem. 408(19):5277-84. AbstractWebsite

Gold nanoparticles functionalized with thiolated oligonucleotides (Au-nanoprobes) have been used in a range of applications for the detection of bioanalytes of interest, from ions to proteins and DNA targets. These detection strategies are based on the unique optical properties of gold nanoparticles, in particular, the intense color that is subject to modulation by modification of the medium dieletric. Au-nanoprobes have been applied for the detection and characterization of specific DNA sequences of interest, namely pathogens and disease biomarkers. Nevertheless, despite its relevance, only a few reports exist on the detection of RNA targets. Among these strategies, the colorimetric detection of DNA has been proven to work for several different targets in controlled samples but demonstration in real clinical bioanalysis has been elusive. Here, we used a colorimetric method based on Au-nanoprobes for the direct detection of the e14a2 BCR-ABL fusion transcript in myeloid leukemia patient samples without the need for retro-transcription. Au-nanoprobes directly assessed total RNA from 38 clinical samples, and results were validated against reverse transcription-nested polymerase chain reaction (RT-nested PCR) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The colorimetric Au-nanoprobe assay is a simple yet reliable strategy to scrutinize myeloid leukemia patients at diagnosis and evaluate progression, with obvious advantages in terms of time and cost, particularly in low- to medium-income countries where molecular screening is not routinely feasible. Graphical abstract Gold nanoprobe for colorimetric detection of BCR-ABL1 fusion transcripts originating from the Philadelphia chromosome.

Vinhas, R, Cordeiro M, Pedrosa P, Fernandes AR, Baptista PV.  2016.  Current trends in molecular diagnostics of chronic myeloid leukemia. Leukemia & Lymphoma. :1-14. AbstractWebsite

Nearly 1.5 million people worldwide suffer from chronic myeloid leukemia (CML), characterized by the genetic translocation t(9;22)(q34;q11.2), involving the fusion of the Abelson oncogene (ABL1) with the breakpoint cluster region (BCR) gene. Early onset diagnosis coupled to current therapeutics allow for a treatment success rate of 90, which has focused research on the development of novel diagnostics approaches. In this review, we present a critical perspective on current strategies for CML diagnostics, comparing to gold standard methodologies and with an eye on the future trends on nanotheranostics.

Conde, J, Tian F, de la Fuente JM, Baptista PV.  2016.  Editorial: Cancer Nanotheranostics: What Have We Learned So Far? Frontiers in Chemistry. 71(3)Website
Cordeiro, M, Carlos FF, Pedrosa P, Lopez A, Baptista PV.  2016.  Gold Nanoparticles for Diagnostics: Advances towards Points of Care. Diagnostics. 6(4):43. AbstractWebsite

The remarkable physicochemical properties of gold nanoparticles (AuNPs) have prompted developments in the exploration of biomolecular interactions with AuNP-containing systems, in particular for biomedical applications in diagnostics. These systems show great promise in improving sensitivity, ease of operation and portability. Despite this endeavor, most platforms have yet to reach maturity and make their way into clinics or points of care (POC). Here, we present an overview of emerging and available molecular diagnostics using AuNPs for biomedical sensing that are currently being translated to the clinical setting.

Martins, M, Baptista PV, Mendo AS, Correia C, Videira PA, Rodrigues AS, Muthukumaran J, Santos-Silva T, Silva A, da Silva FG, Gigante J, Duarte A, Gajewska MJ, Fernandes AR.  2016.  In vitro and in vivo biological characterization of the anti-proliferative potential of a cyclic trinuclear organotin(IV) complex. Molecular BioSystems. 12(3)
Roma-Rodrigues, C, Alves-Barroco C, Raposo LR, Costa MN, Fortunato E, Baptista PV, Fernandes AR, Santos-Sanches I.  2016.  Infection of human keratinocytes by Streptococcus dysgalactiae subspecies dysgalactiae isolated from milk of the bovine udder. Microbes and Infection. 9(4):290-293.
Corvo, LM, Mendo AS, Figueiredo S, Gaspar R, Larguinho M, da Silva FGMC, Baptista PV, Fernandes AR.  2016.  Liposomes as Delivery System of a Sn(IV) Complex for Cancer Therapy. Pharmaceutical Research.
Mendes, R, Carreira B, Baptista PV, Fernandes AR.  2016.  Non-small cell lung cancer biomarkers and targeted therapy - two faces of the same coin fostered by nanotechnology. Expert Review of Precision Medicine and Drug Development: Personalized medicine in drug development and clinical practice. 1(2)
Baptista, PV.  2016.  Precision nanomedicine in cancer: how far are we from personalization? Expert Review of Precision Medicine and Drug Development: Personalized medicine in drug development and clinical practice. 1(3)Website
Ma, Z, Zhang B, da Silva FGMC, Silva J, Mendo AS, Baptista PV, Fernandes AR.  2016.  Synthesis, Characterization, Thermal Properties and Antiproliferative Potential of Copper(II) 4′-phenyl-terpyridine Compounds. Dalton Transactions. 45(12)
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.