Search

The issue of gender equality in public organizations is a relevant subject of academic and practitioners’ management debate as gender balance represents a symbol of democracy and good governance, leading to a more equitable and sustainable economy and improving trust in public entities. It has also attracted the attention of institutions and society, as confirmed by the commitment in European financial programs Horizon 2020 and Horizon 2021-2027. Nevertheless, women under-representation in workplaces still exists and scholars highlight the need to conceptualize the effect of gender in public employment, with a broader perspective in terms of settings and sectors. The study aims to address these requirements through a literature review on gender and public sector considering the studies on the topic published by the IPAZIA Observatory since its inception, both in volumes and in conference proceedings. Mainly using qualitative methods, the papers analysed show that public institutions are strongly gendered and do not allow women equal work opportunities compared to men, especially in technological fields. However, encouraging women's involvement in public organizations may have a positive effect on public administration outcomes as female engagement creates high level of cooperation reducing conflicts, generates a positive push for innovation and in co-production of corporate value. Besides, our results prove a positive relationship between both gender diversity and accountability for sustainability and gender diversity and disclosure of diversity information as the presence of women at different levels of the organization generates positive expectations of quality, credibility, and transparency by reducing information asymmetry and by signaling legitimacy. In achieving its aim, our study provides both theoretical and practical contributions in order to give a research agenda useful to guide future research efforts, and also highlight how the implementation of gender equality and work-life balance policies can create a system of benefits for public entities.

The chapter aims to deepen the emerging issue of cyber-risk that, among non-financial (NF) risks, represents a major threat for organizations due to the growing sophistication and variety of data breaches and cyber attacks. The research provides a general background for NF risks disclosure illustrating the path that led from external voluntary to mandatory frameworks for the disclosure of NF risks following the EU Directive. Then, we move on to describe the role of internal auditors for the management and disclosure of the digital risk. In order to better understand the effectiveness of corporate governance mechanisms for digital risk disclosure, we conduct a review of literature and a visualization to provide the most frequent topics and their chronological evolution. The chapter contributes to the risk disclosure and corporate governance literature, by providing some theoretical and practical implications.

Purpose: Different mechanisms allow intellectual capital (IC) to affect performance. In this paper, we set out to analyze the value of relations for the academic performance effect of IC and explore how the university’s reliance on digital technologies facilitates the contribution of IC to the overall academic performance. Design/methodology/approach: We develop a model linking elements of IC to academic performance in the form of teaching, research, and entrepreneurial activity. Our model is centred on relational capital that is supposed to directly fuel performance and mediate the link between the other two IC dimensions and performance. From a methodological point of view, we base our empirical investigation on a sample of Italian public universities and applied structural equation modeling to test the mediation and a group comparison to disentangle the effect of universities’ digitalization. Findings: We find a significant and positive effect of relational capital on performance. Relational capital fully mediates the relationship between structural capital and academic performance whereas, it only partially mediates the link between human capital and academic performance. We also suggest that digital technologies guide the prominence of the relationship in the university ability to fulfil teaching, research and entrepreneurship missions through IC. Originality/value: This study offers a representation of how the relational dimension of IC is the mean through which the stock of knowledge inside IC can be translated into entrepreneurial, education and research achievements and how digital technologies are essential for the exploitation of the performance effect of IC in the digital era.

Non-GAAP reporting has become popular in the capital market over the last two decades and has generated considerable concerns among external users of the financial report. Since the 1990s, academics and practitioners have started questioning the usefulness of non-GAAP metrics. Most of the studies on pro-forma indicators advocates that managers are mainly driven by the desire to provide more precise information to stakeholders on core earnings, in particular on permanent earnings. However, other researchers find that opportunism might be the reason behind the voluntary disclosure of non-GAAP indicators, especially before the regulatory intervention. Therefore, two opposing theoretical perspectives have emerged: informativeness and opportunism. The informative perspective suggests that non-GAAP earnings tend to be more permanent than GAAP earnings and are more useful in the prediction of future firm performance. Other research plays importance on the value relevance of non-GAAP earnings compared to GAAP results, as they are strongly associated with stock price. Further studies highlight that companies which voluntarily disclose non-GAAP results present a lower quality of GAAP earnings and the non-GAAP reporting serves the purpose to compensate for the lower informativeness of GAAP results. Finally, more recent research has highlighted the positive link between non-GAAP disclosure and the reduction of information asymmetries. Differently, the opportunistic perspective assumes that non-GAAP disclosure serves the purpose of misleading the users of financial statements, presenting a higher business performance compared to that emerging from the use of GAAP metrics. Empirical evidence shows that managers disclose pro forma earnings to conceal losses, to report positive earnings growth, to meet or beat analysts’ expectations and to increase investor perceptions of earning credibility. Although most of the studies have examined the US setting, the phenomenon of non-GAAP earnings is not confined exclusively to the US. Additional research has recently been conducted also in Australia, New Zealand, Canada, South Africa and Europe. Studies in the European settings have shown that almost 80% of companies in the largest cities reports at least one non-GAAP metric in their earning releases. With reference to the UK setting the percentage of companies that communicate non-GAAP earnings has increased from 40% in 1993 to 75% in 2001, reaching a peak of 90% after the transition to IFRS in the 2005. In spite of the relevance of non-GAAP earnings, there are several differences among countries related to both institutional and economic factors. For example, in the US context the non-GAAP earnings are mainly reported by hi-tech companies, while outside US there is no sector specificity. Furthermore, European companies are more consistent in non-GAAP reporting policies than their US counterparts and are less prone to opportunistically exclude recurring items, such as depreciation. Moving from the dual nature of non-GAAP reporting, this study provides a systematic review of the literature with the aim to identify the main empirical evidence supporting the informative or the opportunistic perspective, pointing out the areas that need further investigation by scholars and practitioners.

The paper aims to examine the influence of gender diversity among hospital directors on the adoption of innovation. To this aim, it empirically analyses a sample of 108 Italian public hospitals, including general, teaching and research hospitals, for the 2015-2016 time-frame. Findings from our OLS regression analysis show that female directors enable hospitals to successfully face the innovation challenge. In particular, female directors bring specific skills to executives and enhance their knowledge base. In addition, the results of our analysis suggest that work-abroad experience promote the implementation of innovative solutions as it provides women directors with a global view and open-mindedness that enrich their intercultural skills, and therefore their attitude towards innovation. The results contribute to the existing empirical research on women in governance by providing insights into the healthcare sector that is still under-explored. Moreover, the paper suggests that policy makers should pay attention to combine a stronger participation of female in hospital leadership, and call for proper normative actions able to improve the background requirements for the recruitment of directors.

Nell’ultimo decennio, il settore pubblico è stato interessato da un significativo processo di innovazione indotto dalla spinta delle riforme di New Public Management. Tali misure hanno coinvolto le innovazioni di prodotto, di servizio e di governo aziendale, interessando lo sviluppo di nuovi processi volti a superare le criticità esistenti e a favorire azioni di miglioramento dell’attività amministrativa, anche attraverso l’avanzamento tecnologico. Similmente, il ricorso all’innovazione digitale può essere circoscritto all’ambito di operatività dell’azienda pubblica ovvero investire le relazioni tra di essa, i cittadini, le imprese private e, più in generale,gli utenti. . L’innovazione di cui si discute, infatti, prende ipicamente forma attraverso il cambiamento delle procedure e delle routine di front e back office, accompagnandosi frequentemente all’introduzione di nuovi servizi e/o al miglioramento della qualità di quelli in essere allo scopo di soddisfare i bisogni degli utenti attraverso l’uso delle tecnologie digitali. Partendo da queste premesse, il capitolo si concentra sul setting delle aziende sanitarie pubbliche e indaga il grado di diffusione dell'e-health. Nonostante la rilevanza del tema in ambito nazionale e l’interesse del legislatore verso l’implementazione dell’e-health, come sottolineato anche dalle recenti riforme legislative, si rileva una scarsità di studi empirici volti ad indagare il grado di diffusione delle soluzioni digitali in sanità. Al fine di contribuire al dibattito su questo tema, è stata condotta una analisi esplorativa di carattere descrittivo su un campione di 108 aziende ospedaliere pubbliche italiane, osservate nell’anno 2016. L’indagine condotta mostra che il grado di diffusione dell’e-health in Italia è soddisfacente ma disomogenea e dipende da una molteplicità di fattori organizzativi e di contesto.

Exosomes are emerging as promising target for early diagnosis and therapy in different oncological conditions including breast cancer (BC). However, the development of tools able to easily and specifically target cancer cell-derived exosomes still represent a fundamental issue that is required to realize their clinical utility. Nucleic-acid aptamers are a promising class of structured single stranded oligonucleotides that serve as high affinity ligands of disease-associated proteins. Given their high potential in diagnosis and therapy, we addressed the development of aptamers specific for BC-derived exosomes. To this end, we developed a novel SELEX strategy by using exosomes purified from primary BC cells as positive selection target. By such a strategy we isolated nuclease resistant RNA aptamers able to specifically discriminate BC-derived exosomes from those produced by normal cells. The best sequences were optimized identifying short molecules (about 30-35 mer) that was characterized as tools for exosome detection. Further, we demonstrated that the developed aptamers inhibited exosome cellular uptake antagonizing cancer exosome-induced cell migration. By proteomic approach we identified possible targets that we are characterizing. Our results underline the great potential of isolated aptamers as tools for the development of innovative strategies for BC early diagnosis and therapy.

Nel corso degli ultimi decenni, il tema della diversità di genere ha assunto un ruolo rilevante nel dibattito accademico. Invero, il recente proliferarsi di riforme sia a livello nazionale che internazionale ha promosso e favorito il coinvolgimento delle donne nelle posizioni dirigenziali delle aziende pubbliche. In tale contesto le riforme sono state orientate ad accrescere la diversità di genere, a favorire l’inclusione delle donne, nonché a migliorare la loro qualità della vita e il livello di soddisfazione negli ambienti di lavoro. Nonostante tali interventi abbiano stimolato l’interesse degli accademici, la letteratura sul tema si dimostra ancora limitata e inadeguata, soprattutto per ciò che riguarda gli studi sulle aziende di tutela della salute. Poco spazio è stato dedicato all’esame delle implicazioni, dei problemi, delle opportunità, delle sfide manageriali poste dal coinvolgimento delle donne nelle posizioni dirigenziali delle aziende pubbliche e private di tutela della salute, anche rispetto all’adozione e impiego di soluzioni digitali. Pertanto, l'articolo si pone l’obiettivo di stimolare il dibattito sul tema della diversità di genere, della leadership e della performance nelle aziende di tutela della salute, incoraggiando gli accademici a sviluppare nuove linee di ricerca e ad ampliare le prospettive di interpretazione del fenomeno, anche mediante l'impiego di diverse metodologie.

In letteratura è ampiamente riconosciuta la rilevanza delle risorse intangibili del capitale mediante cui le università generano e diffondono conoscenza. La definizione del capitale intellettuale si è evoluta alla luce del nuovo ruolo economico e pubblico che l’università è chiamata a svolgere nei confronti dell’ambiente istituzionale di riferimento. Ciononostante, la creazione di valore del capitale intellettuale nelle tre missioni di didattica, ricerca e territorio risulta tutt’ora poco investigata. Impiegando il framework teorico della publicness e considerando la rilevanza del ruolo economico, pubblico e sociale il presente studio si propone di individuare un modello di public value accounting del capitale intellettuale delle università in grado di coniugare la creazione e la gestione del valore generato nelle tre missioni con gli strumenti di monitoraggio e misurazione delle performance. Il lavoro offre contribuiti al dibattito della letteratura sul capitale intellettuale e suggerisce alcune implicazioni pratiche.

La terza missione (TM) è una tematica emergente nelle università, in virtù della quale le stesse università promuovono nella società l’applicazione dei risultati della ricerca scientifica e della didattica, contribuendo allo sviluppo economico, sociale e culturale del Paese. Le attività di TM rappresentano, infatti, un motore di sviluppo per la società in quanto favoriscono l’incremento di competenze diffuse nei territori in cui le università insistono. Pertanto, la governance delle università ricopre un ruolo centrale nel formulare strategie atte a perseguire obiettivi e performance di TM. Studi recenti (Mazzotta et al., 2020; Galizzi & Siboni, 2016) hanno portato all’attenzione degli studiosi di discipline economico-aziendali l’esistenza di un legame tra strategia e diversità di genere negli organi di governance nelle università. La diversa composizione di genere negli organi di governance potrebbe, dunque, influire sulla capacità delle università di sviluppare le attività di TM. In quest’ottica, il presente lavoro si propone di indagare se e in che misura una composizione di genere femminile degli organi di middle management degli atenei, con particolare riferimento ai direttori di dipartimento, contribuisce al perseguimento degli obiettivi di TM. Il lavoro presenta un inquadramento teorico della TM nelle università, della sua evoluzione e misurazione; l’analisi empirica considera alcuni indicatori di TM, rile-vanti nel caso delle università in Italia, in relazione alla diversa distribuzione di genere dei direttori di dipartimento in 59 università pubbliche ita-liane. L’originalità del lavoro risiede, infatti, nella focalizzazione sulla diversità di genere nelle posizioni di middle-management, analizzata come driver fondamentale per far fronte alle sfide derivanti dal perseguimento della TM nelle università. Il capitolo è strutturato nel modo seguente: il paragrafo 1.2. è volto all’analisi a livello internazionale e in Italia della TM, il paragrafo 1.3. è volto all’analisi della misurazione della TM, il paragrafo 1.4. è volto a riflessioni sulla governance di genere nelle università, il paragrafo 1.5. riguarda l’analisi empirica dell’impatto del genere sulla TM nelle università pubbliche italiane, il paragrafo 1.6 evidenzia il contributo e le implicazioni che emergono dalla ricerca.

The reliable targeting of cell surface disease-associated proteins is a major challenge in chemical biology and molecular medicine. In this regard, aptamers represent a very attractive and innovative class of ligand molecules. Aptamers are generated by a reiterated in vitro procedure, named SELEX (Systematic Evolution of Ligands by Exponential enrichment). In order to generate aptamers for heavily modified cell surfacebound proteins and transmembrane receptors, the SELEX procedure has been recently adapted to the use of living cells as complex targets (referred as "cell-SELEX"). Here we give an overview on the most recent advances in the field of cell-SELEX technology, providing a detailed description of the differential cell-SELEX approach that has been developed in our laboratory to identify specific signatures for human malignant glioma and non-small-cell lung cancer. The procedures used for the evaluation of binding specificity and for the preliminary identification of potential target receptors will be also described.

Il saggio è frutto del lavoro da un gruppo di docenti costituito in seno alla SIDREA (Società Italiana Docenti di Ragioneria e di Economia Aziendale) con lo scopo di analizzare e valutare le eventuali nuove prospettive di studio della disciplina economico-aziendale.

Platelet-derived growth factor receptor ? (PDGFR?) is a cell-surface tyrosine kinase receptor implicated in several cellular processes including proliferation, migration, and angiogenesis. It represents a compelling therapeutic target in many human tumors, including glioma. A number of tyrosine kinase inhibitors under development as antitumor agents have been found to inhibit PDGFR?. However, they are not selective as they present multiple tyrosine kinase targets. Here, we report a novel PDGFR?-specific antagonist represented by a nuclease-resistant RNA-aptamer, named Gint4.T. This aptamer is able to specifically bind to the human PDGFR? ectodomain (Kd: 9.6 nmol/l) causing a strong inhibition of ligand-dependent receptor activation and of downstream signaling in cell lines and primary cultures of human glioblastoma cells. Moreover, Gint4.T aptamer drastically inhibits cell migration and proliferation, induces differentiation, and blocks tumor growth in vivo. In addition, Gint4.T aptamer prevents PDGFR? heterodimerization with and resultant transactivation of epidermal growth factor receptor. As a result, the combination of Gint4.T and an epidermal growth factor receptor-targeted aptamer is better at slowing tumor growth than either single aptamer alone. These findings reveal Gint4.T as a PDGFR?-drug candidate with translational potential.Molecular Therapy (2014); doi:10.1038/mt.2013.300.

While miRNAs clearly regulate multiple pathways integral to disease development and progression, the lack of safe and reliable means for specific delivery of miRNAs to target tissues represents a major obstacle to their broad therapeutic application. Our objective was to explore the use of nucleic acid aptamers as carriers for cell-targeted delivery of a miRNA with tumor suppressor function, let-7g. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase Axl (GL21.T), here we describe the development of aptamer-miRNA conjugates as multifunctional molecules that inhibit growth of Axl-expressing tumors. We conjugated the let-7g miRNA to GL21.T and demonstrate selective delivery to target cells, processing by the RNAi machinery, and silencing of let-7g target genes. Importantly, the multifunctional conjugate reduced tumor growth in a xenograft model of lung adenocarcinoma. Therefore, our data establish aptamer-miRNA conjugates as a novel tool for targeted delivery of miRNAs with therapeutic potential.Molecular Therapy (2014); doi:10.1038/mt.2014.5.

The authors sought to define the prevalence of Fabry disease and to establish the incidence and its natural history in Italy. The aim of this study was to point out the first clinical signs and symptoms to perform an early diagnosis and hence to start a specific therapeutic treatment. Fabry disease is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme alpha-galactosidase A. Fabry disease is a severe X-linked disorder presenting with a higher morbidity between the third and the fourth decade of life. Fabry disease may be confused with other diseases or completely misdiagnosed: its frequency is estimated worldwide to be 1:117000. In Italy, 65 patients have been identified by several specialized institutions; age, sex, onset of first clinical signs and symptoms were analyzed and reported. In conclusion, this is the first Italian collaborative study that allows to delineate and point out the clinical signs of Fabry disease to perform a correct and early diagnosis. Enzyme replacement therapy is now available and its early beginning can prevent renal and cardiac failure, improve the quality of life and life expectancy in these patients.

MicroRNAs (miRNAs, miRs) are naturally occurring small RNAs (approximately 22 nucleotides in length) that have critical functions in a variety of biological processes, including tumorigenesis. They are an important target for detection technology for future medical diagnostics. In this paper we report an electrochemical method for miRNA detection based on paramagnetic beads and enzyme amplification. In particular, miR 222 was chosen as model sequence, because of its involvement in brain, lung, and liver cancers. The proposed bioassay is based on biotinylated DNA capture probes immobilized on streptavidin-coated paramagnetic beads. Total RNA was extracted from the cell sample, enriched for small RNA, biotinylated, and then hybridized with the capture probe on the beads. The beads were then incubated with streptavidin-alkaline phosphatase and exposed to the appropriate enzymatic substrate. The product of the enzymatic reaction was electrochemically monitored. The assay was finally tested with a compact microfluidic device which enables multiplexed analysis of eight different samples with a detection limit of 7 pmol L(-1) and RSD = 15 %. RNA samples from non-small-cell lung cancer and glioblastoma cell lines were also analyzed.

Aptamers are short non-naturally occurring single stranded DNA or RNA able to bind tightly, due to their specific three-dimensional shapes, to a multitude of targets ranging from small chemical compounds to cells and tissues. Since their first discovery, aptamers became a valuable research tool and show great application to fundamental research, drug selection and clinical diagnosis and therapy. Thanks to their unique characteristics (low size, good affinity for the target, no immunogeneicity, chemical structures that can be easily modified to improve their in vivo applications), aptamers may represent a valid alternative to antibodies particularly for the treatment of neurological disorders that urgently need modalities for drug delivery through the blood brain barrier. Aptamers have excellent potential as reagents for the targeted delivery of active drug substances, either through direct conjugation to the aptamer, or through their encapsulation in aptamer-coated vesicles. We will review here the recent and innovative methods that have been developed and the possible applications of aptamers as inhibitors or tracers in neurological disorders and brain cancer.

The use of non-GAAP performance measures is a widespread, and certainly not a recent, phenomenon. In fact, companies increasingly believe that non-GAAP financial measures play a critical role in their financial communication strategy, and investors often rely on a wide range of non-GAAP measures to evaluate companies’ performance. However, anecdotal evidence also highlights a misleading use of non-GAAP financial measures, these metrics being disclosed more prominently than comparable GAAP metrics, and inconsistently presented from period to period. The apparent ‘schizophrenic’ nature of non-GAAP measures has often attracted scholars’ attention, while national and international security agencies and standard setters have recently renewed their interest in this topic. Therefore, this paper reviews the nearly two decades of research on non-GAAP reporting to offer insights into what academics have learned so far about non-GAAP reporting practices. In particular, this paper analyses the main objectives of the research, the related setting under investigation, the role of non-GAAP disclosure, and the type of non-GAAP metrics, with the aim of describing the evolution of this field of research over time and providing a structured reference point to carry research forward into specific sub-areas of interest.

Breast cancer is a leading cause of cancer mortality in women. Despite advances in its management, the identification of new options for early-stage diagnosis and therapy of this tumor still represents a crucial challenge. Increasing evidence indicates that extracellular vesicles called exosomes may have great potential as early diagnostic biomarkers and regulators of many cancers, including breast cancer. Therefore, exploiting molecules able to selectively recognize them is of great interest. Here, we developed a novel differential SELEX strategy, called Exo-SELEX, to isolate nucleic acid aptamers against intact exosomes derived from primary breast cancer cells. Among the obtained sequences, we optimized a high-affinity aptamer (ex-50.T) able to specifically recognize exosomes from breast cancer cells or patient serum samples. Furthermore, we demonstrated that the ex.50.T is a functional inhibitor of exosome cellular uptake and antagonizes cancer exosome-induced cell migration in vitro. This molecule provides an innovative tool for the specific exosome detection and the development of new therapeutic approaches for breast cancer., Graphical Abstract, Extracellular vesicles are important biomarkers and therapeutic targets for breast cancer (BC). However, specific tools for their recognition are lacking. Condorelli and colleagues describe the finding of a high-affinity aptamer (ex-50.T) able to specifically target BC exosomes acting as a promising diagnostic and therapeutic tool.

An important drawback in the management of glioblastoma (GBM) patients is the frequent relapse upon surgery and therapy. A likely explanation is that conventional therapies poorly affect a small population of stem-like cancer cells (glioblastoma stem cells, GSCs) that remain capable of repopulating the tumour mass. Indeed, the development of therapeutic strategies able to hit GSCs while reducing the tumour burden has become an important challenge to increase a patient&rsquo, s survival. The signal transducer and activator of transcription-3 (STAT3) has been reported to play a pivotal role in maintaining the tumour initiating capacity of the GSC population. Therefore, in order to impair the renewal and propagation of the PDGFR&beta, expressing GSC population, here we took advantage of the aptamer&ndash, siRNA chimera (AsiC), named Gint4.T-STAT3, that we previously have shown to efficiently antagonize STAT3 in subcutaneous PDGFR&beta, positive GBM xenografts. We demonstrate that the aptamer conjugate is able to effectively and specifically prevent patient-derived GSC function and expansion. Moreover, because of the therapeutic potential of using miR-10b inhibitors and of the broad expression of the Axl receptor in GBM, we used the GL21.T anti-Axl aptamer as the targeting moiety for anti-miR-10b, showing that, in combination with the STAT3 AsiC, the aptamer&ndash, miR-10b antagonist treatment further enhances the inhibition of GSC sphere formation. Our results highlight the potential to use a combined approach with targeted RNA therapeutics to inhibit GBM tumour dissemination and relapse.

Nucleic acid therapeutics, including siRNAs, miRNAs/antimiRs, gRNAs and ASO, represent innovative and highly promising molecules for the safe treatment of a wide range of pathologies. The efficiency of systemic treatments is impeded by 1) the need to overcome physical and functional barriers in the organism, and 2) to accumulate in the intracellular active site at therapeutic concentrations. Although oligonucleotides either as modified naked molecules or complexed with delivery carriers have revealed to be effectively delivered to the affected target cells, this is restricted to topic treatments or to a few highly vascularized tissues. Therefore, the development of effective strategies for therapeutic nucleic acid selective delivery to target tissues is of primary importance in order to reduce the occurrence of undesired effects on non-target healthy tissues and to permit their translation to clinic. Due to their high affinity for specific ligands, high tissue penetration and chemical flexibility, short single-stranded nucleic acid aptamers are emerging as very attractive carriers for various therapeutic oligonucleotides. Yet, different aptamer-based bioconjugates, able to provide accumulation into target tissues, as well as efficient processing of therapeutic oligonucleotides, have been developed. In this respect, nucleic acid aptamer-mediated delivery strategies represent a powerful approach able to increase the therapeutic efficacy also highly reducing the overall toxicity. In this review, we will summarize recent progress in the field and discuss achieved objectives and optimization of aptamers as delivery carriers of short oligonucleotides.

[object Object]Small therapeutic peptides represent a promising field for the treatment of pathologies such as cardiac diseases. However, the lack of proper target-selective carriers hampers their translation towards a potential clinical application. Aptamers are cell-specific carriers that bind with high affinity to their specific target. However, some limitations on their conjugation to small peptides and the functionality of the resulting aptamer-peptide chimera exist. Here, we generated a novel aptamer-peptide chimera through conjugation of the PDGFR?-targeting Gint4.T aptamer to MP, a small mimetic peptide that via targeting of the Cav?2 subunit of the L-type calcium channel (LTCC) can recover myocardial function in pathological heart conditions associated with defective LTCC function. The conjugation reaction was performed by click chemistry in the presence of N,N,N',N',N"-pentamethyldiethylenetriamine as a Cu (I) stabilizing agent in a DMSO-free aqueous buffer. When administered to cardiac cells, the Gint4.T-MP aptamer-peptide chimera was successfully internalized in cells, allowing the functional targeting of MP to LTCC. This approach represents the first example of the use of an internalizing aptamer for selective delivery of a small therapeutic peptide to cardiac cells.

Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults, and despite advances in neuro-oncology, the prognosis for patients remains dismal. The signal transducer and activator of transcription-3 (STAT3) has been reported as a key regulator of the highly aggressive mesenchymal GBM subtype, and its direct silencing (by RNAi oligonucleotides) has revealed a great potential as an anti-cancer therapy. However, clinical use of oligonucleotide-based therapies is dependent on safer ways for tissue-specific targeting and increased membrane penetration. The objective of this study is to explore the use of nucleic acid aptamers as carriers to specifically drive a STAT3 siRNA to GBM cells in a receptor-dependent manner. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase PDGFRβ (Gint4.T), here we describe the design of a novel aptamer-siRNA chimera (Gint4.T-STAT3) to target STAT3. We demonstrate the efficient delivery and silencing of STAT3 in PDGFRβ+GBM cells. Importantly, the conjugate reduces cell viability and migration in vitro and inhibits tumor growth and angiogenesis in vivo in a subcutaneous xenograft mouse model. Our data reveals Gint4.T-STAT3 conjugate as a novel molecule with great translational potential for GBM therapy. Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults, and despite advances in neuro-oncology, the prognosis for patients remains dismal. The signal transducer and activator of transcription-3 (STAT3) has been reported as a key regulator of the highly aggressive mesenchymal GBM subtype, and its direct silencing (by RNAi oligonucleotides) has revealed a great potential as an anti-cancer therapy. However, clinical use of oligonucleotide-based therapies is dependent on safer ways for tissue-specific targeting and increased membrane penetration. The objective of this study is to explore the use of nucleic acid aptamers as carriers to specifically drive a STAT3 siRNA to GBM cells in a receptor-dependent manner. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase PDGFRβ (Gint4.T), here we describe the design of a novel aptamer-siRNA chimera (Gint4.T-STAT3) to target STAT3. We demonstrate the efficient delivery and silencing of STAT3 in PDGFRβ+ GBM cells. Importantly, the conjugate reduces cell viability and migration in vitro and inhibits tumor growth and angiogenesis in vivo in a subcutaneous xenograft mouse model. Our data reveals Gint4.T-STAT3 conjugate as a novel molecule with great translational potential for GBM therapy.