Passive drug targeting and delivery of antitumor Pt(IV) prodrugs

Cisplatin and its analogues are important drugs for the treatment of many malignant tumors, but many side effects and deactivation processes may occur. In order to overcome these limits, the Pt(IV) complexes higher inertness can be exploited. They are activated to their corresponding Pt(II) active metabolite only in the tumor site, taking advantage of the hypoxic and reducing milieu of neoplastic cells: for this reason, they are considered prodrugs. Furthermore, passive Drug Targeting and Delivery (DTD) strategies can be developed to improve the selective accumulation of such species. The tumor tissue increased vascular permeability, due to an irregular architecture of the blood vessels, and the reduced drainage of the lymphatic system allow macromolecules of suitable dimensions (e.g. nanoparticles (NPs), liposomes, etc.) to extravasate and to be retained for longer time. Therefore, nanosized carriers decorated with anticancer molecules should be accumulated into the tumor cells increasing the drug selectivity. This Ph.D. work is focused on the exploration of several passive DTD methods. The first phase consists in the synthesis of Pt(IV) complexes, containing suitable functionalities to be exploited in coupling reactions with nanosized vectors. Alternatively, Pt complexes can be encapsulated into liposomes. Then, the loading of selected nanocarriers with the metal complexes and the biological evaluation of the resulting conjugates are performed. The developed projects are listed below: - synthesis, characterization of Pt(IV) complexes, their couplings with different types of amino-functionalized nonporous silica NPs and in vitro tests of the resulting conjugates; - coupling reactions of the previously prepared Pt(IV) compounds with chitosan and its derivatives; - synthesis, characterization of Pt(IV) prodrugs able to link magnetic iron oxide NPs and their couplings with such vectors; - encapsulation of antitumor drugs into liposomes and their in vitro studies

Physiotherapy care of children from Bengali families: a survey in the venetian area

openBackground: nel comune di Venezia la popolazione straniera è in continuo aumento e la cittadinanza più numerosa è quella bengalese. Anche presso i servizi di Neuropsichiatria Infantile del territorio il numero di bambini con disabilità provieniti da famiglie bengalesi è in considerevole aumento negli ultimi anni. Quando tra il fisioterapista e la famiglia del bambino si interpone una barriera linguistico-culturale che rende difficile la comunicazione e la comprensione reciproca, instaurare una relazione terapeutica efficace appare più complesso. Anche il gioco, mezzo attraverso cui si declina l’intervento fisioterapico, è soggetto ad interpretazioni strettamente legate alla cultura d’origine della persona, che possono influenzare il trattamento. Obiettivi: fare uno stato dell’arte sulla presa in carico fisioterapica del bambino figlio di genitori bengalesi nel contesto del territorio veneziano, con particolare attenzione al ruolo del gioco come strumento riabilitativo a supporto della relazione terapeutica. Materiali e metodi: sono state create e proposte alcune interviste semi-strutturate a tre fisioterapiste esperte nell’ambito dell’età evolutiva, che operano nel territorio di Venezia-Mestre. I risultati delle interviste sono stati condivisi e discussi con una mediatrice culturale del Bangladesh che lavora nell’area del veneziano e che conosce molto bene le realtà delle madri con bambini portatori di disabilità e con un antropologo che ha lavorato con la comunità bengalese di Mestre c/o il Comune di Venezia. Per analizzare e presentare i risultati della ricerca qualitativa è stato utilizzato il metodo delle thematic networks (Attride&Stirling, 2001). Risultati: l’analisi delle interviste ha permesso di individuare cinque temi organizzanti: la storia d’immigrazione, la famiglia bengalese, la relazione terapeutica, il gioco, i mezzi e gli aiuti per i futuri fisioterapisti. I temi di base di ognuna di queste cinque aree tematiche hanno fatto emergere gli aspetti salienti e trasversali della presa in carico del bambino con disabilità e del valore del gioco nella cultura bengalese. Discussione: la condivisione dei risultati delle interviste con la mediatrice culturale ha permesso di individuare alcune questioni di rilievo nell’approccio al bambino bengalese, relative alla famiglia, alla relazione madre-bambino, alla concezione di cura e di gioco, alla concezione di disabilità in Bangladesh e alla relazione terapeutica. Conclusioni: questo modesto progetto, teso alla ricerca di una sorta di punto di incontro tra il mondo della riabilitazione occidentale e quello della cultura del Bangladesh, ha portato l’attenzione su come la conoscenza e la formazione continua appaiano delle basi fondanti per divenire dei professionisti sempre più consapevoli dei pregiudizi, riconoscere e dare uguale importanza ai propri e altrui valori e, in tal senso, favorire il processo di costruzione della relazione terapeutica con bambini e famiglie che arrivano da culture e mondi diversi.Background: in the municipality of Venice, the foreign population is constantly increasing and the most numerous citizenship is Bangladeshi. Even at the local child neuropsychiatry services, the number of children with disabilities from Bangladesh families has increased considerably in recent years. When there is a language-cultural barrier between the physiotherapist and the child's family that makes communication and mutual understanding difficult, establishing an effective therapeutic relationship appears more complex. Even play, the medium through which physiotherapy intervention is carried out, is subject to interpretations closely linked to the person's culture of origin, which can influence treatment. Aims: make a state of the art on the physiotherapeutic care of the child of Bangladesh parents in the context of the Venetian territory, with particular attention to the role of play as a rehabilitative tool to support the therapeutic relationship. Materials and methods: A number of semi-structured interviews were created and proposed to three physiotherapists, experts in the field of children physiotherapic care, who work in the Venice-Mestre area. The results of the interviews were shared and discussed with a Bangladeshi cultural mediator who works in the Venice-Mestre area and who is very familiar with the realities of mothers with children with disabilities and with an anthropologist who has worked with the Bangladesh community in Mestre c/o the municipality of Venice. The method of thematic networks (Attride&Stirling, 2001) was used to analyze and present the results of the qualitative research. Results: the analysis of the interviews made it possible to identify five organizing themes: immigration history, the Bangladeshi family, the therapeutic relationship, play, means and aids for future physiotherapists. The underlying themes of each of these five areas brought out the salient and cross-cutting aspects of caring for the child with disabilities and the value of play in Bangladesh culture. Discussion: sharing the results of the interviews with the cultural mediator made it possible to identify some important issues in the approach to the Bangladesh child, relating to the family, the mother-child relationship, the conception of care and play, the conception of disability in Bangladesh and the therapeutic relationship. Conclusions: this modest project, aimed at finding a sort of meeting point between the world of Western rehabilitation and that of Bangladeshi culture, has brought attention to how knowledge and continuous formation appear to be fundamental foundations for becoming increasingly aware of prejudices, recognizing and giving equal importance to one's own and others' values and, in this sense, favouring the process of building a therapeutic relationship with children and families who come from different cultures and worlds

Polyanionic Biopolymers for the Delivery of Pt(II) Cationic Antiproliferative Complexes

Phenanthriplatin, that is, (SP-4-3)-diamminechlorido(phenanthridine)platinum(II) nitrate, an effective antitumor cationic Pt(II) complex, was loaded on negatively charged dextran sulfate (DS) as a model vector for drug delivery via electrostatic interactions. The free complex and the corresponding conjugate with DS were tested on two standard human tumor cell lines, namely, ovarian A2780 and colon HCT 116, and on several malignant pleural mesothelioma cell lines (namely, epithelioid BR95, mixed/biphasic MG06, sarcomatoid MM98, and sarcomatoid cisplatin-resistant MM98R). The in vitro results suggest that the conjugate releases the active metabolite phenanthriplatin with a biphasic fashion. In these experimental conditions, the conjugate is slightly less active than free phenanthriplatin; but both exhibited antiproliferative potency higher than the reference metallodrug cisplatin and were able to overcome the acquired cisplatin chemoresistance in MM98R cells

How to obtain Pt(IV) complexes suitable for the conjugation to nanovectors from the oxidation of [PtCl(terpyridine)]+

Oxidation of [Pt(II)Cl(terpy)]+ (terpy = 2,2’:6’,2”-terpyridine) has been attempted with several oxidizing agents and in different experimental conditions in order to obtain a Pt(IV) complex suitable for the conjugation to nanovectors to be used in drug delivery targeting for anticancer therapy. The best compromise in terms of yield and purity of the final complex was obtained by microwave-assisted reaction at 70 °C in 50% aqueous H2O2 for 2 h. Under these conditions the quantitative formation of [Pt(IV)Cl(OH)2(terpy)]+ was observed. Subsequent synthetic steps were i) functionalization of [Pt(IV)Cl(OH)2(terpy)]+ in the axial position with succinic anhydride to obtain [Pt(IV)Cl(OH)(succinato)(terpy)]+, and ii) reaction of the latter with nonporous silica nanoparticles (SNPs) with an external shell containing primary amino groups to obtain a nanovector able to transport the Pt(IV) antitumor prodrug in form of conjugate Pt-SNP. Finally, the antiproliferative activity and cell accumulation of [Pt(II)Cl(terpy)]+, [Pt(IV)Cl(OH)2(terpy)]+, and Pt-SNP conjugate were measured on three cancer cell lines. Despite highly effective accumulation of Pt-SNP into cells, a modest increase in activity was observed with respect to the molecular species. Further experiments showed that the Pt-SNP conjugate can release [Pt(II)Cl(terpy)]+ upon reduction, but this metabolite may undergo hydrolysis, and the resulting aquo complex could coordinate once again the free amino groups of the SNPs. In the resulting tetraamine form, the Pt(II) complex conjugated to the SNPs cannot completely exert its antiproliferative activity

Pt(IV)/Re(I) Chitosan Conjugates as a Flexible Platform for the Transport of Therapeutic and/or Diagnostic Anticancer Agents

New chitosan derivatives modified with (3-carboxypropyl) trimethylammonium chloride (1) and coupled with (OC-6-44)-diammine(4-carboxypropanoato) dichloridoethanolatoplatinum(IV) (2), were synthesized and their preliminary biological evaluation carried out in human tumor cells. Some of these derivatives were also loaded with a chelating ligand (3) that was derived from bis(quinolin-2-ylmethyl) amine to obtain chitosan-based nanoparticles for an EPR-mediated delivery of Pt(IV) prodrugs and Re(I) tricarbonyl complexes (4), to explore a multimodal theranostic approach to cancer. The cytotoxicity of the different chitosan conjugates (C12, C123, and C1234), carrying different combinations of the Pt(IV) complex, the chelator and the Re(I) complex, was evaluated in the A2780 human ovarian cancer cell line using the MTT assay. The Pt(IV)-containing nanosystems showed low to moderate cytotoxic activity (IC50 values in the range 13.5-33.7 uM) and was comparable to that found for the free Pt(IV) complex (IC50 = 13.7 uM). Therefore, the Pt(IV)-chitosan conjugation did not enhance the cytotoxic activity of the Pt(IV) prodrug, which certainly reflects the inefficient cellular uptake of the nanoconjugates. Nevertheless, a clearer view of their potential for the delivery of anticancer agents requires further in vivo tests because the EPR effect increases extravasation and retention within the tumor tissue, not necessarily within the tumor cells

Thymus vulgaris Essential Oil in Beta-Cyclodextrin for Solid-State Pharmaceutical Applications

: Antimicrobial resistance related to the misuse of antibiotics is a well-known current topic. Their excessive use in several fields has led to enormous selective pressure on pathogenic and commensal bacteria, driving the evolution of antimicrobial resistance genes with severe impacts on human health. Among all the possible strategies, a viable one could be the development of medical features that employ essential oils (EOs), complex natural mixtures extracted from different plant organs, rich in organic compounds showing, among others, antiseptic properties. In this work, green extracted essential oil of Thymus vulgaris was included in cyclic oligosaccharides cyclodextrins (CD) and prepared in the form of tablets. This essential oil has been shown to have a strong transversal efficacy both as an antifungal and as an antibacterial agent. Its inclusion allows its effective use because an extension of the exposure time to the active compounds is obtained and, therefore, a more marked efficacy, especially against biofilm-producing microorganisms such as P. aeruginosa and S. aureus, was registered. The efficacy of the tablet against candidiasis opens their possible use as a chewable tablet against oral candidiasis and as a vaginal tablet against vaginal candidiasis. Moreover, the registered wide efficacy is even more positive since the proposed approach can be defined as effective, safe, and green. In fact, the natural mixture of the essential oil is produced by the steam current method; therefore, the manufacturer employs substances that are not harmful, with very low production and management costs

What causes hidradenitis suppurativa? - 15 years after

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30?April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as ?the only inflammatory skin disease than can be healed?. This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future

A different immunologic profile characterizes patients with HER-2-overexpressing and HER-2-negative locally advanced breast cancer: implications for immune-based therapies

INTRODUCTION: The clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses. On these grounds, a careful analysis of basal immune profile may be capital to dissect the heterogeneity of clinical responses to these drugs in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. METHODS: Blood samples were collected from 61 locally advanced breast cancers (36 HER2- and 25 HER2+) at diagnosis and from 23 healthy women. Immunophenotypic profiling of circulating and intratumor immune cells, including regulatory T (Treg) cells, was assessed by flow cytometry and immunohistochemistry, respectively. Serum levels of 10 different cytokines were assessed by multiplex immunoassays. CD8+ T cell responses to multiple tumor-associated antigens (TAA) were evaluated by IFN-γ-enzyme-linked immunosorbent spot (ELISPOT). The Student's t test for two tailed distributions and the Wilcoxon two-sample test were used for the statistical analysis of the data. RESULTS: The proportion of circulating immune effectors was similar in HER2+ patients and healthy donors, whereas higher percentages of natural killer and Treg cells and a lower CD4+/CD8+ T cell ratio (with a prevalence of naïve and central memory CD8+ T cells) were observed in HER2- cases. Higher numbers of circulating CD8+ T cells specific for several HLA-A*0201-restricted TAA-derived peptides were observed in HER2+ cases, together with a higher prevalence of intratumor CD8+ T cells. Serum cytokine profile of HER2+ patients was similar to that of controls, whereas HER2- cases showed significantly lower cytokine amounts compared to healthy women (IL-2, IL-8, IL-6) and HER2+ cases (IL-2, IL-1β, IL-8, IL-6, IL-10). CONCLUSIONS: Compared to HER2- cases, patients with HER2-overexpressing locally advanced breast cancer show a more limited tumor-related immune suppression. This may account for the clinical benefit achieved in this subset of patients with the use of drugs acting through, but also promoting, immune-mediated effects