In vitro cell models merging circadian rhythms and brain waves for personalized neuromedicine

New evidence is emerging about the dynamics of interaction between circadian rhythms and brain waves, whose coordination occurs through the entrainment process. The so-called “oscillopathies” or dysfunctions in synchronization of neuronal oscillation in key brain networks lead to the onset of neurodegenerative diseases. A typical example of alteration is insomnia, a risk factor for the oscillopathies, increasingly widespread worldwide. Recently, synchronization of circadian rhythms in cell cultures has allowed an improvement in the physiological relevance of responses to stimuli. Furthermore, brain organoids and neurons cultured in microfluidic systems are the latest frontiers for in vitro reproduction of rhythmic electrical signals. In this review, the combination of these in vitro experimental approaches is proposed as suitable for a more direct investigation on the common mechanisms and neurophysiological substrates underlying brain waves and circadian oscillations, and useful to evaluate the effects of “oscillotherapeutic” drugs for personalized neuromedicine

Effects of Microencapsulated Ferulic Acid or Its Prodrug Methyl Ferulate on Neuroinflammation Induced by Muramyl Dipeptide

Ferulic acid (Fer) is known for its antioxidant and anti-inflammatory activities, which are possibly useful against neurodegenerative diseases. Despite the ability of Fer to permeate the brain, its fast elimination from the body does not allow its therapeutic use to be optimized. The present study proposes the preparation and characterization of tristearin- or stearic acid-based solid lipid microparticles (SLMs) as sustained delivery and targeting systems for Fer. The microparticles were produced by conventional hot emulsion techniques. The synthesis of the methyl ester of Fer (Fer-Me) allowed its encapsulation in the SLMs to increase. Fer-Me was hydrolyzed to Fer in rat whole blood and liver homogenate, evidencing its prodrug behavior. Furthermore, Fer-Me displayed antioxidant and anti-inflammatory properties. The amount of encapsulated Fer-Me was 0.719 +/- 0.005% or 1.507 +/- 0.014% in tristearin or stearic acid SLMs, respectively. The tristearin SLMs were able to control the prodrug release, while the stearic acid SLMs induced a significant increase of its dissolution rate in water. Jointly, the present results suggest that the tristearin SLMs loaded with Fer-Me could be a potential formulation against peripheral neuropathic pain; conversely, the stearic acid SLMs could be useful for Fer-Me uptake in the brain after nasal administration of the formulation

Use of Telemedicine Healthcare Systems in Pediatric Assistance at Territorial Level: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP) and of the Syndicate of Family Pediatrician Doctors (SIMPeF)

Technological innovation can contribute to a reorganization of healthcare, particularly by supporting the shift in the focus of care from the hospital to the territory, through innovative citizen-centered models, and facilitating access to services in the territory. Health and social care delivery modalities, enabled by telemedicine, are crucial in this regard. The objective of this Consensus document, written by the main Italian Scientific Societies involved in the use of telemedicine in pediatrics, is to define a standard for its use at the territorial level in various declinations in the pediatric field; this paper also identifies priority areas for its application and the types of services that most require intervention and investment. The changes that are underway in digital transformation in all sectors are unstoppable, and for the digital transformation to take place in a productive sense, the contribution of not only all health professionals, but also of patients, is necessary. From this perspective, authors from different backgrounds were involved in the drafting of this Consensus and, in the future, other figures, primarily patients, are expected to be involved. In fact, this belongs to the vision of connected care, in which the citizen/patient actively participates in the treatment path so that they are assisted in a personalized, predictive and preventive way. The future scenario must be able to provide for the involvement of patients from the initial stages of planning any treatment path, even in the pediatric age, and increasing, where possible, the proximity of the health service to the families

Information and Training on the Use of Telemedicine in Pediatric Population: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP), and of the Syndicate of Family Pediatrician Doctors (SIMPeF)

Telemedicine has entered the daily lives of doctors, although the digital skills of healthcare professionals still remain a goal to be achieved. For the purpose of a large-scale development of telemedicine, it is necessary to create trust in the services it can offer and to favor their acceptance by healthcare professionals and patients. In this context, information for the patient regarding the use of telemedicine, the benefits that can be derived from it, and the training of healthcare professionals and patients for the use of new technologies are fundamental aspects. This consensus document is a commentary that has the aim of defining the information on and training aspects of telemedicine for pediatric patients and their caregivers, as well as pediatricians and other health professionals who deal with minors. For the present and the future of digital healthcare, there is a need for a growth in the skills of professionals and a lifelong learning approach throughout the professional life. Therefore, information and training actions are important to guarantee the necessary professionalism and knowledge of the tools, as well as a good understanding of the interactive context in which they are used. Furthermore, medical skills can also be integrated with the skills of various professionals (engineers, physicists, statisticians, and mathematicians) to birth a new category of health professionals responsible for building new semiotics, identifying criteria for predictive models to be integrated into clinical practice, standardizing clinical and research databases, and defining the boundaries of social networks and new communication technologies within health services

Use of Telemedicine Healthcare Systems in Pediatric Assistance at Territorial Level: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP) and of the Syndicate of Family Pediatrician Doctors (SIMPeF)

Technological innovation can contribute to a reorganization of healthcare, particularly by supporting the shift in the focus of care from the hospital to the territory, through innovative citizen-centered models, and facilitating access to services in the territory. Health and social care delivery modalities, enabled by telemedicine, are crucial in this regard. The objective of this Consensus document, written by the main Italian Scientific Societies involved in the use of telemedicine in pediatrics, is to define a standard for its use at the territorial level in various declinations in the pediatric field; this paper also identifies priority areas for its application and the types of services that most require intervention and investment. The changes that are underway in digital transformation in all sectors are unstoppable, and for the digital transformation to take place in a productive sense, the contribution of not only all health professionals, but also of patients, is necessary. From this perspective, authors from different backgrounds were involved in the drafting of this Consensus and, in the future, other figures, primarily patients, are expected to be involved. In fact, this belongs to the vision of connected care, in which the citizen/patient actively participates in the treatment path so that they are assisted in a personalized, predictive and preventive way. The future scenario must be able to provide for the involvement of patients from the initial stages of planning any treatment path, even in the pediatric age, and increasing, where possible, the proximity of the health service to the families

Use of Telemedicine Healthcare Systems in Children and Adolescents with Chronic Disease or in Transition Stages of Life: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP) and of the Syndicate of Family Pediatrician Doctors (SIMPeF)

: Telemedicine is considered an excellent tool to support the daily and traditional practice of the health profession, especially when referring to the care and management of chronic patients. In a panorama in which chronic pathologies with childhood onset are constantly increasing and the improvement of treatments has allowed survival for them into adulthood, telemedicine and remote assistance are today considered effective and convenient solutions both for the chronic patient, who thus receives personalized and timely assistance, and for the doctors, who reduce the need for direct intervention, hospitalizations and consequent management costs. This Consensus document, written by the main Italian Scientific Societies involved in the use of telemedicine in pediatrics, has the objectives to propose an organizational model based on the relationships between the actors who participate in the provision of a telemedicine service aimed at minors with chronic pathologies, identifying specific project links between the areas of telemedicine in the developmental age from the first 1000 days of life to the age adult. The future scenario will have to be able to integrate digital innovation in order to offer the best care to patients and citizens. It will have to be able to provide the involvement of patients from the very beginning of the design of any care pathway, increasing where possible the proximity of the health service to citizens

Cocrystals, prodrugs, microparticles, cyclodextrins and nasal administration of active pharmaceutical substances: innovative strategies to modulate their oral bioavailability or their action site targeting

The experimental work presented in this Thesis involves new strategies focused during my Ph.D. activity to improve drug oral bioavailability, avoid side effects or promote the targeting of therapeutic agents to their action site. The co-crystallization strategy was applied to increase the dissolution rate and the permeability across the intestinal barrier of nitrofurantoin (NITRO), an antibiotic characterized by low aqueous solubility and low oral bioavailability. In particular, NITRO dissolution rate and permeability were compared with those of its cocrystals containing isoniazid (ISO), bipyridyl (BIP), or phenanthroline (PHE) as coformers, and their parent mixtures. NITRO dissolution profiles were evaluated via High-Performance Liquid Chromatography (HPLC), whereas permeation studies were performed by using an in vitro model of the small intestine based on rat intestine epithelial cells (IEC-6). The research activity was then focused on D-limonene, eugenol and cinnamaldehyde, natural compounds derived from essential oils promising in the prevention and protection of neurodegenerative diseases. In particular, I contributed to perform a systematic in vivo study to elucidate their pharmacokinetic profile, oral bioavailability, and aptitude to permeate the central nervous system from the bloodstream. Based on obtained data, eugenol was recruited for in vitro studies of viability and time/dose-dependent dopamine release in neuronal differentiated PC12 cells, a recognized cellular model mimicking dopaminergic neurons. The prodrug approach was considered to study self-assemble nanomicelles consisting in amphiphilic inulin-D-α-tocopherol succinate bioconjugates (INVITE) and loaded with an antioxidant compound, curcumin (INVITE C), to enhance curcumin biopharmaceutical properties and induce its targeting to the retina from the bloodstream. Transport experiments on polarized monolayers of human retinal pigment epithelium (HRPE) cells were performed, evaluating the transepithelial electrical resistance of the HRPE monolayer in physiologic and diabetic conditions. The prodrug approach for nasal formulations and brain targeting was then focused on ferulic acid (Fer), known for its antioxidant and anti-inflammatory activities, potentially useful against neurodegenerative diseases. A prodrug of Fer (methyl ferulate, Fer-Me) was synthesised and loaded in tristearin or stearic acid solid lipid microparticles (SLMs) as sustained delivery and targeting systems for Fer. In vitro pharmacokinetic studies were performed via HPLC to evaluate the prodrug behaviour of Fer-Me. The ability of SLMs to control the prodrug release and the dissolution rate were observed via dissolution and release from SLMs studies and quantification via HPLC. The prodrug approach on Fer was further developed and a conjugate of Fer itself methylated on the carboxylic moiety, without the use of linkers, was synthesised (Fer-Fer-Me). Fer-Fer-Me and its potential hydrolysis products, namely the non-methylated homologous (Fer-Fer-OH), Fer-Me and Fer, after appropriate purification of blood samples, were quantified via HPLC. The prodrug behaviour of Fer-Fer-Me was evidenced by in vitro pharmacokinetic studies, then it was loaded in tristearin and stearic acid SLMs. The results obtained by their characterization allowed to select the stearic acid SLMs loaded with Fer-Fer-Me for a nasal administration in rats, quantifying the prodrug in the cerebrospinal fluid of rats (CSF). A further approach related to nasal administration and brain targeting was studied considering the use of cyclodextrins focusing on geraniol (GER), a natural compound derived from essential oils that may exert anti-inflammatory effects in neurodegenerative diseases. Inclusion complexes with β-cyclodextrin (βCD) and its hydrophilic derivative hydroxypropyl-β-cyclodextrin (HPβCD) were formulated and the biocompatibility with nasal mucosae and drug bioavailability into CSF were studied in rats.Nuove strategie per migliorare la biodisponibilità orale dei farmaci, limitare effetti collaterali o promuovere il direzionamento di agenti terapeutici al loro sito di azione sono state presentate in questa Tesi. I cocristalli sono stati sfruttati per aumentare la velocità di dissoluzione e la permeabilità attraverso la barriera intestinale della nitrofurantoina (NITRO), antibiotico caratterizzato da bassa solubilità acquosa e biodisponibilità orale. NITRO è stata confrontata, in termini di velocità di dissoluzione e permeazione, con i cocristalli contenenti isoniazide, bipiridile o fenantrolina come coformeri e con le miscele fisiche. I profili di dissoluzione della NITRO sono stati valutati via cromatografia liquida ad alta prestazione (HPLC), gli studi di permeazione sono stati eseguiti su un modello in vitro basato su cellule epiteliali di intestino di ratto. Ho contribuito ad effettuare uno studio in vivo per valutare il profilo farmacocinetico, biodisponibilità orale e tendenza a permeare nel sistema nervoso centrale dal sangue di D-limonene, eugenolo e cinnamaldeide, composti naturali derivati da oli essenziali promettenti nella prevenzione e protezione di patologie neurodegenerative. In base ai risultati, l’eugenolo è stato selezionato per studi in vitro su vitalità e rilascio tempo/dose-dipendente della dopamina in cellule PC12 differenziate a fenotipo neuronale, un modello di neuroni dopaminergici. Sono state studiate nanomicelle self-assemblanti costituite da bioconiugati anfifilici di inulina-D-α-tocoferolo succinato caricate con un composto antiossidante (INVITE C), la curcumina, per migliorarne le proprietà biofarmaceutiche e indurne il direzionamento alla retina. Sono stati effettuati esperimenti di trasporto su monostrati polarizzati di cellule di epitelio pigmentato umano, valutandone la resistenza elettrica transepiteliale e il beneficio di INVITE C in condizioni diabetiche simulate. Sono stati progettati e sintetizzati profarmaci dell’acido ferulico (Fer), noto per le attività antiossidanti e antinfiammatorie, potenzialmente utili contro patologie neurodegenerative. È stato sintetizzato un profarmaco di Fer (metil ferulato, Fer-Me). Fer-Me è stato caricato in microparticelle solide lipidiche (SLM) di tristearina o acido stearico come sistema di trasporto e di direzionamento per Fer. Studi farmacocinetici in vitro sono stati condotti via HPLC per valutare se Fer-Me fosse un profarmaco. La capacità delle SLM di controllare il rilascio del profarmaco e la velocità di dissoluzione sono stati osservati attraverso studi di dissoluzione e rilascio dalle SLM, quantificando via HPLC. Inoltre, è stato sintetizzato un coniugato di Fer con se stesso senza l’uso di linkers, metilato sul carbossile (Fer-Fer-Me). Fer-Fer-Me e i suoi potenziali prodotti di idrolisi, ovvero l’omologo non metilato (Fer-Fer-OH), Fer-Me e Fer, sono stati quantificati via HPLC in seguito ad appropriate procedure di estrazione da fluidi fisiologici. Studi farmacocinetici in vitro hanno dimostrato che Fer-Fer-Me è un profarmaco di Fer, ed è stato caricato in SLM di tristearina e acido stearico. I risultati ottenuti dalla caratterizzazione hanno permesso di selezionare le SLM di acido stearico per una somministrazione nasale a ratti, quantificando il profarmaco nel liquido cerebrospinale (CSF) per dimostrare la capacità della formulazione di indurre il direzionamento nel sistema nervoso centrale. È stato studiato un ulteriore approccio relativo alla somministrazione nasale e al direzionamento centrale utilizzando ciclodestrine e geraniolo (GER), un composto naturale derivato dagli oli essenziali che potrebbe esercitare effetti antinfiammatori in patologie neurodegenerative. Sono stati formulati complessi di inclusione con β-ciclodestrina (β-CD) e il suo derivato idrofilico idrossipropil-β-ciclodestrina (HP-β-CD), studiando la biocompatibilità con la mucosa nasale e la biodisponibilità di GER nel CSF nei ratti

New strategies to overcome poor oral bioavailability of drugs by increasing their water solubility

The oral administration of drugs can induce poor therapeutic effects if they are unable to reach the bloodstream from the intestinal lumen. The poor oral bioavailability of drugs can be associated to their poor dissolution rate in physiologic fluids. Indeed, great amount of drugs are lipophilic, showing high ability to permeate across the intestinal barrier, but their very poor dissolution in water sensibly reduces their oral bioavailability. Deferoxamine is an iron-chelant drug, used in severe forms of Thalassemia, characterized by very poor water solubility and short in vivo half-life. As a consequence, the administration of this drug requires the intravenous way with high frequency, inducing the low compliance of patients. Taking into account that the clusterization can help the dissolution of drugs and protect them from the metabolism, and that can be apply to this drug too1, I have contributed to design a strategy in order to synthetize one omodimer and two omotetramers of deferoxamine (Figure 1). According to this strategy, the drug can be conjugated, through linkers, to cores such as the PWTs (Peptide Welding Technology), currently known to increase the dissolution of some peptides and to reduce their metabolism in the bloodstream, extending their half-time and allowing less administrations2. Preliminary results indicate that the omodimer an omotetramers of deferoxamine obtained with this strategy allow to sensibly increase its dissolution in aqueous medium and to reduce its metabolism in the bloodstream, allowing to extend its half-life and to maintain its chelating properties. Another way to avoid the poor water dissolution of lipophilic drugs is the formulation of pharmaceutical co-crystals, known to potentially induce an increase of their dissolution rate in water with consequent enhancement of oral bioavailability. Very recently it has been demonstrated that co-crystals can also modulate the permeation of drugs across the intestinal barriers3. These aspects will be accurately studied in vitro by using intestinal cells monolayers, in order to verify if co-crystals can be considered as a simple mixture of compounds or a new pharmaceutical and pharmacological entities. REFERENCES [1] Z. Liu, T.-M. Lin, M. Purro, and M. P. Xiong. “Enzymatically Biodegradable Polyrotaxane-Deferoxamine Conjugates for Iron Chelation”, ACS Appl. Mater. Interfaces, 2016, 8, 25788-25797. [2] R. Guerrini, E. Marzola, C. Trapella, M. Pelà, S. Molinari, M.C. Cerlesi, D. Malfacini, A. Rizzi, S. Salvadori, G. Calò. “A novel and facile synthesis of tetra branched derivatives of no-ciceptin/orphanin FQ”, Bioorg. Med. Chem. 2014, 22(14), 3703-3712. [3] A. Dalpiaz, V. Ferretti, G. Botti, B. Pavan, “Drug Release from Pharmaceutical Co-Crystals: Are Therapeutic and Safety Properties of Active Pharmaceutical Substances Retained?”, Curr Drug Deliv. 2019;16(6):486-489

Pharmacokinetic and Permeation Studies in Rat Brain of Natural Compounds Led to Investigate Eugenol as Direct Activator of Dopamine Release in PC12 Cells

Eugenol, cinnamaldehyde and D-limonene, the main components of natural essential oils, are endowed with antioxidant and anti-inflammatory properties which allow them to induce beneficial effects on intestinal, cardiac and neuronal levels. In order to characterize their pharmacokinetic profiles and aptitude to permeate in the central nervous system after intravenous and oral administration to rats, new analytical procedures, easily achievable with HPLC-UV techniques, were developed. The terminal half-lives of these compounds range from 12.4 ± 0.9 (D-limonene) and 23.1 ± 1.6 min (cinnamaldehyde); their oral bioavailability appears relatively poor, ranging from 4.25 ± 0.11% (eugenol) to 7.33 ± 0.37% (cinnamaldehyde). Eugenol evidences a marked aptitude to permeate in the cerebrospinal fluid (CSF) of rats following both intravenous and oral administrations, whereas cinnamaldehyde appears able to reach the CSF only after intravenous administration; limonene is totally unable to permeate in the CSF. Eugenol was therefore recruited for in vitro studies of viability and time-/dose-dependent dopamine release in neuronal differentiated PC12 cells (a recognized cellular model mimicking dopaminergic neurons), evidencing its ability to increase cell viability and to induce dopamine release according to a U-shaped time-course curve. Moreover, concentration-response data suggest that eugenol may induce beneficial effects against Parkinson’s disease after oral administration

PRODRUGS, MICRO OR NANOPARTICULATE SYSTEMS AND NASAL ADMNISTRATION AS NON INVASIVE APPROACHES AGAINST BRAIN DISEASES AND AIRBORNE INFECTIONS. LOCO-REGIONAL THERAPY OF CANCER

The prodrug of potential neuroactive agents can offer several advantages in order to obtain their brain targeting. Prodrugs obtained as conjugate with essential nutrients can allow the brain targeting of neuroactive agents, unable to permeate in the brain from the bloodstream, via influx transporters expressed in the blood brain barrier (BBB). For example, nipecotic acid can induce antiepileptic effects as a prodrug obtained by ester conjugation with vitamin C, being uptaken in the brain by the SVCT2 transporter. Similarly, dopamine can induce antiparkinsonian effects as a prodrug obtained by conjugation with glucose, being uptaken in the brain via the GLUT1 transporter [1]. Alternatively, the prodrug approach can allow to elude the active efflux transporters (AETs) whose expression on the BBB is essential for brain protection from potential damaging molecules. Zidovudine (AZT), a reverse transcriptase inhibitor, is a substrate of AETs, and it is consequently unable to permeate in the brain or in macrophages. AZT conjugation with ursodeoxycholic acid (UDCA), a bile acid permeating into the brain, allows to obtain a prodrug (UDCA-AZT) able to elude the AETs without inhibiting them. This ability allows the UDCA-AZT prodrug to permeate and remain in murine macrophages (that may constitute HIV reservoirs in the brain) with an efficiency twenty times higher than that of AZT. Moreover, the prodrug UDCA-AZT can self-assemble as nanoparticle cores coated with a bile acid salt (taurocholate or ursodeoxycholate) corona without any other excipients. The taurocholate-coated nanoparticles appear able to interact with serum proteins, differently from the ursodeoxycholate-coated particles. Accordingly, the taurocholate-coated nanoparticles show in vitro uptake by murine macrophages about 70 times higher than that obtained with the free prodrug, whereas no significant uptake increase can be registered for ursodeoxycholate-coated particles. Taurocholate-coated nanoparticles may be useful against intracellular infections of the MPS system, whereas ursodeoxycholate-coated particles could have “stealth” properties in the bloodstream. The nasal administration can offer a direct nose-to-brain delivery of the molecules allowing bypass the BBB. Indeed, drug molecules able to pass the mucus layer can permeate across the olfactory mucosa and directly reach the cerebrospinal fluid (CSF) or the brain parenchyma. In general, the brain uptake of nasally administered drugs is allowed by appropriate formulations able to provide several advantages, such as high local concentration of the free drug for diffusion processes. Micro or nanoparticulate systems have been designed in this aim and several neuroprotective agents have been studied concerning their brain delivery nasally, including anti-ischemic, anti-inflammatory, anti-Parkinson, antiepileptic and antimigraine drugs. The small size and large surface area of micro and nanoparticles can limit the loading of drugs, in particular when the particulate systems are hydrophobic and the encapsulated drugs are poorly hydrophobic. When properly designed, hydrophobic prodrugs can solve these difficulties, allowing appropriate encapsulation efficiencies. As an example, the prodrug UDCA-AZT allowed zidovudine encapsulation in solid lipid microparticles (SLMs), whose nasal administration induced selective SNC targeting. Very recently, the volatile geraniol was efficiently encapsulated in solid lipid nanoparticles (SLNs) only as a prodrug obtained by its ester conjugation with ursodeoxycholic acid (GER-UDCA). In this case, the nasal administration of the nanoparticles induced selective SNC targeting of the prodrug obtained by the ester conjugation of two antiparkinsonian agents. Anti-inflammatory drugs in the asymptomatic initial phase of Alzheimer’s disease (AD) could slow down AD progression, provided they enter the brain. Nasal administration may enable the drug direct access to brain. Flurbiprofen powders for nose-to-brain drug transport in early AD-related neuroinflammation were produced by spray drying. Flurbiprofen sodium nasal powders disclosed prompt dissolution and fast ex vivo transport across rabbit nasal mucosa. Microparticles as such or soft pellets obtained by their agglomeration resulted into rapid flurbiprofen absorption in rats. Compared to intravenous flurbiprofen, the microparticles were more efficient than soft pellets at enhancing direct drug transport to CNS. Direct Transport Percentage index evidenced that more than 60% of the intranasal dose reached the brain via direct nose-to-brain transport for both powders. Airborne infections by viruses like SARS-CoV-2 and other pathogens can be tackled by antinfective drug targeted delivery to infected cells. Timely drug treatment at symptom onset would stop virus spreading to lung and other organs, sparing severe disease. We are studying the formulation of repurposed drugs into microparticles for deposition into the upper airways by nasal powder administration. 29 million cases of cancers are estimated by 2040. Site-specific delivery of drugs right to target with less systemic side effects, is an ongoing challenge of chemotherapy. In this context, a cisplatin (cisPt)-loaded sodium hyaluronate polymeric film was proposed for loco-regional anticancer therapy. In a malignant pleural mesothelioma rat model, the film was applied directly on the pleural surface and effectively reduced recurrences. Moreover, despite the high cisplatin (cisPt) plasma concentrations over time, organ toxicity was lower in comparison with the standard treatments (i.e., intrapleural or intravenous cisPt solution). This was attributed to the formation of complex between cisplatin and hyaluronan. Currently, our studies pursue the goal of delivering cisPt/NaHA complex locally, in dosage forms other than film and in different cancers, especially in tumors where CD44 receptor is over expressed