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.