Prodrugs, micro- and nano-particulate systems: are they suitable tools for drug targeting into the central nervous system?

Hydrophilic drugs, or neuroactive agents characterized by high molecular weight, do not have the physico-chemical properties required for passive diffusion across the blood brain barrier (BBB). The prodrug approach by lipidization of hydrophilic drugs can allow to sensibly increase their permeability across BBB but, unfortunately, this phenomenon is often not associated to an effective entry into the brain of the lipidized drugs. Carrier mediated transporters (CMT), able to transfer essential nutrients and hormones from the bloodstream to the central nervous system (CNS), can be employed for the brain targeting of appropriated designed prodrugs. This approach consists on the chemical modification of a drug into a “pseudonutrient” or, differently, on drug conjugation to essential nutrients transported by CMT systems. In particular, prodrugs able to act as substrates of neutral amino acids (LAT1), glucose (GLUT1) or vitamin C (SVCT2) transporters appear promising for the uptake of neuroactive drugs in the brain from the bloodstream. On the other hand, it has been understood that active efflux transporters (AET) can have a very important role in extruding from the brain not only prodrugs obtained by lipidization processes, but also lipophilic drugs. AET expression maintains in general the homeostasis in healthy tissues and in the blood–brain barrier it often prevents drugs from reaching the brain. Inhibition of AETs could therefore be a valuable solution for the brain targeting of neuroactive drugs, but nonselective longterm AET blocking can be harmful toward healthy tissues and, in particular, the brain itself. As a consequence, only the circumvention of efflux pumps appears to be a valuable strategy for targeting neuroactive drugs in the CNS. The knowledge of the molecular aspects that regulate the activity of the CMT and AET systems for the transport of their substrates, appear of great importance in order to evaluate the molecular keys for the design of prodrugs efficacious in the brain targeting. These studies can be performed in vitro, by employing monocellular layers able to selectively express on their membranes CMT or AET systems. The design of new prodrugs able to elude the efflux pumps can offer therefore new opportunities for brain targeting. Polymeric nanoparticles with appropriate surface properties can target the CNS, allowing the encapsulated drugs to exert their therapeutic effects against brain diseases. Each single nanoparticle can incorporate the neuroactive drugs and the targeting agents able to promote their BBB permeation via receptor mediated transport (RMT) systems. It is also known that poly(butyl cyanoacrylate) (PBCA) or poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with certain surfactants, such as polysorbate 80 (Tween 80) or poloxamer 188 (Pluronic F68), are able to induce the brain targeting of their loaded neuroactive drugs. Polymeric microparticles can be employed as promising formulations for nasal administrations that allow their incapsulated drugs to target the CNS by eluding the BBB. In this case, the polymer itself that constitutes the particles can have properties able to enhance the drug permeation across the olfactory mucosa. A new promising strategy for brain targeting of neuroactive drugs is represented by the encapsulation in nano- or micro-particulate systems of prodrugs able to elude the efflux pumps (AET), thus increasing the concentration of neuroactive agents in the CNS after non-invasive administration of the particles. As an example, zidovudine (AZT) is an antiviral drug employed against HIV, but unable to reach the brain being substrate of AET systems. HIV is instead able to easily invade the CNS that becomes a sanctuary of the virus from which the periphery can be continuously re-infected. The conjugation of AZT with a bile acid (ursodeoxycholic acid, UDCA), allows to obtain a prodrug (UDCA-AZT) able to elude the AET systems expressed by BBB. Solid lipid microparticles loaded with UDCA-AZT constitute a nasal formulation able to induce the uptake of the prodrug in the cerebro spinal fluid (CSF). Upon uptake, the prodrug appears able to prolong its permanence in the CSF, in accordance with its ability to elude the AET systems.