Challenges in the Design of Clinically Useful Brain-targeted Drug Nanocarriers
L. Costantino, D. Boraschi and M. Eaton
Affiliation: University of Modena e Reggio Emilia, Dipartimento di Scienze della Vita, Via Campi 183, 41100 Modena, Italy.
Keywords: Blood-brain barrier, carriers, CNS, drug delivery, glioma, liposomes, nanoparticles, targeting, tumours.
Nowadays, the delivery of drugs by means of intravenously administered nanosized drug carriers - polymerdrug
conjugates, liposomes and micelles, is technically possible. These delivery systems are mainly designed for tumour
therapy, and accumulate passively into tumours by means of the well known EPR effect. Targeted nanocarriers, that additionally
contain ligands for receptors expressed on cell surfaces, are also widely studied but products of this kind are not
marketed, and only a few are in clinical trial. Polymeric nanoparticles (Np) able to deliver drugs to the CNS were pioneered
in 1995; a number of papers have been published dealing with brain-targeted drug delivery using polymeric Np
able to cross the BBB, mainly for the treatment of brain tumours. At present, however, the translation potential of these
Np seems to have been exceeded by targeted liposomes, a platform based on a proven technology. This drug delivery system
entered clinical trials soon after its discovery, while the challenges in formulation, characterization and manufacturing
of brain-targeted polymeric Np and the cost/benefit ratio could be the factors that have prevented their development. A
key issue is that it is virtually impossible to define the in vivo fate of polymers, especially in the brain, which is a regulatory
requirement; perhaps this is why no progress has been made. The most advanced Np for brain tumours treatment will
be compared here with the published data available for those in clinical trial for tumours outside the CNS, to highlight the
knowledge gaps that still penalise these delivery systems. At present, new approaches for brain tumours are emerging,
such as lipid Np or the use of monoclonal antibody (mAb)-drug conjugates, which avoid polymers. The success or failure
in the approval of the polymeric Np currently in clinical trials will certainly affect the field. At present, the chances of
their approval appear to be very low.
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