Biomedical Engineering Reference
In-Depth Information
HIRMAb was rapidly transported into all parts of the primate brain after
intravenous administration, suggesting its potential for delivering both drug
and gene across the BBB in human [208].
Low-density lipoprotein receptor related proteins 1 and 2 (LRP1 and
LRP2) are multifunctional, multi-ligand scavenger and signaling receptors.
They can interact with a diverse range of molecules and mediators, including
ApoE, tissue plasminogen activator (tPA), plasminogen activator inhibitor
1 (PAI-1), lactoferrin, melanotransferrin, a2 macroglobulin (a2 M), recep-
tor associated protein (RAP), HIV-1 TAT protein, Heparin cofactor II,
heat shock protein 96 (HSP-96), and engineered angiopeps. Several drugs
that normally do not cross the BBB, including tubocurarine, loperamide,
dalargin, 8-chloro-4-hydroxy-1-oxol, quinoline-5-oxide choline salt (MRZ
2/576), and doxorubicin show higher concentrations in the brain when as-
sociated with polysorbate 80-coated nanoparticles.
Lactoferrin (Lf ) is a mammalian cationic iron-binding glycoprotein be-
longing to the transferrin family. Lf was reported to be transported into the
brain via LRP mediated transcytosis. Drug-loaded Lf-NPs were taken up
by the brain and produced therapeutic efficacy, as demonstrated by the sig-
nificant attenuation of the striatum lesion [209].
Another group of LRP ligands, known as angiopeps, has also been re-
ported as a highly effective BBB targeting ligand. Angiopeps belong to a
family of peptides derived from the Kunitz domains of aprotinin and other
human proteins. The most studied is angiopep 2, which has shown greater
transcytosis capacity and parenchymal accumulation. Moreover, their abil-
ity in efficiently facilitating nanocarrier transport across the BBB in vivo
has been confirmed with dendrimers, and more recently with amphoteri-
cin B-loaded polymeric micelles [180]. Chemical conjugation of angiopep
2 with 3 molecules of paclitaxel (ANG1005) was shown to be particularly
effective in enhancing drug uptake into the brain using an in situ rat brain
perfusion model.
Recently Tosi et al. [210] developed a poly(D,L-lactide-co-glycolide)
(PLGA) nanoparticles with two surface modified ligands namely a BBB-
penetrating peptide (similopioid peptide, g7) for transporting across the
BBB, and a sialic acid residue (SA) for the interaction with receptors in the
brain tissue to prolong the NP residence time. The researchers reported a
remarkably high dose in the CNS over a prolonged period of time (24 h).
These results were attributed to the ability of SA g7 nanoparticles to cross
the BBB and remain within the brain parenchyma.
6.1.2.2 Adsorptive-mediated transcytosis
During the past decade, several peptides have been described that allow the
intracellular delivery of polar biologically active compounds in vitro and in
vivo. These peptides possess multiple positive charges, and some of them
share common features, such as hydrophobicity and helical moment, the
