Biomedical Engineering Reference
In-Depth Information
ability to interact with a lipid membrane and the ability to adopt a significant
secondary structure upon binding to lipids. Since these peptides penetrate
into cells by a receptor-independent non-endocytotic process, attempts have
been made to demonstrate that the interaction with the lipid matrix of the
plasma membrane could play a key role in peptides cell uptake. They have
been successfully used as vectors for the delivery of drugs that are P-gp sub-
strates, by effectively by-passing the P-gp in the BBB. The application of
CPPs is based on the premise that a biologically active cargo can be attached
to CPPs and translocated into cells. The link between the CPPs and the
cargo is commonly a covalent bond and seldom a non-covalent bond. A large
variety of cargo molecules/materials have been effectively delivered into cells
via CPPs, including small molecules, proteins, peptides, fragments of DNA,
liposomes and nanoparticles.
SynB vectors are a new family of vectors derived from the antimicrobial
peptide protegrin 1 (PG-1), a 18-amino-acid peptide. These linear peptides
are able to interact with the cell surface and cross the plasma membrane with-
out any membrane-disrupting activity. Furthermore, the internalization of
these peptide vectors into cells does not appear to depend on a chiral recep-
tor, since the D-enantio form penetrates as efficiently as the parent peptide
(L-form), and retro-inverso sequences exhibit identical penetrating activity.
These linear protegrin analogues were the starting point for developing a new
potent strategy for drug delivery into complex biological membranes. Adenot
and colleagues [211] studied brain uptake of a number of free and SynB3
vectorized chemotherapeutic agents using both in situ brain perfusion and
in vitro BBB/cell model. They reported that SynB3's conjugation with vari-
ous poorly brain-penetrating drugs enhanced their brain penetration, with
no effect on tight junction integrity. The transcription factor Tat, involved
in the replication cycle of human immunodeficiency virus (HIV), was dem-
onstrated to penetrate into cells [212]. One of the most interesting demon-
strations of the effectiveness of TAT-shuttled nanocarriers across the BBB
was accomplished by TAT-conjugated CdS:Mn/ZnS quantum dots [213].
Histological data showed that TAT-Qdots migrated beyond endothelial cells
and reached the brain parenchyma. Recently, Liu et al. [214] produced com-
pelling evidence that TAT facilitates human brain endothelial cell uptake
of nanoparticles self-assembled from TAT-PEG-b-cholesterol in vitro, and
that the nanoparticles with TAT were able to cross the BBB and translocate
around the cell nucleus of neurons. Biodistribution studies of FITC-loaded
NPs in rabbits and efficacy studies in a C. neoformans meningitis rabbit
model, revealed that these NPs crossed the BBB and produced antimicro-
bial activity against the pathological strains in the brain tissue with a similar
efficacy as amphotericin B, suggesting a therapeutic dose was delivered by
TAT containing nanoparticles. Qin et al. [215] prepared liposomes using
cholesterol-PEG2000-TAT (TAT-LIP) and compared them to liposomes
fabricated from cholesterol-PEG2000 polymer (LLIP) and conventional
