Biomedical Engineering Reference
In-Depth Information
activator (TAT), polyarginine, antennapedia (Antp), penetratin, transportan, and
mitogen-activated protein (MAP) have been shown to deliver a wide variety of thera-
peutic loads to target cells, and some of the most well characterized PTDs are cur-
rently being tested in preclinical and clinical trials (Gump and Dowdy 2007 ).
The most commonly used PTDs is the HIV TAT peptide, a small polypeptide of
86 amino acids with a cysteine-rich region derived from the HIV TAT protein (Rao
et al. 2009 ). This peptide possesses an arginine-rich sequence and is highly posi-
tively charged enable permeation of the cell membrane in a receptor- and transporter-
independent fashion (Vives et al. 1997 ). Strong experimental results have validated
the effectiveness of TAT-directed drug delivery. The TAT peptide directly conju-
gated with various agents, including horseradish peroxidase, b-galactosidase and
nucleic acids, or decorated on the surfaces of nanocarriers such as liposomes and
PEI, is able to deliver these molecules to various cells and tissues in the mouse,
displaying high accumulation in the heart, lung and spleen (Pangburn et al. 2009 ).
Chiu et al. covalently linked a TAT peptide to the 3¢-terminus of the antisense strand
of an siRNA (Chiu et al. 2004b ). The Tat-siRNA conjugate showed rapid internal-
ization into cells and specific siRNA mediated knockdown of the target gene.
Despite of these advances in PTD-mediated siRNA delivery, direct conjugation
of a cationic PTD to an anionic siRNA often results in insoluble complexes thereby
reducing the delivery efficiency and inducing some cytotoxicities (Turner et al.
2007 ; Meade and Dowdy 2008 ). In order to overcome this shortcoming, an efficient
“mask” PTD-directed siRNA delivery approach that uses a TAT peptide transduction
domain-double stranded RNA-binding domain (PTD-DRBD) fusion protein has
been developed (Eguchi and Dowdy 2009, 2010 ; Eguchi et al. 2009 ). The DRBD
is known to bind siRNA with high avidity, which functions as a “mask” to shield
the negative charge of the siRNA allowing the PTD to efficiently deliver the siRNA
into cells.
3.4
Folate-Mediated Drug Delivery
Folate is also known as folic acid or vitamin B 9 , which is able to specifically bind
to the folate receptor with nanomolar binding affinity (Weitman et al. 1992 ; Wang
et al. 1996 ). It has been known that folate receptors are over-expressed in many
human cancer cells including ovarian, breast, pharyngeal and liver cancer, while
their distribution in normal tissues is minimal. In particular, it was found that
expression of folate receptors are elevated on epithelial tumors of various organs
such as colon, lung, prostate, ovaries, mammary lands and brain. To date, folate is
well-characterized and shows many benefits, including a low-molecular weight
(MW 441 Da), good stability, no immunogenicity and well-defined conjugation
chemistry. Therefore, it has become one of the most popular targeting moieties for
tumor specific drug delivery (Sudimack and Lee 2000 ). Numerous studies have
already demonstrated that attachment of folate to various molecules allows rapid
internalization by endocytosis and high accumulation in tumor cells.
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