Artificial cells as a novel approach to gene therapy - Artificial Cells, Cell Engineering and Therapy - page 270

10.6.3 Molecular targeting
Delivery of the therapeutic product systemically is appropriate for the treatment
of diseases such as hemophilia and many inborn errors of metabolism. However,
when the product delivered has potent and even toxic side effects, e.g. cytokines,
additional molecular targeting signals may be necessary, both to decrease
toxicity and to improve efficacy. For example, cytokines such as IL-2, IL-12,
and interferon have a clearly demonstrated anti-tumor effect but can produce
severe side effects in normal cells when high levels were administrated (Siegel
and Puri, 1991; Edwards et al., 1992; Atkins et al., 1997; Sabel and Sondak,
2003). In general, targeting complements artificial cell technology as the
microcapsules are compartmentally fixed (i.e. at the site of implantation) and
any secreted products would have to enter systemic circulation to approach a
therapeutic target. The ability to home in to tumors would mean that potentially
a higher concentration of products could reach the tumors from these capsules.
Targeting to tumor-associated antigens (i.e. to HER2-expressing cells in breast
cancer) or to the tumor vasculature are some of these potential targets.
Increasing specificity in cancer gene therapy
When the strategy of targeting via microencapsulated cells was applied with a
fusion protein of IL-2 and antibody specific for the HER2/neu receptor,
however, no enhancement of tumor-specific delivery of IL-2 was obtained
(Cirone et al., 2002). The fusion protein, which should have targeted the B16-
F10/neu tumor cells, did poorly compared to other antibody-IL-2 fusion proteins
targeting tumors (Becker et al., 1996a,b; Lode and Reisfeld, 2000), or even other
melanoma models (Xiang et al., 1997; Gillies et al., 1992; Niethammer et al.,
2001). The immunoconjugate accumulated in lymphoid tissues instead. This was
possibly due to the affinity of IL-2 to its receptors that were plentiful on
lymphocytes in these tissues (Foss, 2001; Yao et al., 2004). Therefore, targeting
by molecular fusion to antibody (or antibody fragments) would likely work best
where the endogenous antigens are not widely distributed.
In spite of the above reservation, apparent targeting in a different context was
claimed to have been achieved by using a common peptide motif Arg-Gly-Asp
(RGD) widely distributed in the plasma membrane of many cell types. Bio-
degradable poly(lactic glycolic acid) (PLGA) microcapsules were developed as
ultrasound contrast agents for tumors by modifying the microcapsule surface
with the RGD ligand. The modified microcapsules were found adhering
specifically to a breast cancer cell line MDA-MB-231 in static experiments
(Lathia et al., 2004). The RGD peptide sequence targets integrins expressed
during angiogenesis, alphavbeta3 and alphavbeta5 as well as other integrins.
These are membrane-spanning proteins in cells that play a vital role in cell
attachment and many other processes. Since the integrins specific to angio-