Biomedical Engineering Reference
In-Depth Information
and/or convection of therapeutic agents across the vessel, are anti-angiogenic
therapies (Ferrara and Kerbel
2005
), employed in cancer therapy as well as other
chronic diseases such as psoriasis (
Buckland
), rheumatoid arthritis (Longo et al.
2002
) or diabetic retinopathy (Avery et al.
2006
). Various compounds have been
developed to block VEGF pathways such as monoclonal antibodies (Avastin), small
molecules tyrosine kinases inhibitors such as lapatinib and sunitinib. These mole-
cules have been shown to enhance the effect of chemotherapeutics normalizing the
architecture of the tumor vasculature and reducing interstitial fluid pressure, hence
increasing the pressure gradient across the tumor vessels, which leads to greater
extravasation and deeper penetration of macromolecules into tumors.
As stated previously, high cellular and collagen densities have also been associ-
ated with increased interstitial fluid pressure and various strategies have also been
employed to reduce both factors before administering the therapy. Possible methods
include pretreatment with anti-adhesive agents or bacterial collagenases (Minchinton
and Tannock
2006
; McKee et al.
2006
), although there are concerns about the pos-
sible effect on metastasis. For some tumors, it is possible to identify the pathway
responsible for the overexpression of ECM components. For instance there is an
abundance of evidence that indicates that advanced-stage pancreatic tumors over-
produce transforming growth factor (TGF)-b1 which is involved in the functional
regulation of tumor interstitium (Roberts and Wakefield
2003
; Pasche
2001
). In
light of these findings, recent research has focused on strategies that antagonize the
TGF-b1 pathway as a possible treatment modality for tumors with a fibrotic
microenvironment (Biswas et al.
2006
). Strategies include the use of monoclonal
TGF-b1-neutralizing antibodies (Arteaga et al.
1993
), antisense technology to
reduce the translational efficacy of TGF-b1 ligands (Spearman et al.
1994
), and
small molecule inhibitors that antagonize the TGF-b1 receptor I/II kinase function
(Peng et al.
2005
).
Other approaches to enhance drug extravasation and tissue penetration rely on
the conjugation or co-administration of peptides containing a tissue penetration
motif, such as the CendR (C end Rule) motif of the cyclic tumor penetrating peptide
iRGD (internalizing Arginine-Glycine-Aspartic acid) (
Ruoslahti et al.
;
Sugahara
et al.
). iRGD targets tumors by binding to integrins expressed on the tumor vascu-
lature. The peptide is then proteolytically cleaved, generating a peptide fragment
with the CendR motif exposed which interacts with the neuropilin-1 receptor, pro-
moting drug penetration into tissues. iRGD has been shown to improve penetration
of different types of molecules and particles in four different cancer models.
Local hyperthermia treatment, which is usually employed to improve radiation
therapy, also increases blood flow and tumor microvascular permeability, thereby
enhancing the extravasation and interstitial diffusion of therapeutic agents such as
liposomes or antibodies (Kong et al.
2000
).
All of the above mentioned mechanisms for enhancing the permeation to the
target tissue should be taken into consideration when the delivery to the specific
population of the cells or to the specific cell organelles is desired. The following
sections will deal with the mechanisms of cellular uptake and targeting the thera-
peutic entities to their intended site of action intracellularly.
Search WWH ::
Custom Search