Translation of Pro-Angiogenic and Anti-Angiogenic Therapies into Clinical Use - Mechanical and Chemical Signaling in Angiogenesis - page 263

pro-angiogenic cytokines at ischemic sites, and limiting the side effects of
angiogenic growth factors (such as hypotension) outside the heart. For instance,
the adhesion molecule P-selectin is upregulated on endothelial cells in myocar-
dium, and may be targeted for delivery of angiogenic therapy. Anti-P-selectin
coated liposomes have been designed as delivery vehicles for VEGF [ 53 ]. In a rat
model of myocardial infarction, the VEGF-encapsulated immunoliposomes were
injected systemically, and successfully concentrated VEGF in the ischemic heart.
Treatment with VEGF-loaded immunoliposomes improved systolic function in
rats, while systemic injection of non-targeted VEGF had no therapeutic effect.
Targeted drug delivery is a promising approach for therapeutic angiogenesis,
deserving of further investigation. In addition, the spatial and temporal presenta-
tion of VEGF has recently been demonstrated to influence angiogenesis [ 54 ].
Polymeric materials that control and regulate the spatial and temporal presentation
of pro-angiogenic factors may be critical for optimizing therapeutic angiogenesis.
4 Suppression of Angiogenesis for Cancerous Tumors
Cancer is a disease of uncontrolled cellular proliferation and unchecked tissue
growth. Tumor growth may lead to compression and disruption of local anatomical
structures, as well as invasion of adjacent tissue, and infiltration beyond the
primary tumor during metastasis. Cancerous tumors are caused by the accumu-
lation of genetic alterations over time. Such alterations may be the result of
inheritance or environmental exposures to carcinogens. As genetic alterations
accumulate, cells transform from a normal phenotype into a malignant phenotype.
Infiltration of malignant cells into the underlying stromal tissue signals the first
sign of invasive cancer. The process of carcinogenesis may take 10-20 years to
evolve [ 55 ]. Because of Judah Folkman's pioneering work [ 56 ], it is now well-
known that a sustained level of tumor growth requires an adequate vascular
supply. Tumors must have an ongoing blood supply to grow beyond a minimum
size of 2-3 mm 3 . Neovascularization of tumors is also a necessary prerequisite for
escape and metastasis of cells; once metastatic cells arrive at a distant site,
angiogenesis is again required to establish a new tumor [ 57 ]. For these reasons, the
tumor vascular supply is a widely recognized target for anti-angiogenic treatments.
The chief objective of pharmacologic anti-angiogenic agents is to target
disease-driven angiogenesis within cancerous tumors, while sparing healthy
tissues from damage. Efforts toward anti-angiogenic therapies for cancer have
yielded notable clinical successes; several anti-angiogenic agents are already part
of standard treatment regimens for cancer. Yet these efforts have also been marked
by clinical disappointment, as tumors tend to develop resistance to anti-angiogenic
agents over time. The ultimate result is that patients experience a transitory
improvement in cancer, followed by tumor recurrence and cancer progression.
This phenomenon has been revealed during the development and clinical adoption
of VEGF-targeting agents in cancer treatment.