Selective therapy remains a key issue for successful treatment in cancer therapy. Prolonged administration of effective concentrations of chemotherapeutic or anti-angiogenic agents is usually not possible because of dose-limiting systemic toxicities involving non-malignant tissues. Therefore, a constant effort has been the development of new drug delivery systems that mediate drug release selectively at the tumor site. Multimodality targeted nanomedicines offer the potential for improved efficacy and diminished toxicity. One way to achieve such selectivity is to activate a prodrug specifically by a confined enzymatic activity. In this concept, the enzyme is either expressed by the tumor cells or the tumor endothelial cells, or is brought to the tumor by a targeting moiety. The prodrug is converted to an active drug by the local or localized enzyme at the tumor site. Alternatively, the lower pH in the tumor microenvironment can be utilized for selectively activating a prodrug.
Figure 1. The angiogenic switch and the use of nanomedicines such as Polymer Therapeutics (A), to treat angiogenic tumors (B-C). The enhanced permeability and retention (EPR) effect allows nanoconjugates to extravasate through the tumor leaky vessels (D-E), accumulate in the tumor bed selectively and internalize into the tumor epithelial and tumor endothelial cells via endocytosis (F).
- Characterization of tumor vasculature for tailored-made therapy. Identifying new molecular markers on tumor endothelial cells in order to develop better drugs and better targeting moieties.
- Design of novel nanocarriers as strategies to target angiogenesis inhibitors to tumor vasculature. To improve the therapeutic index of chemotherapeutic and antiangiogenic agents by conjugation to polymeric nanocarriers.
- Investigation of the mechanism of action of angiogenesis inhibitors (endogenous and pharmacological inhibitors).
- Intravital non-invasive molecular imaging of treated tumor-bearing mice to follow tumor progression, pharmacodynamics and pharmacokinetics of the synthesized nanomedicines.
- Shedding light on the molecular basis of tumor dormancy using polymer therapeutics.