Table 1.
Factors affecting the EPR effect of macromolecular drugs in solid tumors.
| Mediators | Responsible enzymes and mechanisms | Possible application to therapeutic modality and mechanism |
|---|---|---|
| Bradykinin | Kallikrein/protease | ACE inhibitors (eg. Enalapril®); blocking of kinin degradation elevates local kinin level → more EPR. |
| NO | iNOS | NO releasing agents (eg. nitroglycerin, ISDN, etc) via denitrase and nitrite reductase to generate NO2. |
| VPF/VEGF | Involved in NO generation | |
| Prostaglandins | Cyclooxygenase (COX) 1 | Beraprost sodium: PGI2 agonist works via vascular dilatation and extravasation3. |
| Collagenase (MMPs) | Activated from proMMPs by peroxynitrite, or proteases | |
| Peroxynitrite | NO + O2 | |
| Carbon monoxide (CO) | Heme oxygenase (HO)-1 | PEG-hemine via induction of HO-1 in tumor → CO generation13 |
| Induced hypertension | Using angiotensin II | Slow iv infusion → systemic hypertension, vascular extravasation selectively in tumor tissue. |
| Inflammatory cells and H2O2 | Neutrophil/NADPH oxidase, etc | |
| Transforming growth factor (TGF)-β inhibitor | Inducing multiple inflammatory cytokines; NOS, COX etc: NO, PGs etc. | |
| Tumor necrosis factor (TNF)-α | Inducing multiple inflammatory cytokines; NOS, COX etc: NO, PGs etc. | |
| Anticancer agents | ||
| Heat | Vascular dilation | Gold nanoparticle or ferrite nanoparticle using electromagnetic, or laser, or microwave. |