Table 1.

Factors affecting the EPR effect of macromolecular drugs in solid tumors (modified after references 4 and 5)

MediatorsResponsible enzymes and mechanismsPossible application to therapeutic modality and mechanism
BradykininKallikrein/proteaseACE inhibitors (e.g., enalapril); blocking of kinin degradation elevates local kinin level → more EPR.
NOiNOSNO-releasing agents (e.g., nitroglycerin, ISDN, etc.) via denitrase and nitrite reductase to generate NO.
VPF/VEGFInvolved in NO generation
ProstaglandinsCOX-1Beraprost sodium: PGI2 agonist works via vascular dilatation and extravasation (5).
Collagenase (MMP)Activated from proMMPs by peroxynitrite, or proteases
PeroxynitriteNO + O2
Carbon monoxide (CO)Heme oxygenase (HO)-1PEG-hemine via induction of HO-1 in tumor → CO generation (15).
Induced hypertensionUsing angiotensin IISlow i.v. infusion → systemic hypertension, vascular extravasation selectively in tumor tissue.
Inflammatory cells and H2O2Neutrophil/NADPH oxidase, etc.
TGF-β inhibitorInducing multiple inflammatory cytokines; NOS, COX, etc.: NO, PGs, etc.
TNF-αInducing multiple inflammatory cytokines; NOS, COX, etc.: NO, PGs, etc.
Anticancer agents
HeatVascular dilationGold nanoparticle or ferrite nanoparticle using electromagnetic, or laser, or microwave.