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- Table 1.
Factors affecting the EPR effect of macromolecular drugs in solid tumors (modified after references 4 and 5)
Mediators Responsible enzymes and mechanisms Possible application to therapeutic modality and mechanism Bradykinin Kallikrein/protease ACE inhibitors (e.g., enalapril); blocking of kinin degradation elevates local kinin level → more EPR. NO iNOS NO-releasing agents (e.g., nitroglycerin, ISDN, etc.) via denitrase and nitrite reductase to generate NO. VPF/VEGF Involved in NO generation Prostaglandins COX-1 Beraprost sodium: PGI2 agonist works via vascular dilatation and extravasation (5). Collagenase (MMP) 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 generation (15). Induced hypertension Using angiotensin II Slow i.v. infusion → systemic hypertension, vascular extravasation selectively in tumor tissue. Inflammatory cells and H2O2 Neutrophil/NADPH oxidase, etc. TGF-β inhibitor Inducing multiple inflammatory cytokines; NOS, COX, etc.: NO, PGs, etc. 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. - Table 2.
Survival benefits from the FDA-approved nanomedicines to date
Generic drug Trade name(s) Indication Benefit PEGylated liposomal doxorubicin Doxil and Caelyx HIV-related Kaposi's sarcoma No statistically significant change in overall survival (23 wks) vs. doxorubicin, bleomycin, and vincristine treatment (22.3 wks) for HIV-related Kaposi's sarcoma Metastatic ovarian cancer Statistically significant overall survival improvement (108 wks, P = 0.008) vs. topotecan treatment (71.1 wks) for platinum-sensitive patients with ovarian cancer Metastatic breast cancer No statistically significant overall survival change (84 wks) vs. conventional doxorubicin (88 wks) for patients with breast cancer receiving first-line therapy Liposomal daunorubicin DaunoXome HIV-related Kaposi's sarcoma No statistically significant overall survival change (52.7 wks) vs. doxorubicin, bleomycin, vincristine treatment (48.9 wks) Poly (styren-co-maleic acid)–conjugated naocarzinostatin SMANCS Liver cancer, renal cancer Approved in 1993 in Japan. Far more effective when the EPR is enhanced by increasing the blood pressure in difficult-to-treat tumors, including metastatic liver cancer, cancers of pancreas, gall bladder, etc. Liver cancer: 5-year survival (%)** Metastasis 1 seg.+ > 2 seg. Child A >90% ∼ >50% Child B 40% 30% Five-year survival (%) based on the liver function (cirrhosis) by child classification and intrahepatic+ metastasis within one segment or more Albumin-bound paclitaxel Abraxane Metastatic breast cancer Statistically significant overall survival change (56.4 wks, P = 0.024) vs. polyethoxylated castor oil–based paclitaxel treatment (46.7 wks) for patients receiving second-line treatment NOTE: The polymeric platform methoxy PEG-poly(d,l-lactide) taxol with the trade name Genexol-PM (Sanayang Co.) has been approved in Korea for the treatment of metastatic breast cancer. Adapted from the work of Jain and Stylianopoulos (16).
**, SMANCS data in the table were provided by H. Maeda.
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April 2013
Volume 73, Issue 8
Volume 73, Issue 8
Challenges and Key Considerations of the Enhanced Permeability and Retention Effect for Nanomedicine Drug Delivery in Oncology
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