Tumor-Selective Delivery of Macromolecular Drugs via the EPR Effect: Background and Future Prospects

Abstract

This paper briefly documents the history of the discovery of the EPR (enhanced permeability and retention) effect and elucidates an analogy between bacterial infection involving proteases that trigger kinin generation and cancer. The EPR effect of macromolecules in cancer tissues is defined, and the distinction between the EPR effect (with reference to clearance of macromolecules from the interstitial space of tumor tissues) and the simple passive targeting of drugs to tumors is described. Additional points of discussion include the uniqueness of tumor vessels, the influence of kinin and other vascular mediators such as nitric oxide (NO) and prostaglandins, and the heterogeneity of the EPR effect. Two different strategies to augment the EPR effect that were discovered are elevating blood pressure artificially via slow infusion of angiotensin II and applying nitroglycerin or other NO donors. Use of the nitroagent increased not only the blood flow of the tumor, but also the delivery of drug to the tumor and the drug's therapeutic effect. This finding shows an intriguing analogy to hypoxic cardiac infarct tissue, in that both are improved by NO. These two methods were applied to treatment of rodents and human cancers, in combination with other anticancer agents, with successful results achieved in rodents as well as humans. These data suggest very appealing prospects for utilization of the EPR effect in future development of cancer therapeutics.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…To exploit the singularities of the tumor vasculature, nanocarriers must have enough circulation half-life to passively target the tumor environment, avoiding the action of the mononuclear phagocyte system (MPS) and the reticulo-endothelial system (RES) during their transportation throughout the bloodstream, and releasing the anticancer drugs in tumor [63][64][65]. For this purpose, nanocarrier size must not exceed 400 nm to escape from the MPS and achieve the extravasation into tumors by the EPR effect, which is much more effective with diameters below 200 nm [66][67][68].…”

Maghemite Functionalization for Antitumor Drug Vehiculization

“…When dealing with tumors, the magnetic colloids with long half-life get to the target site by means of passive extravasation, profiting from the augmented tumor permeability proceeding from the EPR effect in the tumor vasculature (Maeda, 2010). Otherwise, magnetic colloids can be lively gathered within the tumor site using an external magnetic field.…”

Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging

“…HPMA copolymers are prototypic and routinely used macromolecular drug carriers, which have been extensively employed for EPR-mediated passive drug targeting [15][16][17]. As for other long-circulating nanocarriers, however, such as for liposomes, the tumor accumulation of HPMA copolymers varies quite considerably, both in animal models and in patients, from barely detectable, to up to 5% of the injected dose [18][19][20][21].…”

“…the relative vascular volume of tumors) correlates with the degree of EPR-mediated passive drug targeting, no experimental evidence for this has thus far been provided. Here, we therefore set out to visualize and quantify the tumor accumulation of near-infrared-fluorophore (NIRF) labeled polymeric drug carriers based on N-(2-hydroxypropyl)-methacrylamide HPMA copolymers are prototypic and routinely used macromolecular drug carriers, which have been extensively employed for EPR-mediated passive drug targeting [15][16][17]. As for other long-circulating nanocarriers, however, such as for liposomes, the tumor accumulation of HPMA copolymers varies quite considerably, both in animal models and in patients, from barely detectable, to up to 5% of the injected dose [18][19][20][21].…”