Augmentation of EPR Effect and Efficacy of Anticancer Nanomedicine by Carbon Monoxide Generating Agents

Abstract

One obstacle to the successful delivery of nanodrugs into solid tumors is the heterogeneity of an enhanced permeability and retention (EPR) effect as a result of occluded or embolized tumor blood vessels. Therefore, the augmentation of the EPR effect is critical for satisfactory anticancer nanomedicine. In this study, we focused on one vascular mediator involved in the EPR effect, carbon monoxide (CO), and utilized two CO generating agents, one is an extrinsic CO donor (SMA/CORM2 micelle) and another is an inducer of endogenous CO generation via heme oxygenase-1 (HO-1) induction that is carried out using pegylated hemin. Both agents generated CO selectively in solid tumors, which resulted in an enhanced EPR effect and a two- to three-folds increased tumor accumulation of nanodrugs. An increase in drug accumulation in the normal tissue did not occur with the treatment of CO generators. In vivo imaging also clearly indicated a more intensified fluorescence of macromolecular nanoprobe in solid tumors when combined with these CO generators. Consequently, the combination of CO generators with anticancer nanodrugs resulted in an increased anticancer effect in the different transplanted solid tumor models. These findings strongly warrant the potential application of these CO generators as EPR enhancers in order to enhance tumor detection and therapy using nanodrugs.

Polymeric Nanoparticles for Drug Delivery: Recent Developments and Future Prospects

“…Only poorly vascularized tumors, mainly pancreatic, prostatic and liver metastatic experience less EPR effect than other types of cancer. Meda et al [ 132 ] discovered that substances that emulate the effect of vascular mediators involved in EPR effect could enhance it, principally nitric oxide (NO), as well as bradykinin, prostaglandins and VEGF, by facilitating tumor angiogenesis and growth. Recent developments have also demonstrated that another vascular mediator, carbon monoxide (CO), also enhances this EPR effect.…”

“…It has been demonstrated that this effect was more present when the systolic blood pressure was higher than normal. In order to intensify the EPR effect, blood pressure can be elevated, or NO-releasing and CO-releasing agents can be administered [ 129 , 130 , 132 , 133 ]. It is important to mention that, with elevated blood pressure, studies showed that the accumulation of nanocarriers in the tumor was significantly higher and the release of these substances in healthy tissues was lower, due to vasoconstriction and compaction of endothelial junctions, translating in less toxicity [ 129 ].…”

HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery

“…Similarly, carbon monoxide (CO) was utilized as a potential enhancer of the EPR effect. Recently, Fang et al employed two CO generating agents, either extrinsic CO donor micelle containing tricarbonyldichlororuthenium (II) dimer or endogenous CO donor using PEGylated hemin inducing heme oxygenase-1 [ 109 ]. It was proved that the agents induced the generation of CO selectively in solid tumors, thus enhanced the EPR effect leading to a two- to three-fold increased tumor accumulation of used nanomedicines.…”

Direct Quantification of Drug Loading Content in Polymeric Nanoparticles by Infrared Spectroscopy

“…The use of nanoparticles as drug delivery systems is already a reality, with more than 50 nanomedicines approved by the Food and Drug Administration (USA) in April 2016, and more to come in the foreseeable future [ 1 ]. The use of nanoparticles as delivery systems may provide numerous benefits [ 2 , 3 , 4 ], including enhanced drug delivery to tumor cells [ 5 , 6 ], controlled release and improved biodistribution [ 7 ], all of which result in a reduction of drug side effects [ 8 , 9 ]. Among polymeric nanoparticles used as delivery systems, silk fibroin-based nanoparticles (SFN) from the silkworm Bombyx mori have shown promising results, partly due to their biodegradability, biocompatibility and nontoxicity [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”