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.

For more than three decades, enhanced permeability and retention (EPR)-effect-based nanomedicines have received considerable attention for tumor-selective treatment of solid tumors. However, treatment of advanced cancers remains a huge challenge in clinical situations because of occluded or embolized tumor blood vessels, which lead to so-called heterogeneity of the EPR effect. We previously developed a method to restore impaired blood flow in blood vessels by using nitric oxide donors and other agents called EPR-effect enhancers. Here, we show that two novel EPR-effect enhancers—isosorbide dinitrate (ISDN, Nitrol^®) and sildenafil citrate—strongly potentiated delivery of three macromolecular drugs to tumors: a complex of poly(styrene-co-maleic acid) (SMA) and cisplatin, named Smaplatin^® (chemotherapy); poly(N-(2-hydroxypropyl)methacrylamide) polymer-conjugated zinc protoporphyrin (photodynamic therapy and imaging); and SMA glucosamine-conjugated boric acid complex (boron neutron capture therapy). We tested these nanodrugs in mice with advanced C26 tumors. When these nanomedicines were administered together with ISDN or sildenafil, tumor delivery and thus positive therapeutic results increased two- to four-fold in tumors with diameters of 15 mm or more. These results confirmed the rationale for using EPR-effect enhancers to restore tumor blood flow. In conclusion, all EPR-effect enhancers tested showed great potential for application in cancer therapy.

Macrophages are critical effector cells of the innate immune system. The presence of microbes or the stimulation by inflammatory factors triggers the metabolic reprogramming of macrophages or macrophage polarization into two phenotypes: the classically activated macrophages (M1) displaying a pro-inflammatory phenotype and the alternatively activated macrophages (M2) having anti-inflammatory functions. The imbalance between the two phenotypes has been linked with various pathological states, such as fibrosis, hepatitis, colitis, and tumor progression. An avenue of potential therapeutic strategies based on macrophage polarization has emerged. Therefore, it is essential to understand the mechanisms of macrophage polarization. In this review, we focus on the macrophage polarization process and discuss the stimuli-dependent conversion into M1 and M2 phenotypes. We also present the metabolic patterns supporting their specific functions. The factors and signaling cascades involved in intra-class switching are also detailed. Finally, the role of macrophage polarization in disease progression is discussed.

Natural products have attracted great interest for some time as alternative methods against cancers by fulfilling immunomodulating properties. In this study, we investigated the activity of hot water extracts (120 °C, >30 min) of Phellinus linteus, fresh leaves of Kumaizasa bamboo and Chaga mushroom which we called MeshimaMax, for cancer prevention and treatment by using different solid tumor models. In the implanted mouse sarcoma S180 tumor, MeshimaMax treatment significantly inhibited tumor growth when it was applied at the early stage of tumor inoculation. The effect was further confirmed by using carcinogen induced tumors, i.e., azoxymethane (AOM)/dextran sulfate sodium (DSS) induced mouse colon cancer and 7,12-dimethylbenz anthracene (DMBA) induced rat breast cancer. In both cases the occurrences of tumors were remarkably suppressed by administration of MeshimaMax which consists of three components above. More importantly, when MeshimaMax was combined with an anticancer chemotherapeutic drug, the therapeutic effect was remarkably improved. In vitro studies showed that when MeshimaMax was applied to mouse macrophage RAW264.7 cells the phagocytosis of macrophages was significantly activated, which was evaluated by using living yeast cells as well as synthetic nanoparticles. A cytotoxicity assay showed the 50% inhibitory concentration (IC₅₀) was higher than 1 mg/mL and normal cells were 2–3 times more tolerant to MeshimaMax than cancer cells. These findings suggest the potential application of MeshimaMax for cancer prevention and as supplement regimen for anticancer chemotherapy, probably functioning through activation of innate immunity, which may benefit cancer patients as an alternative supplement.