Abstract
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.
Highlights
IntroductionHuman tumors diagnosed in clinical situations are frequently larger than 3 mm and up to 10 cm or more
We investigated three enhanced permeability and retention (EPR)-effect enhancers—isosorbide dinitrate (ISDN), sildenafil citrate, and L-Arg—in C26 tumor models in mice, which exhibit less tumor blood flow and are not easy to cure compared to S180 tumor model
We investigated the use of ISDN and sildenafil citrate to increase delivery of different nanomedicines to advanced tumors that were 15–18 mm in diameter, in C26 tumors-model mice
Summary
Human tumors diagnosed in clinical situations are frequently larger than 3 mm and up to 10 cm or more In such large tumors, blood flow is often suppressed or blood vessels are occluded because of the formation of vascular clots or thrombi [9,10,11,12,15,16,17,18]. Blood flow is often suppressed or blood vessels are occluded because of the formation of vascular clots or thrombi [9,10,11,12,15,16,17,18] This blood-flow suppression results in little or no drug delivery and, a highly limited EPR effect [9,12,15,16,17,18]. We demonstrated similar results by using arterial angiography of the polymer-conjugate drug SMANCS, i.e., neocarzinostatin (NCS)
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