Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review.

Nanoparticles in cancer therapy and diagnosis

The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect.

The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting.

https://dash.harvard.edu/bitstream/handle/1/29293165/Cancer%20Nanotechnology.pdf?sequence=1

Cancer Nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

The objective of this study was to investigate the molecular weight (MW) and time-dependence of the phenomenon termed "the enhanced permeability and retention" (EPR) effect in solid tumor, in particular to determine and define the early phase accumulation of macromolecules in tumor and normal tissues and the relationship between blood concentration and tissue clearance. As a model, radioiodinated N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers of MW ranging from 4.5 K to 800 K were administered i.v. to mice bearing sarcoma 180 tumor. Within 10 min all HPMA copolymers accumulated effectively in the tumor regardless of MW (1.0-1.5% of injected dose per g of tumor). However, higher MW copolymers (> 50 K) showed significantly increased tumor accumulation after 6 h, while the lower MW copolymers (< 40 K) were cleared rapidly from tumor tissue due to rapid diffusion back into the bloodstream. Blood clearance was also MW-dependent; the lower MW copolymers displayed rapid clearance, with kidney radioactivity of the copolymers of MW < 20 K representing 24% of injected dose per g kidney at 1 min after i.v. administration. Within 10 min these copolymers passed through the kidney and were excreted in the urine. Higher MW copolymers consistently showed kidney levels of 3-5% dose per g kidney in the early phase with no time-dependent accumulation in kidney. There was also no progressive accumulation in muscle or liver, regardless of polymer MW. These results suggest the "EPR effect" in solid tumor primarily arises from in the difference in clearance rate between the solid tumor and the normal tissues after initial penetration of the polymers into these tissues.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.1998.tb00563.x

Early Phase Tumor Accumulation of Macromolecules: A Great Difference in Clearance Rate between Tumor and Normal Tissues

A newly discovered nitric oxide radical scavenger, an imidazolineoxyl N-oxide derivative, was used to investigate the role of nitric oxide radical (.NO) in the vascular permeability enhancement of solid tumor. Sarcoma-180 solid tumor in ddY mice was used for this experiment. Electron spin resonance spectroscopy was used to quantitate the reacted and unreacted scavenger. The results showed that extensive extravasation, assessed by intravenous injection of Evans blue, could be greatly suppressed by both .NO scavenger administered orally and .NO synthase inhibitor administrated intraperitoneally. This indicates that .NO is responsible for the vascular permeability in solid tumors.

Enhanced Vascular Permeability in Solid Tumor Is Mediated by Nitric Oxide and Inhibited by Both New Nitric Oxide Scavenger and Nitric Oxide Synthase Inhibitor

BACKGROUND. Rapid tumor growth is caused by angiogenesis factors, growth factors, etc. We previously reported a possible connection between nitric oxide (NO) and enhanced vascular permeability in solid tumor. In the present experiment, the role of NO in solid tumor pathology was further investigated in animal tumor. METHODS. To identify NO formed in solid tumor (AH136B) implanted in the feet of rats, electron paramagnetic resonance (EPR) spectroscopy was performed directly on the frozen tumor tissue at 110K by measuring endogenous nitrosyl iron-sulfur complexes, and by using exogenously added NO capturing agents, i.e., diethyldithiocarbamate (DETC)-Fe 2+ and N-(dithiocarboxy)sarcosine (DTCS)-Fe 2+ complexes. Induction of inducible isoform of nosymthase iNOS mRNA was examined with reverse transcriptase-polymerase chain reaction (RT-PCR) combined with Southern blot analysis. In addition, vascular permeability was assessed by measuring extravasation of 51 Cr-labeled bovine serum albumin in solid tumor. RESULTS. Strong EPR signals from NO adducts of DETC-Fe 2+ and DTCS-Fe 2+ as well as strong signals from NO-hemoglobin and dinitrosyl iron sulfur complex were generated by tumor. The signal height of NO-(DTCS) 2 -Fe 2+ observed in AH136B solid tumor was increased as the tumor gained up to 1.75 g. Induction of iNOS mRNA expression was confirmed by the above methods. Enhanced vascular permeability was suppressed by NOS inhibitors N ω -monomethyl-L-arginine or S-methylisothiourea sulfate and augmented with administration of L-arginine. CONCLUSIONS. Excessive NO production by iNOS in solid tumor was identified unequivocally by EPR spectroscopy. NO formed in solid tumor can be involved in enhanced vascular permeability and increased blood flow, and hence sustain tumor growth.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0142%2819960415%2977%3A8%3C1598%3A%3AAID-CNCR27%3E3.0.CO%3B2-U

Youichiro Noguchi

Papers

Early Phase Tumor Accumulation of Macromolecules: A Great Difference in Clearance Rate between Tumor and Normal Tissues

Enhanced Vascular Permeability in Solid Tumor Is Mediated by Nitric Oxide and Inhibited by Both New Nitric Oxide Scavenger and Nitric Oxide Synthase Inhibitor

Excessive production of nitric oxide in rat solid tumor and its implication in rapid tumor growth