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

Abstract

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.

Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

“…Smaller tumours exhibit the highest concentration of polymer-drug. Using HPMA copolymer fractions in the range 10 000-800 000 Da as probes (Seymour et al 1995, Noguchi et al 1998, we found that tumour uptake of polymers (usual molecular diameter 5-20 nm) had broad size tolerance and good intratumoural penetration compared with that reported for liposomes and nanoparticles. Conjugates have also been synthesised to contain ligands that might promote receptor-mediated targeting (including antibodies, peptides and saccharides) (reviewed in Duncan 2005a,b).…”

Enhanced Efficacy of Radioimmunotherapy Combined with Systemic Chemotherapy and Local Hyperthermia in Xenograft Model

“…Furthermore, small molecules such as 5-FU are rapidly cleared from tumors in spite of the increased initial delivery by the enhanced perfusion and permeability of tumor vasculatures. [29][30][31] On the other hand, HT improved the targeting of 131 I-A7, a large molecule, by the phenomenon of so-called "enhanced permeability and retention (EPR)." [29][30][31] Bone marrow suppression is a major toxicity of RIT.…”

“…[29][30][31] On the other hand, HT improved the targeting of 131 I-A7, a large molecule, by the phenomenon of so-called "enhanced permeability and retention (EPR)." [29][30][31] Bone marrow suppression is a major toxicity of RIT. We found in previous studies that the combination of 5-FU slightly increased the myelotoxicity of RIT at its MTD dose, but cell counts recovered similarly to that in the single-modal RIT 21) and local HT did not affect the toxicity.…”

New Experimental Therapies Targetting Breast Cancer Cell

“…These polymers have been developed in the basis of the achieved tumor-specific targeting by the enhanced permeability and retention effect (Ducan et al, 2005;Matsumura et al, 1986). This increasing tumor retention has been observed and attributed to the better extravasation in the blood vessel of macromolecules and the absence of their drainage release (Noguchi Y et al, 1998;Seymour et al, 1995). HPMA copolymer conjugate with chemotherapeutic agents as doxorubicin has shown high retention and efficacy toward tumors without side effects (Ducan et al, 2005).…”