Filtration‐Trap Hypothesis: Nanoparticle Drug delivery System Effectively Targets Tumor through Enhanced Permeability and Retention (EPR) Effect

Abstract

BackgroundsIn the past 30 years, the theory of Enhanced Permeability and Retention (EPR) effect has been dominating the area of nanoparticle drug delivery system targeting at tumor tissues. Inadequate angiogenesis and absence and/or malfunction of lymphatic ducts are the foundation of microcirculation that allows nanoparticles to achieve the EPR effect locally. Despite the many animal studies that yielded promising outcomes, few clinical trials has lead to successful development of marketable new drugs for cancer treatment. Recent studies indicate that nanoparticle delivery systems based on the EPR effect can encounter the paradox of increased interstitial fluid pressure (IFP) caused by lack of lymphatic ducts, which prevents the delivery of the nanoparticles to the tumor tissues. The current study aims to explore the possible existence of certain amount of normofunctional lymphatic ducts, which would prevent abnormally high IFP and maintain the driving force of infusion of the nanoparticles into the tumor tissue.MethodsPreliminary experiments were conducted on animal models established using human colon carcinoma cell line HT‐29 (Balb/c mice), animal S180 cells (KM mice) and Lewis Tumor Model (C57 mice) (n=6). IFP, amount and distribution of lymphatic ducts in tumor tissue and delivery of Austocycin D (AD) nanoparticles (approximately 70 nm in diameter) were measured compared to those in human tumor tissues collected in surgery. Kruskal–Wallis test, Mann– Whitney U‐test and Wilcoxon Signed Rank test were used to determine the statistical differences. P < 0.05 was considered as a statistically significant difference between the compared data.ResultsThe same nanoparticle delivery system delivered more AD particles to tumor tissues with comparatively lower IFP where more lymphatic ducts with normal structure were observed (p<0.05). Compared to human tumor tissues collected in surgery, tumor tissues in the animal models had more lymphatic ducts (p<0.05).ConclusionPreliminary results of this on‐going study confirm that the presence of normofunctional lymphatic ducts in tumor tissue was associated with lower IFP in tumor tissues as well as better delivery of AD nanoparticples, which provides support to the role of normofunctional lymphatic ducts in effective delivery of nanoparticles in tumor tissues. Accordingly, the author would like to propose a “Filtration‐Trap Hypothesis” that, with inadequate angiogenesis, presence of normofunctional lymphatic ducts prevents the local tumor tissue to develop high IFP; therefore, allows effectively delivery of nanoparticles to the tumor tissue. This hypothesis could better explain that the current theory why the nanoparticle drug delivery system dose work effectively in many types of human tumor tissues with high IFP. Therefore, according to this hypothesis, nanoparticle delivery system could achieve better outcome when applied to types and/or stage(s) of tumors that have decent amount of normofunctional lymphatic ducts. This can provide further rational and guidance in development, selection and application of cancer drugs. Follow‐up studies including clinical trials are currently being conducted to further test this hypothesis.