The effect of molecular weight on the biodistribution of hyaluronic acid radiolabeled with111In after intravenous administration to rats

Abstract

Hyaluronic acid (HA), is a high molecular weight (HMW) glucosaminoglycan with significant acitivity, and which influences a number of physiological and pathological processes such as tumorogenesis, arthritis, etc. The aim of this study was to determine the difference in the biodistributional pathways of 111In-labeled diethylenetriaminepentaacetic acid-hyaluronic acid (111In-DTPA-HA) molecule of three different MWs (10, 100 and 450 kDA) in a rat model, and to determine possible relationships between the biodistribution and the MW of the investigated agent for future medical applications. 111In-DTPA-HA was prepared by mixing activated DTPA and activated HA, then adding 111InCl3 to the previously prepared mixture at pH 5,5 in an acetic buffer. Biodistributional studies were performed using 36 male Wistar rats aged 2 months and weighing 280 - 350 g. The radioactivity in the samples was measured via a radiometer and the radioactivity in the different organs, blood, plasma and urine was determined. It was found that 50-54% for 10 and 100 kDa and 80% for 450 kDa of the administered dose of radiolabel was present in the liver after 5 min. Other organs show no significant increase during the experimental period. The elimination of the radiolabel was mostly renal and in low molecular weight (LMW) form. Radioactivity remained in liver throughout the 72h experimental period. A difference in the biodistribution of 450 kDa and LMW radiolabeled molecules was found. Higher amounts of radiolabel were taken up by the liver when the 450 kDa molecule was used. LMW fractions were found in the urine, and could have been a product of non-enzymatic cleavage. The extended retention of radiolabel in the liver could be related to changes in the polarity of DTPA-HA molecules.

Anti-tumor efficacy of hyaluronan-based nanoparticles for the co-delivery of drugs in lung cancer

“…This capture is due to the overexpresion of the hyaluronan receptor for endocytosis (HARE) in the liver. [39,40] Nonetheless, a small proportion of NP reached the tumors, and accumulated more strongly in the CD44-overexpressing A549 tumors compared to H358 (low expression of CD44) and H322 (CD44 negative tumor) tumors (Figure 5B), suggesting that active CD44 receptor targeting could play a role in NP retention. [19] Liver uptake is a common important problem observed with most NP, including targeted ones.…”

“…[41] Our biodistribution observations highlight the need to reduce the hepatic capture of the NP, for instance by pre-injecting free hyaluronan to occupy HARE receptors (supplemetary material S8). [34,40] In addition, the active targeting of CD44-expressing tumors must be enhanced, possibly by modulating the hyaluronan size of the NP. [42,43] In vivo biodistribution of Dy-700-labelled NP in mice with A549, H358, or H322 subcutaneous tumors was studied.…”

Characterization of CD44-Mediated Cancer Cell Uptake and Intracellular Distribution of Hyaluronan-Grafted Liposomes

“…20 Different molecular sizes of HA have differential effects on the rate of early wound contraction. 21 The MW of HA also significantly impacts its biodistribution, 22 cellular permeability, 23 and ligand-receptor interaction. 24 Consequently, the effect of HA MW should be investigated for any ligand-targeted DDS that uses HA as the targeting moiety.…”

Hyaluronic Acid Nanoparticles as Nanomedicine for Treatment of Inflammatory Diseases

“…Although 86.7–95.6% of radioactivity from radiolabeled HA was found to be eliminated by urinary and fecal excretion, incorporation of the radioactivity was detected in al tissues starting at 15 min and persisting for 48 h. HA was delivered to tissues via both lymphatic and blood circulation as well as a non-blood transport system [ 42 , 53 , 54 ]. Several studies have been also evaluated the plasma clearance, tissue distribution, and metabolism of intravenously administered HA using isotopes as tracers and reported that the injected HA was accumulated in the liver and degraded mainly by an efficient extrarenal system present in the liver [ 55 , 56 ]. Indeed, in the rat model, HMW HAs were mainly accumulated and remained throughout the 72 h experimental period in the liver, while LMW HAs were found in the urine [ 56 ], suggesting that both renal and hepatic systems play an essential role for the plasma clearance of HA.…”

“…Several studies have been also evaluated the plasma clearance, tissue distribution, and metabolism of intravenously administered HA using isotopes as tracers and reported that the injected HA was accumulated in the liver and degraded mainly by an efficient extrarenal system present in the liver [ 55 , 56 ]. Indeed, in the rat model, HMW HAs were mainly accumulated and remained throughout the 72 h experimental period in the liver, while LMW HAs were found in the urine [ 56 ], suggesting that both renal and hepatic systems play an essential role for the plasma clearance of HA. The plasma half-life of HA in normal human subjects after HMW HA injection was between 2.5 and 5.5 min, and its elimination was mainly extrarenal with the upper MW limit for renal excretion being 2.5 kDa [ 57 ].…”