Homing of negatively charged albumins to the lymphatic system - General implications for drug targeting to peripheral tissues and viral reservoirsSwart, PJ., Beljaars, L., Kuipers, ME., Smit, C., Nieuwenhuis, P. & Meijer, DKF., 1-Nov-1999, In : Biochemical Pharmacology. 58, 9, p. 1425-1435 11 p.
Research output: Contribution to journal › Article › Academic › peer-review
The present study shows the lymphatic distribution of the negatively charged anti-HIV-l agents succinylated or aconytilated human serum albumins (HSAs) in rats. Quantitation of blood and lymphatic concentrations of these proteins was performed through fluorescence detection of the fluorescein isothiocyanate (FITC)-labeled proteins. At several time points after i.v. injection, samples were taken from the cannulated thoracic duct and the carotid artery. Distribution of the negatively charged albumins (NCAs) to lymph was much more rapid than that of albumin itself and was dependent on the total net negative charge added to the protein: the half-life times of lymphatic equilibration were 15, 30, and 120 min for FITC-labeled aconytilated HSA, FITC-labeled succinylated HSA, and FITC-labeled HSA, respectively. Lymph to blood concentration ratios of the studied compounds obtained at steady state approached unity. In addition, the fluorescence in both body fluids was shown to represent unchanged labeled proteins. It was therefore inferred that the NCAs efficiently passed the endothelial barrier from blood to the interstitial compartment. Subsequently, we studied whether a specialized process was involved in the endothelial passage of the NCAs to the lymph. The following observations supported such a mechanism: a) preinjection of the scavenger receptor blockers polyinosinic- and formaldehyde treated HSA reduced the transport from blood to the lymphatic compartment of FITC-labeled aconytilated HSA by more than 90%; b) the rate of lymphatic distribution was largely reduced when the body temperature of the rat was lowered to 28 degrees; and c) pre-administration of chloroquine resulted in a significant reduction in the lymphatic distribution of the NCAs. These data collectively indicate that a scavenger receptor-mediated process is involved in the transendothelial transport of NCAs. In situ localization in lymph nodes of the rat showed that FITC -labeled aconytilated and succinyrated HSA are mainly present in the germinal center and parafollicular zones. The efficient distribution of these anionized proteins to the lymphatic system is of particular interest for HIV therapy, taking into account that replication of HIV mainly takes place in the lymphoid system. The observation that macromolecules, through charge modification, can extravasate through a receptor-mediated transcytotic process is potentially of major importance for the delivery of drugs with macromolecular carriers to cells not directly in contact with the blood. (C) 1999 Elsevier Science Inc.
|Number of pages||11|
|Publication status||Published - 1-Nov-1999|
- endothelial transcytosis, diacytosis, negatively charged albumins, anti-HIV-1 therapy, scavenger receptor, polyanionic compounds, IMMUNODEFICIENCY-VIRUS TYPE-1, HUMAN SERUM ALBUMINS, CONFORMATIONALLY MODIFIED ALBUMINS, PERFUSED-RAT-LIVER, ANTI-HIV ACTIVITY, SCAVENGER RECEPTOR, ENDOTHELIAL-CELLS, BLOOD LYMPHOCYTES, ANTIVIRAL DRUGS, MILK-PROTEINS