TY - JOUR
T1 - Impact of surface derivatization of poly-L-lysine dendrimers with anionic arylsulfonate or succinate groups on intravenous pharmacokinetics and disposition
AU - Kaminskas, Lisa Michelle
AU - Boyd, Benjamin James
AU - Karellas, Peter
AU - Henderson, Scott
AU - Giannis, Michael
AU - Krippner, Guy Y
AU - Porter, Christopher John
PY - 2007
Y1 - 2007
N2 - Tritium-labeled poly- l-lysine dendrimers displaying 8 or 16 surface lysines have been capped with benzene sulfonate (BS), benzene disulfonate (BDS), or succinate (Succ) groups, and the intravenous pharmacokinetics and disposition profiles of the resulting dendrimers (Lys(8)(BS)(16), Lys(16)(BS)(32), Lys(16)(BDS)(32), Lys(16)(Succ)(32)) have been evaluated. Lys(16)(Succ)(32) was rapidly removed from the plasma primarily via renal elimination. Lys(16)(BS)(32) and Lys(16)(BDS)(32) were opsonized, resulting in more prolonged plasma elimination kinetics and increased uptake by the liver. Data obtained at higher doses suggested some evidence of nonlinear pharmacokinetics. Lys(8)(BS)(16) had reduced affinity for plasma proteins and was cleared more rapidly than the larger Lys(16)(BS)(32) or Lys(16)(BDS)(32) dendrimers. Lys(8)(BS)(16) and Lys(16)(BS)(32) were metabolized in vivo, resulting in the production of a low molecular weight species (possibly the cleavage product Lys(BS) (2)) that was extensively renally eliminated and accounted for almost all of the radioactivity recovered in urine ( approximately 20-45 of administered (3)H). In contrast, only 3-5 of the administered (3)H was recovered in the urine of rats administered Lys(16)(BDS)(32), suggesting increased resistance to in vivo degradation. The plasma clearance, distribution, and metabolic profiles of lysine dendrimers are therefore significantly influenced by the structure and charge of the capping groups. In particular, larger arylsulfonate-capped lysine dendrimers are rapidly opsonized and initially cleared from the plasma by the reticuloendothelial organs. The degree of metabolism is subsequently dictated by the nature of the surface capping group with BDS surfaces seemingly more resistant to breakdown. In contrast, smaller arylsulfonate-capped dendrimers are less readily opsonized and phagocytozed but are metabolically labile, and succinate-capped dendrimers are rapidly eliminated by the kidneys
AB - Tritium-labeled poly- l-lysine dendrimers displaying 8 or 16 surface lysines have been capped with benzene sulfonate (BS), benzene disulfonate (BDS), or succinate (Succ) groups, and the intravenous pharmacokinetics and disposition profiles of the resulting dendrimers (Lys(8)(BS)(16), Lys(16)(BS)(32), Lys(16)(BDS)(32), Lys(16)(Succ)(32)) have been evaluated. Lys(16)(Succ)(32) was rapidly removed from the plasma primarily via renal elimination. Lys(16)(BS)(32) and Lys(16)(BDS)(32) were opsonized, resulting in more prolonged plasma elimination kinetics and increased uptake by the liver. Data obtained at higher doses suggested some evidence of nonlinear pharmacokinetics. Lys(8)(BS)(16) had reduced affinity for plasma proteins and was cleared more rapidly than the larger Lys(16)(BS)(32) or Lys(16)(BDS)(32) dendrimers. Lys(8)(BS)(16) and Lys(16)(BS)(32) were metabolized in vivo, resulting in the production of a low molecular weight species (possibly the cleavage product Lys(BS) (2)) that was extensively renally eliminated and accounted for almost all of the radioactivity recovered in urine ( approximately 20-45 of administered (3)H). In contrast, only 3-5 of the administered (3)H was recovered in the urine of rats administered Lys(16)(BDS)(32), suggesting increased resistance to in vivo degradation. The plasma clearance, distribution, and metabolic profiles of lysine dendrimers are therefore significantly influenced by the structure and charge of the capping groups. In particular, larger arylsulfonate-capped lysine dendrimers are rapidly opsonized and initially cleared from the plasma by the reticuloendothelial organs. The degree of metabolism is subsequently dictated by the nature of the surface capping group with BDS surfaces seemingly more resistant to breakdown. In contrast, smaller arylsulfonate-capped dendrimers are less readily opsonized and phagocytozed but are metabolically labile, and succinate-capped dendrimers are rapidly eliminated by the kidneys
M3 - Article
VL - 4
SP - 949
EP - 961
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 6
ER -