TY - JOUR
T1 - Liver-targeting of primaquine-(poly-γ-glutamic acid) and its degradation in rat hepatocytes
AU - Tomiya, Noboru
AU - Jardim, Juliette G.
AU - Hou, Jennifer
AU - Pastrana-Mena, Rebecca
AU - Dinglasan, Rhoel R.
AU - Lee, Yuan C.
N1 - Funding Information:
Funding for this project was from a Johns Hopkins Malaria Research Institute Pilot Project Award (to YCL and RRD), the Bloomberg Family Foundation (to RRD) and a 5T32AI007417-17 (to RPM).
PY - 2013/9/1
Y1 - 2013/9/1
N2 - We have synthesized poly-γ-glutamic acid (PGA) modified with a synthetic trivalent glyco-ligand (TriGalNAc) for the hepatocyte asialoglycoprotein receptor (ASGP-R). We investigated in vivo distribution of unmodified PGA and TriGalNAc-modified PGA (TriGalNAc-PGA) in mice after intravenous injection. Most of unmodified PGA administered was transported to the bladder over 20-80 min, suggesting a rapid excretion of unmodified PGA into urine. In contrast, TriGalNAc-PGA was found exclusively in the liver over the same period of time. We further synthesized TriGalNAc-PGA-primaquine conjugate (TriGalNAc-PGA-PQ), and investigated binding, uptake, and catabolism of the conjugate by rat hepatocytes. Our studies indicated that approximately 250 ng per million cells of the conjugate bound to one million rat hepatocytes at 0 C, and approximately 2 μg per million cells of the conjugate was taken up over 7 h incubation at 37 C. Furthermore, our results suggested that TriGalNAc-PGA-PQ was almost completely degraded over 24 h, and small degradation products were secreted into cell culture medium. The results described in this report suggest that the TriGalNAc ligand can serve as an excellent targeting device for delivery of PGA-conjugates to the liver hepatocytes, and rat hepatocytes possess sufficient capacity to digest PGA even modified with other substituents.
AB - We have synthesized poly-γ-glutamic acid (PGA) modified with a synthetic trivalent glyco-ligand (TriGalNAc) for the hepatocyte asialoglycoprotein receptor (ASGP-R). We investigated in vivo distribution of unmodified PGA and TriGalNAc-modified PGA (TriGalNAc-PGA) in mice after intravenous injection. Most of unmodified PGA administered was transported to the bladder over 20-80 min, suggesting a rapid excretion of unmodified PGA into urine. In contrast, TriGalNAc-PGA was found exclusively in the liver over the same period of time. We further synthesized TriGalNAc-PGA-primaquine conjugate (TriGalNAc-PGA-PQ), and investigated binding, uptake, and catabolism of the conjugate by rat hepatocytes. Our studies indicated that approximately 250 ng per million cells of the conjugate bound to one million rat hepatocytes at 0 C, and approximately 2 μg per million cells of the conjugate was taken up over 7 h incubation at 37 C. Furthermore, our results suggested that TriGalNAc-PGA-PQ was almost completely degraded over 24 h, and small degradation products were secreted into cell culture medium. The results described in this report suggest that the TriGalNAc ligand can serve as an excellent targeting device for delivery of PGA-conjugates to the liver hepatocytes, and rat hepatocytes possess sufficient capacity to digest PGA even modified with other substituents.
KW - Asialoglycoprotein receptor
KW - Liver targeting
KW - Multivalent ligand
KW - Poly-γ-glutamic acids
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U2 - 10.1016/j.bmc.2013.06.028
DO - 10.1016/j.bmc.2013.06.028
M3 - Article
C2 - 23859775
AN - SCOPUS:84881377416
VL - 21
SP - 5275
EP - 5281
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 17
ER -