gamma-Glutamyl PAMAM dendrimer as versatile precursor for dendrimer-based targeting devices.
Poly(amidoamine) (PAMAM) dendrimers are highly branched spherical polymers that have a unique surface of primary amine groups and provide a versatile design for targeted delivery of pharmaceuticals and imaging agents. Acetylation or succinylation of surface amine groups of PAMAM dendrimer derivatives is frequently performed to reduce nonspecific uptake. However, since targeting molecules, drugs/imaging agents, and acylating reagents react with the amine groups on dendrimer, such modification may limit the number of targeting molecules and/or drugs or may result in insufficient charge reduction. In this study, a gamma-glutamyl PAMAM dendrimer was designed and synthesized as a new precursor for targeting device. The relationship between surface electrical properties of the PAMAM dendrimer derivatives and pharmacokinetics was also determined. A PAMAM dendrimer (generation 4.0) was modified with a small number of Bolton-Hunter reagent to prepare Phe-P (pI 9.2). The amine residues of Phe-P were gamma-glutamylated to prepare Glu-P (pI 7.1). The alpha-amine residues of Glu-P were then acetylated or succinylated to prepare Ac-Glu-P (pI 5.3) or Suc-Glu-P (pI 3.6). For comparison, Phe-P was acetylated or succinylated to prepare Ac-P (pI 6.0) or Suc-P (pI 5.1). All the PAMAM dendrimer derivatives exhibited similar molecular size (7.2 to 7.8 nm) except for Ac-P (5.1 nm). The biodistribution studies were performed after radioiodination of each PAMAM dendrimer derivative with Na[(125)I]I. When injected intravenously to mice, both [(125)I]Ac-P and [(125)I]Suc-P exhibited prolonged radioactivity levels in the blood and significantly lower hepatic and renal radioactivity levels than those of [(125)I]Phe-P. Both [(125)I]Glu-P and [(125)I]Ac-Glu-P showed residence times in the blood similar to those of [(125)I]Ac-P and [(125)I]Suc-P. However, [(125)I]Glu-P also registered higher radioactivity levels in the kidney. High hepatic and renal radioactivity levels were observed with highly anionic [(125)I]Suc-Glu-P. These results indicate that, while the manipulation of pI between 5 to 6 would be appropriate to enhance blood retention and reduce renal and hepatic uptake, the amount of primary amine residues on dendrimer surface may also play a crucial role in their renal uptake. The findings in this study show that gamma-glutamyl PAMAM dendrimers would constitute versatile precursors to prepare PAMAM dendrimer-based targeting devices due to their neutral molecular charge (pI 7.1) and the presence of a large number of alpha-amine residues available for conjugation of targeting molecules and drugs/imaging agents.
Uehara
Tomoya
T
Chiba University, Chiba, Japan.
Ishii
Daisuke
D
Uemura
Tomoe
T
Suzuki
Hiroyuki
H
Kanei
Tomoko
T
Takagi
Kyoko
K
Takama
Masashi
M
Murakami
Masahiro
M
Akizawa
Hiromichi
H
Arano
Yasushi
Y
D000107:Acetylation; D000588:Amines / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism*; D022781:Hepatocytes / Q000000981:diagnostic imaging / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000378:metabolism; D007526:Isoelectric Point; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism; D051379:Mice; D011877:Radionuclide Imaging
D000588:Amines; D001672:Biocompatible Materials; D050091:Dendrimers; D007457:Iodine Radioisotopes; C104700:PAMAM Starburst; D018698:Glutamic Acid