SPL7013 Gel (VivaGel
® ), dendrimers made from poly-L-lysine is in phase 3
clinical trials for prevention of sexual transmitted infections, such as HIV and
genital herpes [39]. It blocks viruses by making biofilm when it is topically applied
to vagina. For the drug delivery, docetaxel linked on PEGylated dendrimers
(DEP™ docetaxel) is in Phase 1 clinical trials for advanced or metastatic cancer.
The size, surface charge and solubility of dendrimers can be precisely controlled
by alteration of both the core and surface repeating units. There are different types
of dendrimers, such as polyamidoamine (PAMAM), polypropylene imine (PPI) and
poly-L-lysine. Among them, PAMAM dendrimers are the most intensively investigated for their biomedical applications. SuperFect
® (Qiagen), well-known gene
transfection agent for cell lines is PAMAM dendrimers.
Biodistribution of dendrimers has been studied by administration of radiolabeled
dendrimers in animals. Charge has a crucial role affecting the biodistribution and
toxicity of dendrimers. The body distribution of
125 I-labelled cationic PAMAM
dendrimers (G3 and G4) and
125 I-labelled anionic ones (G2.5, G3.5 and G5.5) was
investigated after intraperitoneal or intravenous administration to rats [40].
Cationic PAMAM was cleared very rapidly from circulation. Only 0.1–1% was
detected in blood just 1 h after administration due to accumulation of dendrimers
(60–90%) in the liver. Anionic PAMAM showed longer circulation times.
Substantial amount (15–40%) of injected dose still remained in the blood 1 h after
injection. However significant amount (25–70%) of anionic dendrimers accumulated in the liver as well. The cationic dendrimers were cytotoxic at the concentration of 0.05 mg/ml while anionic dendrimers were not cytotoxic up to
concentrations of 1 mg/ml after 72 h of incubation with B16F10 cells. The toxic
effects induced by cationic dendrimers could be related with membrane disruption
due to interactions with negatively charged cell membranes [41].
The preclinical pharmacokinetics of G1 and G4 PAMAM were compared after
111 In labeling via DOTA like chelator (pyridine-N-oxide DOTA) [42]. The G1 was
cleared fast from the blood, with only 0.51 ± 0.07% administered dose remaining
in the blood 2 h after injection. A high radioactivity uptake in the kidney at 5 min
rapidly decreased at 1 h after dosing. This rapid decreasing of radioactivity in the
short time intervals is related with elimination of the agent to urine. G4 revealed a
slower decrease of blood radioactivity over time. Two hours after administration,
4.33 ± 0.70% of the administered activity was still in the blood. G4 administration
led to significant and long-term radioactivity in the liver (20.56 ± 2.59%) and
kidneys (5.85 ± 0.58%) at 48 h post-injection.
The impact of PEGylation on the pharmacokinetics and biodistribution was
investigated after intravenous administration of 3H-labeled poly L-lysine dendrimers to rats [43]. The larger dendrimer constructs (i.e. >30 kDa) were poorly
cleared through kidneys and showed extended elimination half-lives (t½ 1–3 d)
when compared to the smaller dendrimers (i.e. < 20 kDa) which were rapidly
cleared from the plasma into the urine (t½ 1–10 h). The larger dendrimers concentrated in the organs of the MPS (RES) such as liver and spleen later on.
Radiolabeled dendrimers can be used for imaging diagnostics.
64 Cu-labeled
LyP 1-dendrimer designed for PET imaging of atherosclerotic plaque [44]. LyP-1 is
5 Organic Nanomaterials: Liposomes, Albumin, Dendrimer …
115
® ), dendrimers made from poly-L-lysine is in phase 3
clinical trials for prevention of sexual transmitted infections, such as HIV and
genital herpes [39]. It blocks viruses by making biofilm when it is topically applied
to vagina. For the drug delivery, docetaxel linked on PEGylated dendrimers
(DEP™ docetaxel) is in Phase 1 clinical trials for advanced or metastatic cancer.
The size, surface charge and solubility of dendrimers can be precisely controlled
by alteration of both the core and surface repeating units. There are different types
of dendrimers, such as polyamidoamine (PAMAM), polypropylene imine (PPI) and
poly-L-lysine. Among them, PAMAM dendrimers are the most intensively investigated for their biomedical applications. SuperFect
® (Qiagen), well-known gene
transfection agent for cell lines is PAMAM dendrimers.
Biodistribution of dendrimers has been studied by administration of radiolabeled
dendrimers in animals. Charge has a crucial role affecting the biodistribution and
toxicity of dendrimers. The body distribution of
125 I-labelled cationic PAMAM
dendrimers (G3 and G4) and
125 I-labelled anionic ones (G2.5, G3.5 and G5.5) was
investigated after intraperitoneal or intravenous administration to rats [40].
Cationic PAMAM was cleared very rapidly from circulation. Only 0.1–1% was
detected in blood just 1 h after administration due to accumulation of dendrimers
(60–90%) in the liver. Anionic PAMAM showed longer circulation times.
Substantial amount (15–40%) of injected dose still remained in the blood 1 h after
injection. However significant amount (25–70%) of anionic dendrimers accumulated in the liver as well. The cationic dendrimers were cytotoxic at the concentration of 0.05 mg/ml while anionic dendrimers were not cytotoxic up to
concentrations of 1 mg/ml after 72 h of incubation with B16F10 cells. The toxic
effects induced by cationic dendrimers could be related with membrane disruption
due to interactions with negatively charged cell membranes [41].
The preclinical pharmacokinetics of G1 and G4 PAMAM were compared after
111 In labeling via DOTA like chelator (pyridine-N-oxide DOTA) [42]. The G1 was
cleared fast from the blood, with only 0.51 ± 0.07% administered dose remaining
in the blood 2 h after injection. A high radioactivity uptake in the kidney at 5 min
rapidly decreased at 1 h after dosing. This rapid decreasing of radioactivity in the
short time intervals is related with elimination of the agent to urine. G4 revealed a
slower decrease of blood radioactivity over time. Two hours after administration,
4.33 ± 0.70% of the administered activity was still in the blood. G4 administration
led to significant and long-term radioactivity in the liver (20.56 ± 2.59%) and
kidneys (5.85 ± 0.58%) at 48 h post-injection.
The impact of PEGylation on the pharmacokinetics and biodistribution was
investigated after intravenous administration of 3H-labeled poly L-lysine dendrimers to rats [43]. The larger dendrimer constructs (i.e. >30 kDa) were poorly
cleared through kidneys and showed extended elimination half-lives (t½ 1–3 d)
when compared to the smaller dendrimers (i.e. < 20 kDa) which were rapidly
cleared from the plasma into the urine (t½ 1–10 h). The larger dendrimers concentrated in the organs of the MPS (RES) such as liver and spleen later on.
Radiolabeled dendrimers can be used for imaging diagnostics.
64 Cu-labeled
LyP 1-dendrimer designed for PET imaging of atherosclerotic plaque [44]. LyP-1 is
5 Organic Nanomaterials: Liposomes, Albumin, Dendrimer …
115