Albumin-conjugated PEG liposome enhances tumor distribution of liposomal doxorubicin in rats

To evaluate the effect of coupling of recombinant human serum albumin (rHSA) onto the surface of poly(ethylene glycol)-modified liposorne (PEG liposome) on the in vivo disposition characteristics of liposomal doxorubicin (DXR), the pharmacokinetics and tissue distribution of DXR were evaluated after intravenous administration of rHSA-modified PEG (rHSA/PEG) liposomal DXR into tumor-bearing rats. rHSA/PEG liposome prepared using a hetero-bifunctional cross-linker, N- succinimidyl 3-(2-pyridyldithio) propionate (SPDP), efficiently encapsulated DXR (over 95%). rHSA/PEG liposomal DXR showed longer blood-circulating property than PEG liposornal DXR and the hepatic and splenic clearances of rHSA/PEG liposornal DXR were significantly smaller than those of PEG liposomal DXR. It was also demonstrated that the disposition of DXR to the heart, one of the organs for DXR-related side-effects, was significantly smaller than free DXR. Furthermore, the tumor accumulation of rHSA/PEG liposomal DXR was significantly larger than that of PEG liposomal DXR. The &#34;therapeutic index&#34;, a criterion for therapeutic outcome, for rHSA/PEG fiposornal DXR was significantly higher than PEG liposomal DXR. These results clearly indicate that rHSA-conjugation onto the surface of PEG liposome would be a useful approach to increase the effectiveness and safety of PEG liposomal DXR.</p

Up-Regulation of P-Glycoprotein Expression in Small Intestine under Chronic Serotonin-Depleted Conditions in Rats

ABSTRACT To investigate the role of serotonin (5-HT), an important neurotransmitter and hormone/paracrine agent in the small intestine, in the transport activity of P-glycoprotein (P-gp), the intestinal transport of quinidine, a P-gp substrate, was examined in 5-HTdepleted rats prepared by intraperitoneal administration of pchlorophenylalanine, a specific inhibitor of tryptophan hydroxylase in 5-HT biosynthesis. In the in vitro transport study, quinidine transport across rat jejunum was significantly enhanced in both the secretory and absorptive directions under 5-HT-depleted conditions, although the secretory transport was still predominant. The electrophysiological study suggested that the quinidine transport via passive diffusion was enhanced presumably through a paracellular route. This might be due to looser tight junctions under 5-HT-depleted conditions. The voltage-clamp technique clearly indicated that the secretory transport of quinidine through the transcellular pathway was also enhanced by the depletion of 5-HT. Furthermore, 5-HT depletion increased verapamil-sensitive secretory transport of quinidine in rat jejunum. These results indicate that the secretory transport of quinidine via P-gp was significantly enhanced under 5-HT-depleted conditions. The level of ATP, an energy source for functioning P-gp, wet weight of jejunum, and total protein level in rat jejunal mucosa were not changed by 5-HT depletion, but the expression of P-gp in the brush-border membrane of rat jejunum was significantly induced, which is partly responsible for the enhancement of P-gp activity under the 5-HT-depleted condition

Gastrointestinal Absorption of Recombinant Human Insulin-Like Growth Factor-I in Rats

ABSTRACT The GI absorption of recombinant human insulin-like growth factor-I (rhIGF-I) and its improvement were investigated in rats. The 12

Deeper Penetration into Tumor Tissues and Enhanced in Vivo Antitumor Activity of Liposomal Paclitaxel by Pretreatment with Angiogenesis Inhibitor SU5416

The recently emerged concept of "vessel normalization" implies that judicious blockade of vascular endothelial growth factor (VEGF) signaling may transiently "normalize" the tumor vasculature, making it more suitable for tumor disposition of subsequently administered drugs. In this study, therefore, the effect of pretreatment with SU5416, a selective VEGF receptor-2 inhibitor, on tumor disposition and in vivo antitumor activity of polyethylene glycol (PEG)-modified liposomal paclitaxel (PL-PTX) was evaluated in Colon-26 solid tumor-bearing mice. To improve the solubility and in vivo disposition characteristics of SU5416, the inhibitor was formulated in PEGylated O/W emulsion (PE-SU5416). Pretreatment with PE-SU5416 significantly enhanced the in vivo antitumor effect of PL-PTX, although PE-SU5416 administration alone did not show any antitumor effect. Immunostaining for endothelial cells and pericytes demonstrated that the pretreatment with PE-SU5416 enhanced the pericyte coverage of the tumor vasculature. In addition, tumors treated with PE-SU5416 contained significantly smaller hypoxic regions compared with the nontreated control group, demonstrating that structural normalization of the tumor vasculature resulted in an improvement in tumor vessel functions, including oxygen supply. Furthermore, the pretreatment with PE-SU5416 increased the distribution of PEG liposomes and included PTX in the core region of the tumor, as well as conversely decreasing the ratio of their peripheral distribution. These results suggest that the structural and functional normalization of the tumor vasculature by the pretreatment with PE-SU5416 enabled liposomes to reach the deeper regions within tumor tissues, leading to more potent antitumor activity of PL-PTX