Liposome as a carrier of topotecan (TPT), a promising anticancer drug, has been reported in attempt to improve the stability and antitumor activity of TPT. However, the biodistr ibution pattern of TPT liposome in vivo and PEG-modified liposome containing TPT have not been studied systemically. In th...
Liposome as a carrier of topotecan (TPT), a promising anticancer drug, has been reported in attempt to improve the stability and antitumor activity of TPT. However, the biodistr ibution pattern of TPT liposome in vivo and PEG-modified liposome containing TPT have not been studied systemically. In this paper, the in vitro stability and in vivo biodistribution behavior of several liposomes containing TPT with different lipid compositions and PEG-modification were studied. Compared with the 'fluid' liposome (S-Lip) composed of soybean phosphatidylcholine (SPC), the 'solid' liposome (H-Lip) composed of hydrogenated soybean phosphatidylcholine HSPC decreased the leaking efficiency of TPT from liposome and enhanced the stability of liposome in fetal bovine serum (FBS) or human blood plasma (HBP). The results of biodistribution studies in S$_{180}$ tumor-bearing mice showed that liposomal encapsulation increased the concentrations of total TPT and the ratio of lactone form in plasma. Compared with free TPT, S-Lip and H-Lip resulted in 5- and 19- fold increase in the area under the curve (AUC$_{0\rightarrow\propto}$), respectively. PEG- modified H-Lip (H-PEG) showed 3.7-fold increase in AUC$_{0\rightarrow\propto}$ compared with H-Lip, but there was no significant increase in t$_{1/2}$ and AUC$_{0\rightarrow\propto}$ for PEG-modified S-Lip (S-PEG) compared with S-Lip. Moreover, the liposomal encapsulation changed the biodistribution behavior, and H-Lip and H-PEG dramatically increased the accumulation of TPT in tumor, and the relative tumor uptake ratios were 3.4 and 4.3 compared with free drug, respectively. There was also a marked increase in the distribution of TPT in lung when the drug was encapsulated into H-Lip and H-PEG. Moreover, H-PEG decreased the accumulation of TPT in bore marrow compared with unmodified H-Lip. All these results indicated that the membrane fluidity of liposome has an important effect on in vitro stability and in vivo biodistribution pattern of liposomes containing TPT, and PEG-modified 'solid' liposome may be an efficient carrier of TPT.
Liposome as a carrier of topotecan (TPT), a promising anticancer drug, has been reported in attempt to improve the stability and antitumor activity of TPT. However, the biodistr ibution pattern of TPT liposome in vivo and PEG-modified liposome containing TPT have not been studied systemically. In this paper, the in vitro stability and in vivo biodistribution behavior of several liposomes containing TPT with different lipid compositions and PEG-modification were studied. Compared with the 'fluid' liposome (S-Lip) composed of soybean phosphatidylcholine (SPC), the 'solid' liposome (H-Lip) composed of hydrogenated soybean phosphatidylcholine HSPC decreased the leaking efficiency of TPT from liposome and enhanced the stability of liposome in fetal bovine serum (FBS) or human blood plasma (HBP). The results of biodistribution studies in S$_{180}$ tumor-bearing mice showed that liposomal encapsulation increased the concentrations of total TPT and the ratio of lactone form in plasma. Compared with free TPT, S-Lip and H-Lip resulted in 5- and 19- fold increase in the area under the curve (AUC$_{0\rightarrow\propto}$), respectively. PEG- modified H-Lip (H-PEG) showed 3.7-fold increase in AUC$_{0\rightarrow\propto}$ compared with H-Lip, but there was no significant increase in t$_{1/2}$ and AUC$_{0\rightarrow\propto}$ for PEG-modified S-Lip (S-PEG) compared with S-Lip. Moreover, the liposomal encapsulation changed the biodistribution behavior, and H-Lip and H-PEG dramatically increased the accumulation of TPT in tumor, and the relative tumor uptake ratios were 3.4 and 4.3 compared with free drug, respectively. There was also a marked increase in the distribution of TPT in lung when the drug was encapsulated into H-Lip and H-PEG. Moreover, H-PEG decreased the accumulation of TPT in bore marrow compared with unmodified H-Lip. All these results indicated that the membrane fluidity of liposome has an important effect on in vitro stability and in vivo biodistribution pattern of liposomes containing TPT, and PEG-modified 'solid' liposome may be an efficient carrier of TPT.
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제안 방법
intravenous administration was still not clear. In this study, we prepared the liposomes containing TPT by ammonium sulfate gradient method and examined the effect of the membrane fluidity of liposomes on the in vitro release and biodistribution of TPT Liposomes were prepared with unsaturated soybean phosphatidylcholine (SPC) which has a phase transition temperature (Tc) lower than body temperature, and hydrogenated soybean phosphatidylcholine (HSPC) which has a higher phase transition temperature than body temperature. Furthermore, in order to increase the accumulation of liposomal TPT in tumor, the PEG-modified liposomes were also prepared.
The unencapsulated topotecan was separated from liposome by a Sephadex G-50 column, and the content of drug encapsulated into liposome was determined, then the encapsulation efficiency was calculated. Mean size of vesicle was determined using a Laser Diffraction Particle Size Analyzers (LS 230, Beckman Coulter, Inc.
대상 데이터
The mobile phases were filtered and degassed prior to use. The fluorescence spectrofluorometric detector (excitation wavelength 380 nm, emission wavelength 525 nm) was used.
데이터처리
0 was used to calculate the area under the concentration-time curve from time zero to time t (AUCM) value of TPT in various tissues. Students's f-test was performed to compare the parameters between the different groups. Statistically significant differences were assumed when P<0.
성능/효과
Compared with S-Lip, H-up resulted in a sustained release. After 48 h incubation with FBS, TPT percentage retained in H-lip was 76.42% and higher than that in S-Lip (30.56%). The leaking efficiency of H-Lip in plasma was also lower than that of S-Lip, and only 9.
This is because that liposome could avoid TPT to be cleared rapidly in vivo and increase the stability of TPT, thus improving the drug accumulation in marrow when administered at same dose with free drug. However, PEG-modified liposomes decreased the distribution of TPT in bone marrow, and the AUC of S-PEG and H-PEG all decreased approximately one time compared with unmodified liposomes, It indicated that liposome encapsulation might increase the toxicity of TPT while it increases the antitumor activity of TPT. While PEG modified liposome may provide better tumor target ability for TPT and not increase its myelosuppression toxicity.
In conclusion, the liposomal encapsulation improved the stability of TPT and changed its distribution pattern in vivo. The membrane fluidity of liposome has effect on the in vitro and in vivo behavior of TPT liposome.
Thus, for SPC or 너SPC liposomes with equivalent cholesterol, hydrogenated SPC having saturated fatty acid residues and a chain melting transition temperature above 37℃ may be the possible reason of higher stability in vitro for H-Lip compared with S-Lip. Moreover, from our results, the PEG modification did not affect the stability of liposomes in different medium, and there was no significant difference for the release rate of TPT from S-PEG (or 너-PEG) and 니emodified S-Lip (or H-Lip). These results provided the foundation for the following study in vivo.
05). The results were in accordance with the in vitro release characteristics, and PEG-modified SPC liposome did not increase the plasma concentration and half-life time of TPT in vivo. In comparison with other liposomal formulations, PEG-modified 니SPC liposome of TPT has the relatively 이ow 이earance and good stability in vivo.
2 mL) in the right axillary region of the mice for the tumor disteibution shjdy. The tumors were grown until approximat이y 2000 mm3 (2043.6 ± 253.6 mm3, RSD<15%) in size after one week of implantation. The animals were then sorted according to body weight, with three animals per cage.
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