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Improved efficacy and reduced toxicity of doxorubicin encapsulated in sulfatide-containing nanoliposome in a glioma model.

Lin J, Shigdar S, Fang DZ, Xiang D, Wei MQ, Danks A, Kong L, Li L, Qiao L, Duan W - PLoS ONE (2014)

Bottom Line: This simple two-lipid SCN-DOX nanodrug has favourable pharmacokinetic attributes in terms of prolonged circulation time, reduced volume of distribution and enhanced bioavailability in healthy rats.As a result of the improved biodistribution, an enhanced treatment efficacy of SCN-DOX was found in glioma-bearing mice compared to the free drug.Thus, SCN has the potential to be an effective and safer nano-carrier for targeted delivery of therapeutic agents to tumors with elevated expression of tenascin-C in their microenvironment.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria, Australia; Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P. R. China.

ABSTRACT
As a glycosphingolipid that can bind to several extracellular matrix proteins, sulfatide has the potential to become an effective targeting agent for tumors overexpressing tenasin-C in their microenvironment. To overcome the dose-limiting toxicity of doxorubicin (DOX), a sulfatide-containing nanoliposome (SCN) encapsulation approach was employed to improve treatment efficacy and reduce side effects of free DOX. This study analysed in vitro characteristics of sulfatide-containing nanoliposomal DOX (SCN-DOX) and assessed its cytotoxicity in vitro, as well as biodistribution, therapeutic efficacy, and systemic toxicity in a human glioblastoma U-118MG xenograft model. SCN-DOX was shown to achieve highest drug to lipid ratio (0.5∶1) and a remarkable in vitro stability. Moreover, DOX encapsulated in SCN was shown to be delivered into the nuclei and displayed prolonged retention over free DOX in U-118MG cells. This simple two-lipid SCN-DOX nanodrug has favourable pharmacokinetic attributes in terms of prolonged circulation time, reduced volume of distribution and enhanced bioavailability in healthy rats. As a result of the improved biodistribution, an enhanced treatment efficacy of SCN-DOX was found in glioma-bearing mice compared to the free drug. Finally, a reduction in the accumulation of DOX in the drug's principal toxicity organs achieved by SCN-DOX led to the diminished systemic toxicity as evident from the plasma biochemical analyses. Thus, SCN has the potential to be an effective and safer nano-carrier for targeted delivery of therapeutic agents to tumors with elevated expression of tenascin-C in their microenvironment.

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Biodistribution and tumor uptake of DOX encapsulated in SCN in glioma-bearing mice.Nude mice bearing human glioblastomaU-118MGxenografts (s.c.) were treated with 5 mg/kg free DOX or SCN-DOX i.v. once a week for 6 weeks. Mice were euthanized 24 hours after the last treatment. Organs and tissues were harvested, washed, weighed, and the DOX content in tissues, expressed as µg DOX per g tissue, was determined. Data are shown as means ± S.E. (n = 5–6). *, P<0.05 compared to free DOX; **, P<0.01 compared to free DOX; ***, P<0.001 compared to free DOX.
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pone-0103736-g005: Biodistribution and tumor uptake of DOX encapsulated in SCN in glioma-bearing mice.Nude mice bearing human glioblastomaU-118MGxenografts (s.c.) were treated with 5 mg/kg free DOX or SCN-DOX i.v. once a week for 6 weeks. Mice were euthanized 24 hours after the last treatment. Organs and tissues were harvested, washed, weighed, and the DOX content in tissues, expressed as µg DOX per g tissue, was determined. Data are shown as means ± S.E. (n = 5–6). *, P<0.05 compared to free DOX; **, P<0.01 compared to free DOX; ***, P<0.001 compared to free DOX.

Mentions: Next, we investigated the ability of SCN-DOX to enhance the delivery of therapeutic agents to tumor in vivo using a mouse tumor xenograft model. Mice bearing U-118MG tumors were administrated intravenously with5 mg/kg free DOX or SCN-DOX once in a week for 6 weeks when subcutaneous implantation tumors reached a volume of 150 mm3.The uptake of DOX in various organs and tumor was determined 24 h after the last injection. Consistent with the results from the study in healthy SD rats in the preceding section, the DOX concentration in organ responsible for dose-limiting toxicity in clinics, i.e. the heart, in the tumor-bearing mice treated with SCN-DOX was significantly lower than those treated with free DOX (0.81±0.07 µg/g versus 1.45±0.17 µg/g) (Figure 5A). The DOX concentration in the other known major DOX toxicity organ, the skin, was also statistically significantly lower in the SCN-DOX group compared to the free DOX animals (∼15 fold lower), so as in the kidneys (28.05±2.67 versus 20.91±0.82 µg/g) (Figure 5C and 5E). On the other hand, there were significantly higher levels of DOX in the liver, spleen and lung in the groups treated with SCN-DOX when compared to the free DOX group (6.10-fold, 3.16-fold and 1.22-fold, respectively) (Figure 5B and 5E).However, at least in the case of the liver, the increased accumulation of DOX via SCN-DOX delivery did not seem to translate into enhanced hepatic toxicity (see below).As for the xenograft glioma (Figure 5D), there was a statistically significant elevation of DOX level in tumor tissue in the SCN-DOX group compared to that of free DOX (1.30-fold), confirming the enhanced intratumoral DOX delivery by SCN-DOX in vivo.


Improved efficacy and reduced toxicity of doxorubicin encapsulated in sulfatide-containing nanoliposome in a glioma model.

Lin J, Shigdar S, Fang DZ, Xiang D, Wei MQ, Danks A, Kong L, Li L, Qiao L, Duan W - PLoS ONE (2014)

Biodistribution and tumor uptake of DOX encapsulated in SCN in glioma-bearing mice.Nude mice bearing human glioblastomaU-118MGxenografts (s.c.) were treated with 5 mg/kg free DOX or SCN-DOX i.v. once a week for 6 weeks. Mice were euthanized 24 hours after the last treatment. Organs and tissues were harvested, washed, weighed, and the DOX content in tissues, expressed as µg DOX per g tissue, was determined. Data are shown as means ± S.E. (n = 5–6). *, P<0.05 compared to free DOX; **, P<0.01 compared to free DOX; ***, P<0.001 compared to free DOX.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4114873&req=5

pone-0103736-g005: Biodistribution and tumor uptake of DOX encapsulated in SCN in glioma-bearing mice.Nude mice bearing human glioblastomaU-118MGxenografts (s.c.) were treated with 5 mg/kg free DOX or SCN-DOX i.v. once a week for 6 weeks. Mice were euthanized 24 hours after the last treatment. Organs and tissues were harvested, washed, weighed, and the DOX content in tissues, expressed as µg DOX per g tissue, was determined. Data are shown as means ± S.E. (n = 5–6). *, P<0.05 compared to free DOX; **, P<0.01 compared to free DOX; ***, P<0.001 compared to free DOX.
Mentions: Next, we investigated the ability of SCN-DOX to enhance the delivery of therapeutic agents to tumor in vivo using a mouse tumor xenograft model. Mice bearing U-118MG tumors were administrated intravenously with5 mg/kg free DOX or SCN-DOX once in a week for 6 weeks when subcutaneous implantation tumors reached a volume of 150 mm3.The uptake of DOX in various organs and tumor was determined 24 h after the last injection. Consistent with the results from the study in healthy SD rats in the preceding section, the DOX concentration in organ responsible for dose-limiting toxicity in clinics, i.e. the heart, in the tumor-bearing mice treated with SCN-DOX was significantly lower than those treated with free DOX (0.81±0.07 µg/g versus 1.45±0.17 µg/g) (Figure 5A). The DOX concentration in the other known major DOX toxicity organ, the skin, was also statistically significantly lower in the SCN-DOX group compared to the free DOX animals (∼15 fold lower), so as in the kidneys (28.05±2.67 versus 20.91±0.82 µg/g) (Figure 5C and 5E). On the other hand, there were significantly higher levels of DOX in the liver, spleen and lung in the groups treated with SCN-DOX when compared to the free DOX group (6.10-fold, 3.16-fold and 1.22-fold, respectively) (Figure 5B and 5E).However, at least in the case of the liver, the increased accumulation of DOX via SCN-DOX delivery did not seem to translate into enhanced hepatic toxicity (see below).As for the xenograft glioma (Figure 5D), there was a statistically significant elevation of DOX level in tumor tissue in the SCN-DOX group compared to that of free DOX (1.30-fold), confirming the enhanced intratumoral DOX delivery by SCN-DOX in vivo.

Bottom Line: This simple two-lipid SCN-DOX nanodrug has favourable pharmacokinetic attributes in terms of prolonged circulation time, reduced volume of distribution and enhanced bioavailability in healthy rats.As a result of the improved biodistribution, an enhanced treatment efficacy of SCN-DOX was found in glioma-bearing mice compared to the free drug.Thus, SCN has the potential to be an effective and safer nano-carrier for targeted delivery of therapeutic agents to tumors with elevated expression of tenascin-C in their microenvironment.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria, Australia; Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P. R. China.

ABSTRACT
As a glycosphingolipid that can bind to several extracellular matrix proteins, sulfatide has the potential to become an effective targeting agent for tumors overexpressing tenasin-C in their microenvironment. To overcome the dose-limiting toxicity of doxorubicin (DOX), a sulfatide-containing nanoliposome (SCN) encapsulation approach was employed to improve treatment efficacy and reduce side effects of free DOX. This study analysed in vitro characteristics of sulfatide-containing nanoliposomal DOX (SCN-DOX) and assessed its cytotoxicity in vitro, as well as biodistribution, therapeutic efficacy, and systemic toxicity in a human glioblastoma U-118MG xenograft model. SCN-DOX was shown to achieve highest drug to lipid ratio (0.5∶1) and a remarkable in vitro stability. Moreover, DOX encapsulated in SCN was shown to be delivered into the nuclei and displayed prolonged retention over free DOX in U-118MG cells. This simple two-lipid SCN-DOX nanodrug has favourable pharmacokinetic attributes in terms of prolonged circulation time, reduced volume of distribution and enhanced bioavailability in healthy rats. As a result of the improved biodistribution, an enhanced treatment efficacy of SCN-DOX was found in glioma-bearing mice compared to the free drug. Finally, a reduction in the accumulation of DOX in the drug's principal toxicity organs achieved by SCN-DOX led to the diminished systemic toxicity as evident from the plasma biochemical analyses. Thus, SCN has the potential to be an effective and safer nano-carrier for targeted delivery of therapeutic agents to tumors with elevated expression of tenascin-C in their microenvironment.

Show MeSH
Related in: MedlinePlus