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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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Improved therapeutic activity of SCN-DOX against gliomaxenograft.Mice bearing U-118MG xenografts were injected i.v. with saline, 5 mg/kg of free DOX, SCN-DOX or empty SCN once a week for 6 weeks when tumor volume reached approximately 150 mm3. Data shown are means ± S.E. (n = 5–6). *, P<0.05 compared to saline; **, P<0.01 compared to saline; #, P<0.05 compared to free DOX; ***, P<0.001 compared to free DOX; ##, P<0.05 compared to free DOX; &, P<0.01 compared to blank SCN; &&, P<0.01 compared to blank SCN; &&&, P<0.001 compared to blank SCN.
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pone-0103736-g006: Improved therapeutic activity of SCN-DOX against gliomaxenograft.Mice bearing U-118MG xenografts were injected i.v. with saline, 5 mg/kg of free DOX, SCN-DOX or empty SCN once a week for 6 weeks when tumor volume reached approximately 150 mm3. Data shown are means ± S.E. (n = 5–6). *, P<0.05 compared to saline; **, P<0.01 compared to saline; #, P<0.05 compared to free DOX; ***, P<0.001 compared to free DOX; ##, P<0.05 compared to free DOX; &, P<0.01 compared to blank SCN; &&, P<0.01 compared to blank SCN; &&&, P<0.001 compared to blank SCN.

Mentions: Given our SCN-DOX is able to deliver more therapeutic agents to the xenograft tumor (Figure 5), we proceeded to determine the antitumor activity of SCN-DOX in vivo. Mice bearing U-118MG tumors were injected with saline, blank SCN, DOX in solution or encapsulated within SCN once in a week for 6 weeks when subcutaneous implantation tumors reached a volume of 150 mm3. As shown in Figure 6, there was no significant difference of tumor sizes between mice treated with saline control and blank SCN during the study period. At dose of 5 mg/kg, both DOX formulations were effective in suppressing tumor growth compared to saline and blank liposome control after the 2nd injection. Importantly, tumors grew more rapidly in the mice receiving free DOX when compared with those receiving SCN-DOX. The final mean tumor load was 97.29±10.71 mm3 in SCN-DOX treatment group while in free DOX group was 154.76±12.53 mm3. Thus, SCN-DOX formulations displayed stronger tumor growth suppression than free DOX.


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)

Improved therapeutic activity of SCN-DOX against gliomaxenograft.Mice bearing U-118MG xenografts were injected i.v. with saline, 5 mg/kg of free DOX, SCN-DOX or empty SCN once a week for 6 weeks when tumor volume reached approximately 150 mm3. Data shown are means ± S.E. (n = 5–6). *, P<0.05 compared to saline; **, P<0.01 compared to saline; #, P<0.05 compared to free DOX; ***, P<0.001 compared to free DOX; ##, P<0.05 compared to free DOX; &, P<0.01 compared to blank SCN; &&, P<0.01 compared to blank SCN; &&&, P<0.001 compared to blank SCN.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103736-g006: Improved therapeutic activity of SCN-DOX against gliomaxenograft.Mice bearing U-118MG xenografts were injected i.v. with saline, 5 mg/kg of free DOX, SCN-DOX or empty SCN once a week for 6 weeks when tumor volume reached approximately 150 mm3. Data shown are means ± S.E. (n = 5–6). *, P<0.05 compared to saline; **, P<0.01 compared to saline; #, P<0.05 compared to free DOX; ***, P<0.001 compared to free DOX; ##, P<0.05 compared to free DOX; &, P<0.01 compared to blank SCN; &&, P<0.01 compared to blank SCN; &&&, P<0.001 compared to blank SCN.
Mentions: Given our SCN-DOX is able to deliver more therapeutic agents to the xenograft tumor (Figure 5), we proceeded to determine the antitumor activity of SCN-DOX in vivo. Mice bearing U-118MG tumors were injected with saline, blank SCN, DOX in solution or encapsulated within SCN once in a week for 6 weeks when subcutaneous implantation tumors reached a volume of 150 mm3. As shown in Figure 6, there was no significant difference of tumor sizes between mice treated with saline control and blank SCN during the study period. At dose of 5 mg/kg, both DOX formulations were effective in suppressing tumor growth compared to saline and blank liposome control after the 2nd injection. Importantly, tumors grew more rapidly in the mice receiving free DOX when compared with those receiving SCN-DOX. The final mean tumor load was 97.29±10.71 mm3 in SCN-DOX treatment group while in free DOX group was 154.76±12.53 mm3. Thus, SCN-DOX formulations displayed stronger tumor growth suppression than free DOX.

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