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Coating Solid Lipid Nanoparticles with Hyaluronic Acid Enhances Antitumor Activity against Melanoma Stem-like Cells.

Shen H, Shi S, Zhang Z, Gong T, Sun X - Theranostics (2015)

Bottom Line: First, we developed a model system based on melanoma stem-like cells for experiments in vitro and in mouse xenografts, and we showed that cells expressing high levels of CD44 (CD44(+)) displayed a strong CSC phenotype while cells expressing low levels of CD44 (CD44(-)) did not.In the B16F10-CD44(+) lung metastasis model, PTX-loaded HA-SLNs targeted the tumor-bearing lung tissues well and subsequently exhibited significant antitumor effects with a relative low dose of PTX, which provided significant survival benefit without evidence of adverse events.These findings suggest that the HA-SLNs targeting system shows promise for enhancing cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China.

ABSTRACT
Successful anticancer chemotherapy requires targeting tumors efficiently and further potential to eliminate cancer stem cell (CSC) subpopulations. Since CD44 is present on many types of CSCs, and it binds specially to hyaluronic acid (HA), we tested whether coating solid lipid nanoparticles with hyaluronan (HA-SLNs)would allow targeted delivery of paclitaxel (PTX) to CD44-overexpressing B16F10 melanoma cells. First, we developed a model system based on melanoma stem-like cells for experiments in vitro and in mouse xenografts, and we showed that cells expressing high levels of CD44 (CD44(+)) displayed a strong CSC phenotype while cells expressing low levels of CD44 (CD44(-)) did not. This phenotype included sphere and colony formation, higher proportion of side population cells, expression of CSC-related markers (ALDH, CD133, Oct-4) and tumorigenicity in vivo. Next we showed that administering PTX-loaded HA-SLNs led to efficient intracellular delivery of PTX and induced substantial apoptosis in CD44(+) cells in vitro. In the B16F10-CD44(+) lung metastasis model, PTX-loaded HA-SLNs targeted the tumor-bearing lung tissues well and subsequently exhibited significant antitumor effects with a relative low dose of PTX, which provided significant survival benefit without evidence of adverse events. These findings suggest that the HA-SLNs targeting system shows promise for enhancing cancer therapy.

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A) In vivo assessment of hepatotoxicity of HA-SLNs/PTX. Serum levels of ALT and AST were measured after the six dose of free PTX, SLNs/PTX or HA-SLNs/PTX. B) Serum concentrations of IL-12 at 6 h after intravenous injection of C57BL/6 mice with HA-SLNs/PTX (n = 5). *p < 0.05, **p < 0.01, compared with the group treated with HA-SLNs/PTX.
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Figure 9: A) In vivo assessment of hepatotoxicity of HA-SLNs/PTX. Serum levels of ALT and AST were measured after the six dose of free PTX, SLNs/PTX or HA-SLNs/PTX. B) Serum concentrations of IL-12 at 6 h after intravenous injection of C57BL/6 mice with HA-SLNs/PTX (n = 5). *p < 0.05, **p < 0.01, compared with the group treated with HA-SLNs/PTX.

Mentions: In addition to testing antitumor efficacy of our PTX formulations in vivo, we also examined its ability to induce inflammation and toxic effects. In particular, we investigated its hepatotoxicity, since a relatively large proportion of the drug accumulated in liver (Fig. 7A-C). C57BL/6mice treated with PTX-loaded SLNs showed significantly higher serum levels of the liver enzyme aspartate aminotransferase (AST) than animals treated with PTX-loaded HA/SLNs (p < 0.01, Fig. 9A). In fact, typical signs of hepatic injury were not detectable in mice treated with PTX-loaded HA-SLNs. These results suggest that adsorbing HA onto nanoparticles decreased liver toxicity.


Coating Solid Lipid Nanoparticles with Hyaluronic Acid Enhances Antitumor Activity against Melanoma Stem-like Cells.

Shen H, Shi S, Zhang Z, Gong T, Sun X - Theranostics (2015)

A) In vivo assessment of hepatotoxicity of HA-SLNs/PTX. Serum levels of ALT and AST were measured after the six dose of free PTX, SLNs/PTX or HA-SLNs/PTX. B) Serum concentrations of IL-12 at 6 h after intravenous injection of C57BL/6 mice with HA-SLNs/PTX (n = 5). *p < 0.05, **p < 0.01, compared with the group treated with HA-SLNs/PTX.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4402499&req=5

Figure 9: A) In vivo assessment of hepatotoxicity of HA-SLNs/PTX. Serum levels of ALT and AST were measured after the six dose of free PTX, SLNs/PTX or HA-SLNs/PTX. B) Serum concentrations of IL-12 at 6 h after intravenous injection of C57BL/6 mice with HA-SLNs/PTX (n = 5). *p < 0.05, **p < 0.01, compared with the group treated with HA-SLNs/PTX.
Mentions: In addition to testing antitumor efficacy of our PTX formulations in vivo, we also examined its ability to induce inflammation and toxic effects. In particular, we investigated its hepatotoxicity, since a relatively large proportion of the drug accumulated in liver (Fig. 7A-C). C57BL/6mice treated with PTX-loaded SLNs showed significantly higher serum levels of the liver enzyme aspartate aminotransferase (AST) than animals treated with PTX-loaded HA/SLNs (p < 0.01, Fig. 9A). In fact, typical signs of hepatic injury were not detectable in mice treated with PTX-loaded HA-SLNs. These results suggest that adsorbing HA onto nanoparticles decreased liver toxicity.

Bottom Line: First, we developed a model system based on melanoma stem-like cells for experiments in vitro and in mouse xenografts, and we showed that cells expressing high levels of CD44 (CD44(+)) displayed a strong CSC phenotype while cells expressing low levels of CD44 (CD44(-)) did not.In the B16F10-CD44(+) lung metastasis model, PTX-loaded HA-SLNs targeted the tumor-bearing lung tissues well and subsequently exhibited significant antitumor effects with a relative low dose of PTX, which provided significant survival benefit without evidence of adverse events.These findings suggest that the HA-SLNs targeting system shows promise for enhancing cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China.

ABSTRACT
Successful anticancer chemotherapy requires targeting tumors efficiently and further potential to eliminate cancer stem cell (CSC) subpopulations. Since CD44 is present on many types of CSCs, and it binds specially to hyaluronic acid (HA), we tested whether coating solid lipid nanoparticles with hyaluronan (HA-SLNs)would allow targeted delivery of paclitaxel (PTX) to CD44-overexpressing B16F10 melanoma cells. First, we developed a model system based on melanoma stem-like cells for experiments in vitro and in mouse xenografts, and we showed that cells expressing high levels of CD44 (CD44(+)) displayed a strong CSC phenotype while cells expressing low levels of CD44 (CD44(-)) did not. This phenotype included sphere and colony formation, higher proportion of side population cells, expression of CSC-related markers (ALDH, CD133, Oct-4) and tumorigenicity in vivo. Next we showed that administering PTX-loaded HA-SLNs led to efficient intracellular delivery of PTX and induced substantial apoptosis in CD44(+) cells in vitro. In the B16F10-CD44(+) lung metastasis model, PTX-loaded HA-SLNs targeted the tumor-bearing lung tissues well and subsequently exhibited significant antitumor effects with a relative low dose of PTX, which provided significant survival benefit without evidence of adverse events. These findings suggest that the HA-SLNs targeting system shows promise for enhancing cancer therapy.

Show MeSH
Related in: MedlinePlus