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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-C) Biodistribution of PTX in various tissues at 1, 2 and 6 h after intravenous administration of different PTX formulations (n = 3). D) Biodistribution of PTX at 1 h after injection of HA-SLNs/PTX following pretreatment with a high dose of free HA. E) Representative ex vivo fluorescence imaging and confocal laser scanning microscopy of sections of tumor-bearing lung from mice treated with different drug formulations. Mice were injected intravenously SLNs/PTX and HA-SLNs/PTX (PTX represented by DID, red). After 2 h injection, mice were sacrificed and lungs removed. Tissue was frozen, fixed in 4% paraformaldehyde and stained with FITC-labeled anti-CD44 monoclonal antibody (green) and DAPI (blue). Scale bar, 30 μm. F) Flow cytometry detection of drug (DID) in B16F10-CD44+ cells in tumor-bearing lungs from C57BL/6 mice intravenously injected with DID (PTX) loaded SLNs/PTX and HA-SLNs/PTX. Animals were sacrificed at 2 h after i.v. injection and tumor-bearing lungs were lapped to single cell suspensions. The suspensions were incubated for 30 min at 4°C with FITC-labeled anti-CD44 monoclonal antibody, then analyzed by flow cytometry (n = 3). *p < 0.05, **p < 0.01, for comparisons of HA-SLNs/PTX with other groups (PTX, SLNs/PTX, heparin-SLNs/PTX).
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Figure 7: A-C) Biodistribution of PTX in various tissues at 1, 2 and 6 h after intravenous administration of different PTX formulations (n = 3). D) Biodistribution of PTX at 1 h after injection of HA-SLNs/PTX following pretreatment with a high dose of free HA. E) Representative ex vivo fluorescence imaging and confocal laser scanning microscopy of sections of tumor-bearing lung from mice treated with different drug formulations. Mice were injected intravenously SLNs/PTX and HA-SLNs/PTX (PTX represented by DID, red). After 2 h injection, mice were sacrificed and lungs removed. Tissue was frozen, fixed in 4% paraformaldehyde and stained with FITC-labeled anti-CD44 monoclonal antibody (green) and DAPI (blue). Scale bar, 30 μm. F) Flow cytometry detection of drug (DID) in B16F10-CD44+ cells in tumor-bearing lungs from C57BL/6 mice intravenously injected with DID (PTX) loaded SLNs/PTX and HA-SLNs/PTX. Animals were sacrificed at 2 h after i.v. injection and tumor-bearing lungs were lapped to single cell suspensions. The suspensions were incubated for 30 min at 4°C with FITC-labeled anti-CD44 monoclonal antibody, then analyzed by flow cytometry (n = 3). *p < 0.05, **p < 0.01, for comparisons of HA-SLNs/PTX with other groups (PTX, SLNs/PTX, heparin-SLNs/PTX).

Mentions: Mice were injected intravenously with free PTX or with one of three types of PTX-loaded nanoparticles: SLNs, heparin-SLNs or HA-SLNs. Then the biodistribution of PTX was compared among the different conditions (Fig. 7A-C). PTX accumulated in the lungs to a greater extent when delivered in SLNs than when delivered as free drug, and the accumulation was significantly greater with PTX-loaded HA-SLNs than with any other drug formulation at all time points (p < 0.01). Our finding that accumulation was similar for SLNs and heparin-SLNs reinforces our in vitro evidence that coating nanoparticles with HA improves tumor targeting efficiency.


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-C) Biodistribution of PTX in various tissues at 1, 2 and 6 h after intravenous administration of different PTX formulations (n = 3). D) Biodistribution of PTX at 1 h after injection of HA-SLNs/PTX following pretreatment with a high dose of free HA. E) Representative ex vivo fluorescence imaging and confocal laser scanning microscopy of sections of tumor-bearing lung from mice treated with different drug formulations. Mice were injected intravenously SLNs/PTX and HA-SLNs/PTX (PTX represented by DID, red). After 2 h injection, mice were sacrificed and lungs removed. Tissue was frozen, fixed in 4% paraformaldehyde and stained with FITC-labeled anti-CD44 monoclonal antibody (green) and DAPI (blue). Scale bar, 30 μm. F) Flow cytometry detection of drug (DID) in B16F10-CD44+ cells in tumor-bearing lungs from C57BL/6 mice intravenously injected with DID (PTX) loaded SLNs/PTX and HA-SLNs/PTX. Animals were sacrificed at 2 h after i.v. injection and tumor-bearing lungs were lapped to single cell suspensions. The suspensions were incubated for 30 min at 4°C with FITC-labeled anti-CD44 monoclonal antibody, then analyzed by flow cytometry (n = 3). *p < 0.05, **p < 0.01, for comparisons of HA-SLNs/PTX with other groups (PTX, SLNs/PTX, heparin-SLNs/PTX).
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Figure 7: A-C) Biodistribution of PTX in various tissues at 1, 2 and 6 h after intravenous administration of different PTX formulations (n = 3). D) Biodistribution of PTX at 1 h after injection of HA-SLNs/PTX following pretreatment with a high dose of free HA. E) Representative ex vivo fluorescence imaging and confocal laser scanning microscopy of sections of tumor-bearing lung from mice treated with different drug formulations. Mice were injected intravenously SLNs/PTX and HA-SLNs/PTX (PTX represented by DID, red). After 2 h injection, mice were sacrificed and lungs removed. Tissue was frozen, fixed in 4% paraformaldehyde and stained with FITC-labeled anti-CD44 monoclonal antibody (green) and DAPI (blue). Scale bar, 30 μm. F) Flow cytometry detection of drug (DID) in B16F10-CD44+ cells in tumor-bearing lungs from C57BL/6 mice intravenously injected with DID (PTX) loaded SLNs/PTX and HA-SLNs/PTX. Animals were sacrificed at 2 h after i.v. injection and tumor-bearing lungs were lapped to single cell suspensions. The suspensions were incubated for 30 min at 4°C with FITC-labeled anti-CD44 monoclonal antibody, then analyzed by flow cytometry (n = 3). *p < 0.05, **p < 0.01, for comparisons of HA-SLNs/PTX with other groups (PTX, SLNs/PTX, heparin-SLNs/PTX).
Mentions: Mice were injected intravenously with free PTX or with one of three types of PTX-loaded nanoparticles: SLNs, heparin-SLNs or HA-SLNs. Then the biodistribution of PTX was compared among the different conditions (Fig. 7A-C). PTX accumulated in the lungs to a greater extent when delivered in SLNs than when delivered as free drug, and the accumulation was significantly greater with PTX-loaded HA-SLNs than with any other drug formulation at all time points (p < 0.01). Our finding that accumulation was similar for SLNs and heparin-SLNs reinforces our in vitro evidence that coating nanoparticles with HA improves tumor targeting efficiency.

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