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Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS-mixed micelles on targeted delivery of anticancer drugs.

Butt AM, Mohd Amin MC, Katas H - Int J Nanomedicine (2015)

Bottom Line: TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells.Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization.The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX-DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX.

View Article: PubMed Central - PubMed

Affiliation: Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

ABSTRACT

Background: Doxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407) and vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate, TPGS) are widely used polymers as drug delivery carriers and excipients for enhancing the drug retention times and stability. TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells. Keeping in view the problems, we designed a mixed micelle system encapsulating DOX comprising TPGS for its selective anticancer activity and P407 conjugated with folic acid (FA) for folate-mediated receptor targeting to cancer cells.

Methods: FA-functionalized P407 was prepared by carbodiimide crosslinker chemistry. P407-TPGS/FA-P407-TPGS-mixed micelles were prepared by thin-film hydration method. Cytotoxicity of blank micelles, DOX, and DOX-loaded micelles was determined by alamarBlue(®) assay.

Results: The size of micelles was less than 200 nm with encapsulation efficiency of 85% and 73% for P407-TPGS and FA-P407-TPGS micelles, respectively. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX-DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX.

Conclusion: FA-P407-TPGS-DOX micelles show potential as a targeted nano-drug delivery system for DOX due to their multiple synergistic factors of selective anticancer activity, inhibition of multidrug resistance, and folate-mediated selective uptake.

No MeSH data available.


Related in: MedlinePlus

Synthesis of FA-P407 conjugate.Notes: FA and P407 were conjugated by CDI-mediated coupling, purified by dialysis, and recovered by freeze drying.Abbreviations: FA, folic acid; P407, poloxamer 407; CDI, 1,1′-carbonyldiimidazole; DMSO, dimethyl sulfoxide.
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f2-ijn-10-1321: Synthesis of FA-P407 conjugate.Notes: FA and P407 were conjugated by CDI-mediated coupling, purified by dialysis, and recovered by freeze drying.Abbreviations: FA, folic acid; P407, poloxamer 407; CDI, 1,1′-carbonyldiimidazole; DMSO, dimethyl sulfoxide.

Mentions: The synthesis of FA-conjugated P407 (FA-P407) is shown in Figure 2. Firstly, FA was dissolved in DMSO for overnight in a two-neck flask. CDI was then added into the solution, and the reaction mixture was stirred overnight under nitrogen atmosphere and protected from light. P407 was then added, and the reaction was stirred continuously for 24 hours under similar conditions. After the reaction completed, the mixture was dialyzed against deionized water for up to 5 days in order to remove any un-reacted FA. To recover the FA-P407 conjugate, the dialyzed solution was then freeze dried.


Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS-mixed micelles on targeted delivery of anticancer drugs.

Butt AM, Mohd Amin MC, Katas H - Int J Nanomedicine (2015)

Synthesis of FA-P407 conjugate.Notes: FA and P407 were conjugated by CDI-mediated coupling, purified by dialysis, and recovered by freeze drying.Abbreviations: FA, folic acid; P407, poloxamer 407; CDI, 1,1′-carbonyldiimidazole; DMSO, dimethyl sulfoxide.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4335624&req=5

f2-ijn-10-1321: Synthesis of FA-P407 conjugate.Notes: FA and P407 were conjugated by CDI-mediated coupling, purified by dialysis, and recovered by freeze drying.Abbreviations: FA, folic acid; P407, poloxamer 407; CDI, 1,1′-carbonyldiimidazole; DMSO, dimethyl sulfoxide.
Mentions: The synthesis of FA-conjugated P407 (FA-P407) is shown in Figure 2. Firstly, FA was dissolved in DMSO for overnight in a two-neck flask. CDI was then added into the solution, and the reaction mixture was stirred overnight under nitrogen atmosphere and protected from light. P407 was then added, and the reaction was stirred continuously for 24 hours under similar conditions. After the reaction completed, the mixture was dialyzed against deionized water for up to 5 days in order to remove any un-reacted FA. To recover the FA-P407 conjugate, the dialyzed solution was then freeze dried.

Bottom Line: TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells.Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization.The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX-DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX.

View Article: PubMed Central - PubMed

Affiliation: Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

ABSTRACT

Background: Doxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407) and vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate, TPGS) are widely used polymers as drug delivery carriers and excipients for enhancing the drug retention times and stability. TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells. Keeping in view the problems, we designed a mixed micelle system encapsulating DOX comprising TPGS for its selective anticancer activity and P407 conjugated with folic acid (FA) for folate-mediated receptor targeting to cancer cells.

Methods: FA-functionalized P407 was prepared by carbodiimide crosslinker chemistry. P407-TPGS/FA-P407-TPGS-mixed micelles were prepared by thin-film hydration method. Cytotoxicity of blank micelles, DOX, and DOX-loaded micelles was determined by alamarBlue(®) assay.

Results: The size of micelles was less than 200 nm with encapsulation efficiency of 85% and 73% for P407-TPGS and FA-P407-TPGS micelles, respectively. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX-DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX.

Conclusion: FA-P407-TPGS-DOX micelles show potential as a targeted nano-drug delivery system for DOX due to their multiple synergistic factors of selective anticancer activity, inhibition of multidrug resistance, and folate-mediated selective uptake.

No MeSH data available.


Related in: MedlinePlus