Abstract
This study reports on the cellular uptake of folate tethered micelles using a branched skeleton of poly(ethylene glycol) and poly(ε-caprolactone). The chemical structures of the copolymers were characterized by proton nuclear magnetic resonance spectroscopy, and Fourier transform infrared spectroscopy. Doxorubicin (DOX) was utilized as an anticancer drug. The highest drug loading efficiencies of DOX in the folate decorated micelle (DMCF) and folate-free micelle (DMC) were found to be 88.5% and 88.2%, respectively, depending on the segment length of the poly(ε-caprolactone) in the copolymers. A comparison of fluorescent microscopic images of the endocytosis pathway in two cell lines, human breast cancer cells (MCF-7) and human oral cavity carcinoma cells (KB), revealed that the micelles were engulfed by KB and MCF-7 cells following in vitro incubation for one hour. Flow cytometric analysis revealed that free folic acid can inhibit the uptake of DOX by 48%–57% and 26%–39% in KB cells and MCF-7 cells, respectively. These results prove that KB cells are relatively sensitive to folate-tethered micelles. Upon administering methyl-β-cyclodextrin, an inhibitor of the caveolae-mediated endocytosis pathway, the uptake of DOX by KB cells was reduced by 69% and that by MCF-7 cells was reduced by 56%. This finding suggests that DMCF enters cells via multiple pathways, thus implying that the folate receptor is not the only target of tumor therapeutics.
Highlights
Conventional nanocarriers are associated with systemic toxicity and poor bioavailability of anti-tumor drugs because they have undesired specificity
Folic acid was conjugated with poly (D,L-lactic-co-glycolic acid)-poly(ethylene glycol), poly(L-histidine-co-L-phenlyalanine-b-polyethylene glycol (PEG) and poly(L-lactic acid)-bPEG-folate [10], and such conjugation was demonstrated to enhance doxorubicin and paclitaxel delivery to folate receptor-expressing cancer cells in vitro and in vivo
These star-shaped copolymers were conjugated with folic acid using DMAP and DCC
Summary
Conventional nanocarriers are associated with systemic toxicity and poor bioavailability of anti-tumor drugs because they have undesired specificity. Cellular uptake of folate is increased by a reduced folate carrier and/or the proton-coupled folate transporter or the glycosylphosphatidylinositol-linked folate receptor [5]. To exploit these effects, folic acid was conjugated with macromolecules [6], liposomes [7] or nanoparticles [8,9] to target malignant cells with the drug molecules. More detailed knowledge of the cellular uptake and cell internalization mechanism is required because each pathway has its own characteristics, which should be taken into account in the optimization of drug delivery systems. Understanding the detailed mechanism of cellular uptake is an important step towards understanding the biological fate of nanoparticles, both adverse and favorable aspects
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
