Bio-functional micelles self-assembled from a folate-conjugated block copolymer for targeted intracellular delivery of anticancer drugs

Liu, Shaoqiong; Wiradharma, Nikken; Gao, Shujun; Tong, Yen Wah; Yang, Yi-Yan

doi:10.1016/j.biomaterials.2006.11.013

Cited by 188 publications

(108 citation statements)

References 19 publications

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“…31,41 Aliquots of pyrene solution (6×10 −6 M, 1 mL) in acetone were added to volumetric flasks and the acetone was removed by vacuum drying followed by mixing with blank mixed micelle solutions dispersed in PBS (pH 7.4, 6.5, 5.0) with concentrations ranging from 1×10 −4 mg/mL to 1×10 −1 mg/mL. The final pyrene concentration in the copolymer solution was fixed at 6×10 −7 mol/L.…”

Section: Characterization Of Mixed Micellesmentioning

confidence: 99%

pH-sensitive and folic acid-targeted MPEG-PHIS/FA-PEG-VE mixed micelles for the delivery of PTX-VE and their antitumor activity

Yan¹,

Li²,

Zhu³

et al. 2017

IJN

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The aim of this study was to simultaneously introduce pH sensitivity and folic acid (FA) targeting into a micelle system to achieve quick drug release and to enhance its accumulation in tumor cells. Paclitaxel-(+)-α-tocopherol (PTX-VE)-loaded mixed micelles (PHIS/FA/PM) fabricated by poly(ethylene glycol) methyl ether-poly(histidine) (MPEG-PHIS) and folic acid-poly(ethylene glycol)-(+)-α-tocopherol (FA-PEG-VE) were characterized by dynamic light scattering and transmission electron microscopy (TEM). The mixed micelles had a spherical morphology with an average diameter of 137.0±6.70 nm and a zeta potential of −48.7±4.25 mV. The drug encapsulation and loading efficiencies were 91.06%±2.45% and 5.28%±0.30%, respectively. The pH sensitivity was confirmed by changes in particle size, critical micelle concentration, and transmittance as a function of pH. MTT assay showed that PHIS/FA/PM had higher cytotoxicity at pH 6.0 than at pH 7.4, and lower cytotoxicity in the presence of free FA. Confocal laser scanning microscope images demonstrated a time-dependent and FA-inhibited cellular uptake. In vivo imaging confirmed that the mixed micelles targeted accumulation at tumor sites and the tumor inhibition rate was 85.97%. The results proved that the mixed micelle system fabricated by MPEG-PHIS and FA-PEG-VE is a promising approach to improve antitumor efficacy.

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Section: Characterization Of Mixed Micellesmentioning

confidence: 99%

pH-sensitive and folic acid-targeted MPEG-PHIS/FA-PEG-VE mixed micelles for the delivery of PTX-VE and their antitumor activity

Yan¹,

Li²,

Zhu³

et al. 2017

IJN

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“…In tumor treatment the micelles system has proven effective in regression of tumor size while minimizing damage to the healthy tissues [4] and is being actively investigated in conjunction with hyperthermia [5], ultrasound [6], specific enzyme-induced cleavable bonds [7][8][9], and specific ligands or antibodies [10][11][12][13] for active targeting purposes.…”

Section: Introductionmentioning

confidence: 99%

Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)

Lee

Kim

et al. 2007

Journal of Controlled Release

420

267

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Polymeric micelles were constructed from poly(L-lactic acid) (PLA; M n 3K)-b-poly(ethylene glycol) (PEG; M n 2K)-b-poly(L-histidine) (polyHis; M n 5K) as a tumor pH-specific anticancer drug carrier. Micelles (particle diameter: ~ 80 nm; critical micelle concentration (CMC): 2 µg/ml) formed by dialysis of the polymer solution in dimethylsulfoxide (DMSO) against pH 8.0 aqueous solution, are assumed to have a flower-like assembly of PLA and polyHis blocks in the core and PEG block as the shell. The pH-sensitivity of the micelles originates from the deformation of the micellar core due to the ionization of polyHis at a slightly acidic pH. However, the co-presence of pH-insensitive lipophilic PLA block in the core prevented disintegration of the micelles and caused swelling/ aggregation. A fluorescence probe study showed that the polarity of pyrene retained in the micelles increased as pH was decreased from 7.4 to 6.6, indicating a change to a more hydrophilic environment in the micelles. Considering that the size increased up to 580 nm at pH 6.6 from 80 nm at pH 7.4 and that the transmittance of micellar solution increased with decreasing pH, the micelles were not dissociated but rather swollen/aggregated. Interestingly, the subsequent decline of pyrene polarity below pH 6.6 suggested re-self-assembly of the block copolymers, most likely forming a PLA block core while polyHis block relocation to the surface. Consequently, these pH-dependent physical changes of the PLA-b-PEG-b-polyHis micelles provide a mechanism for triggered drug release from the micelles triggered by the small change in pH (pH 7.2-6.5).

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“…As presented in Figure 6, KB cells that were exposed to DOX-loaded 4SPCL-PEG-Folic micelles exhibited a higher fluorescence intensity of DOX than did MCF-7 cells. Strong DOX fluorescence was observed in the cytoplasm, revealing that the DOX-loaded micelles were internalized by the cells via endocytosis and that DOX was distributed throughout the cytoplasm after escaping from the endosome and/or the lysosome [3,32]. Furthermore, the DOX-loaded 4SPCL-PEG-Folic micelles had a greater fluorescence intensity than the DOX-loaded 4SPCL-PEG micelles in KB and MCF-7 cells.…”

Section: Flow Cytometrymentioning

confidence: 96%

“…Folate receptor (FR) is a membrane-bound protein with high affinity for binding and transporting physiological levels of folate into cells. FR is over-expressed in the apical membrane surface of certain cancer cells including ovary, kidney, uterus, colon, and lung, making a potential target for tumor therapeutics [2][3][4]. 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].…”

Section: Introductionmentioning

confidence: 99%

Endocytosis Pathways of the Folate Tethered Star-Shaped PEG-PCL Micelles in Cancer Cell Lines

Nguyen

Hsieh

2014

Polymers

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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, OPEN ACCESSPolymers 2014, 6 635 thus implying that the folate receptor is not the only target of tumor therapeutics.

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Bio-functional micelles self-assembled from a folate-conjugated block copolymer for targeted intracellular delivery of anticancer drugs

Cited by 188 publications

References 19 publications

pH-sensitive and folic acid-targeted MPEG-PHIS/FA-PEG-VE mixed micelles for the delivery of PTX-VE and their antitumor activity

pH-sensitive and folic acid-targeted MPEG-PHIS/FA-PEG-VE mixed micelles for the delivery of PTX-VE and their antitumor activity

Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)

Endocytosis Pathways of the Folate Tethered Star-Shaped PEG-PCL Micelles in Cancer Cell Lines

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