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Multi-small molecule conjugations as new targeted delivery carriers for tumor therapy.

Shan L, Liu M, Wu C, Zhao L, Li S, Xu L, Cao W, Gao G, Gu Y - Int J Nanomedicine (2015)

Bottom Line: In vitro and acute toxicity studies demonstrated the low toxicity of the prodrug formulations compared with the free drug.Notably, compared with free PTX and with PTX-loaded macromolecular carriers from our previous study, this multi-small molecule-conjugated strategy improved the water solubility, loading rate, targeting ability, antitumor activity, and toxicity profile of PTX.These results support the use of multi-small molecules as tumor-targeting drug delivery systems.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People's Republic of China.

ABSTRACT
In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting ability, and harmful side effects, we developed a new tumor-targeted multi-small molecule drug delivery platform. Using paclitaxel (PTX) as a model therapeutic, we prepared two prodrugs, ie, folic acid-fluorescein-5(6)-isothiocyanate-arginine-paclitaxel (FA-FITC-Arg-PTX) and folic acid-5-aminofluorescein-glutamic-paclitaxel (FA-5AF-Glu-PTX), composed of folic acid (FA, target), amino acids (Arg or Glu, linker), and fluorescent dye (fluorescein in vitro or near-infrared fluorescent dye in vivo) in order to better understand the mechanism of PTX prodrug targeting. In vitro and acute toxicity studies demonstrated the low toxicity of the prodrug formulations compared with the free drug. In vitro and in vivo studies indicated that folate receptor-mediated uptake of PTX-conjugated multi-small molecule carriers induced high antitumor activity. Notably, compared with free PTX and with PTX-loaded macromolecular carriers from our previous study, this multi-small molecule-conjugated strategy improved the water solubility, loading rate, targeting ability, antitumor activity, and toxicity profile of PTX. These results support the use of multi-small molecules as tumor-targeting drug delivery systems.

No MeSH data available.


Related in: MedlinePlus

In vitro antitumor effects of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX.Notes: (A) A cell viability ratio assay was used to qualitatively display the antitumor activity and cytotoxicity of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in the tumor cell lines and normal HEK293 cell line (MTT assay, n=6). (B) The cells were then incubated in the free PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX drug formulations. One day later, the morphology of cell apoptosis was observed by fluorescence microscopy. (C) The number of late apoptosis/necrotic value (Q4) of the three cell lines (MDA-MB-231, MCF-7, and A549) was 25.8%/36.5%/34.1%, 19.9%/26.7%/27.9%, and 14.6%/16.8%/16.3%, respectively.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.
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f4-ijn-10-5571: In vitro antitumor effects of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX.Notes: (A) A cell viability ratio assay was used to qualitatively display the antitumor activity and cytotoxicity of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in the tumor cell lines and normal HEK293 cell line (MTT assay, n=6). (B) The cells were then incubated in the free PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX drug formulations. One day later, the morphology of cell apoptosis was observed by fluorescence microscopy. (C) The number of late apoptosis/necrotic value (Q4) of the three cell lines (MDA-MB-231, MCF-7, and A549) was 25.8%/36.5%/34.1%, 19.9%/26.7%/27.9%, and 14.6%/16.8%/16.3%, respectively.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Mentions: The cell viability ratio assay was used to qualitatively determine in vitro the antitumor activity and cytotoxicity of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in MDA-MB-231, MCF-7, and A549 cancer cells. and in normal HEK293 cells. The results are shown in Figure 4A. All the drug formulations showed dose-dependent antitumor activity at the different PTX concentrations. In the three tumor cell lines, the inhibition ratios of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX were over 78.1% of total cells, whereas PTX inhibited a maximum of 62.4% of total cells. Importantly, the concentration of free PTX at each point was 2-fold when compared with the corresponding conjugated PTX formulation. A high concentration of free PTX still showed a lower tumor inhibition rate when compared with the conjugated PTX. In addition, the inhibition rates achieved by FA-FITC-Arg-PTX and FA- 5AF-Glu-PTX were not significantly different in any of the cell lines tested. All drugs displayed an increased inhibition ratio for MDA-MB-231 tumor cells with relatively high-level expression of FR-α when compared with MCF-7 and A549. Moreover, the two prodrug formulations showed a very high viability rate in normal HEK293 cells, even at the highest concentration (0.459 µg/mL). These findings suggest that multi-small molecule-conjugated PTX delivery systems have low cytotoxicity to normal cells and enhance the antitumor ability of free PTX in tumors overexpressing FR-α.


Multi-small molecule conjugations as new targeted delivery carriers for tumor therapy.

Shan L, Liu M, Wu C, Zhao L, Li S, Xu L, Cao W, Gao G, Gu Y - Int J Nanomedicine (2015)

In vitro antitumor effects of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX.Notes: (A) A cell viability ratio assay was used to qualitatively display the antitumor activity and cytotoxicity of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in the tumor cell lines and normal HEK293 cell line (MTT assay, n=6). (B) The cells were then incubated in the free PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX drug formulations. One day later, the morphology of cell apoptosis was observed by fluorescence microscopy. (C) The number of late apoptosis/necrotic value (Q4) of the three cell lines (MDA-MB-231, MCF-7, and A549) was 25.8%/36.5%/34.1%, 19.9%/26.7%/27.9%, and 14.6%/16.8%/16.3%, respectively.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562733&req=5

f4-ijn-10-5571: In vitro antitumor effects of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX.Notes: (A) A cell viability ratio assay was used to qualitatively display the antitumor activity and cytotoxicity of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in the tumor cell lines and normal HEK293 cell line (MTT assay, n=6). (B) The cells were then incubated in the free PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX drug formulations. One day later, the morphology of cell apoptosis was observed by fluorescence microscopy. (C) The number of late apoptosis/necrotic value (Q4) of the three cell lines (MDA-MB-231, MCF-7, and A549) was 25.8%/36.5%/34.1%, 19.9%/26.7%/27.9%, and 14.6%/16.8%/16.3%, respectively.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.
Mentions: The cell viability ratio assay was used to qualitatively determine in vitro the antitumor activity and cytotoxicity of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in MDA-MB-231, MCF-7, and A549 cancer cells. and in normal HEK293 cells. The results are shown in Figure 4A. All the drug formulations showed dose-dependent antitumor activity at the different PTX concentrations. In the three tumor cell lines, the inhibition ratios of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX were over 78.1% of total cells, whereas PTX inhibited a maximum of 62.4% of total cells. Importantly, the concentration of free PTX at each point was 2-fold when compared with the corresponding conjugated PTX formulation. A high concentration of free PTX still showed a lower tumor inhibition rate when compared with the conjugated PTX. In addition, the inhibition rates achieved by FA-FITC-Arg-PTX and FA- 5AF-Glu-PTX were not significantly different in any of the cell lines tested. All drugs displayed an increased inhibition ratio for MDA-MB-231 tumor cells with relatively high-level expression of FR-α when compared with MCF-7 and A549. Moreover, the two prodrug formulations showed a very high viability rate in normal HEK293 cells, even at the highest concentration (0.459 µg/mL). These findings suggest that multi-small molecule-conjugated PTX delivery systems have low cytotoxicity to normal cells and enhance the antitumor ability of free PTX in tumors overexpressing FR-α.

Bottom Line: In vitro and acute toxicity studies demonstrated the low toxicity of the prodrug formulations compared with the free drug.Notably, compared with free PTX and with PTX-loaded macromolecular carriers from our previous study, this multi-small molecule-conjugated strategy improved the water solubility, loading rate, targeting ability, antitumor activity, and toxicity profile of PTX.These results support the use of multi-small molecules as tumor-targeting drug delivery systems.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People's Republic of China.

ABSTRACT
In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting ability, and harmful side effects, we developed a new tumor-targeted multi-small molecule drug delivery platform. Using paclitaxel (PTX) as a model therapeutic, we prepared two prodrugs, ie, folic acid-fluorescein-5(6)-isothiocyanate-arginine-paclitaxel (FA-FITC-Arg-PTX) and folic acid-5-aminofluorescein-glutamic-paclitaxel (FA-5AF-Glu-PTX), composed of folic acid (FA, target), amino acids (Arg or Glu, linker), and fluorescent dye (fluorescein in vitro or near-infrared fluorescent dye in vivo) in order to better understand the mechanism of PTX prodrug targeting. In vitro and acute toxicity studies demonstrated the low toxicity of the prodrug formulations compared with the free drug. In vitro and in vivo studies indicated that folate receptor-mediated uptake of PTX-conjugated multi-small molecule carriers induced high antitumor activity. Notably, compared with free PTX and with PTX-loaded macromolecular carriers from our previous study, this multi-small molecule-conjugated strategy improved the water solubility, loading rate, targeting ability, antitumor activity, and toxicity profile of PTX. These results support the use of multi-small molecules as tumor-targeting drug delivery systems.

No MeSH data available.


Related in: MedlinePlus