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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

Targeting capability of fluorescence dye-labeled PTX prodrug formulations in different tumor cell lines with different FA-α receptor expression levels.Notes: (A) Protein levels of FR-α in the tumor and normal cell lines were determined by Western blot. (B) Targeting ability of PTX prodrug formulations in MDA-MB-231, MCF-7, A549, and HEK293 cells. Tumor cells show increased uptake of PTX prodrug compared with the normal cell lines with low expression of FR protein. (C) Flow cytometric analysis of FA-modified PTX prodrug formulation in MDA-MB-231, MCF-7, A549, and HEK293 cells. FA-FITC-Arg-PTX and FA-5AF-Glu-PTX prodrug formulations were taken up into the MDA-MB-231 cell lines at a rate of 89.6% and 85.9%, respectively, but at a rate of only 2.1% and 1.9% in HEK293 cells.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; FA-α, folate receptor alpha.
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f3-ijn-10-5571: Targeting capability of fluorescence dye-labeled PTX prodrug formulations in different tumor cell lines with different FA-α receptor expression levels.Notes: (A) Protein levels of FR-α in the tumor and normal cell lines were determined by Western blot. (B) Targeting ability of PTX prodrug formulations in MDA-MB-231, MCF-7, A549, and HEK293 cells. Tumor cells show increased uptake of PTX prodrug compared with the normal cell lines with low expression of FR protein. (C) Flow cytometric analysis of FA-modified PTX prodrug formulation in MDA-MB-231, MCF-7, A549, and HEK293 cells. FA-FITC-Arg-PTX and FA-5AF-Glu-PTX prodrug formulations were taken up into the MDA-MB-231 cell lines at a rate of 89.6% and 85.9%, respectively, but at a rate of only 2.1% and 1.9% in HEK293 cells.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; FA-α, folate receptor alpha.

Mentions: To explain the receptor-mediated targeting of multi-small molecule-conjugated PTX vectors to HEK293, MDA-MB-231, MCF-7, and A549 cells, expression levels of FR-α protein were investigated by Western blot, and were found to be in the following order: MDA-MB-231 > MCF-7 > A549 > HEK293, as shown in Figure 3A.


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)

Targeting capability of fluorescence dye-labeled PTX prodrug formulations in different tumor cell lines with different FA-α receptor expression levels.Notes: (A) Protein levels of FR-α in the tumor and normal cell lines were determined by Western blot. (B) Targeting ability of PTX prodrug formulations in MDA-MB-231, MCF-7, A549, and HEK293 cells. Tumor cells show increased uptake of PTX prodrug compared with the normal cell lines with low expression of FR protein. (C) Flow cytometric analysis of FA-modified PTX prodrug formulation in MDA-MB-231, MCF-7, A549, and HEK293 cells. FA-FITC-Arg-PTX and FA-5AF-Glu-PTX prodrug formulations were taken up into the MDA-MB-231 cell lines at a rate of 89.6% and 85.9%, respectively, but at a rate of only 2.1% and 1.9% in HEK293 cells.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; FA-α, folate receptor alpha.
© Copyright Policy
Related In: Results  -  Collection

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

f3-ijn-10-5571: Targeting capability of fluorescence dye-labeled PTX prodrug formulations in different tumor cell lines with different FA-α receptor expression levels.Notes: (A) Protein levels of FR-α in the tumor and normal cell lines were determined by Western blot. (B) Targeting ability of PTX prodrug formulations in MDA-MB-231, MCF-7, A549, and HEK293 cells. Tumor cells show increased uptake of PTX prodrug compared with the normal cell lines with low expression of FR protein. (C) Flow cytometric analysis of FA-modified PTX prodrug formulation in MDA-MB-231, MCF-7, A549, and HEK293 cells. FA-FITC-Arg-PTX and FA-5AF-Glu-PTX prodrug formulations were taken up into the MDA-MB-231 cell lines at a rate of 89.6% and 85.9%, respectively, but at a rate of only 2.1% and 1.9% in HEK293 cells.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; FA-α, folate receptor alpha.
Mentions: To explain the receptor-mediated targeting of multi-small molecule-conjugated PTX vectors to HEK293, MDA-MB-231, MCF-7, and A549 cells, expression levels of FR-α protein were investigated by Western blot, and were found to be in the following order: MDA-MB-231 > MCF-7 > A549 > HEK293, as shown in Figure 3A.

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