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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 vivo therapeutic experiment.Notes: (A) Tumor volumes for MCF-7-bearing mice as a function of time (days). (B) Animal weights of MCF-7-bearing mice as a function of time (days). Data are shown as the mean (n=6). (C) Tumor volumes for A549-bearing mice as a function of time (days). (D) Animal weights of A549-bearing mice as a function of time (days). Data are shown as the mean (n=6). (E) Tissue sections of tumor excised from MCF-7-bearing nude mice 15 days after administration of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX. More than 98% of mice in the groups treated with PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX showed tumor tissue with spotty necrosis, spherical cells, and loose order under higher than normal doses. (Magnification 400×).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.
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f7-ijn-10-5571: In vivo therapeutic experiment.Notes: (A) Tumor volumes for MCF-7-bearing mice as a function of time (days). (B) Animal weights of MCF-7-bearing mice as a function of time (days). Data are shown as the mean (n=6). (C) Tumor volumes for A549-bearing mice as a function of time (days). (D) Animal weights of A549-bearing mice as a function of time (days). Data are shown as the mean (n=6). (E) Tissue sections of tumor excised from MCF-7-bearing nude mice 15 days after administration of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX. More than 98% of mice in the groups treated with PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX showed tumor tissue with spotty necrosis, spherical cells, and loose order under higher than normal doses. (Magnification 400×).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Mentions: The in vivo antitumor efficacy of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX was evaluated in MCF-7-tumor-bearing mice and A549 tumor-bearing mice by measuring tumor growth rate and body weight. Figure 7A indicates that treatment with PBS produced the fastest tumor growth, while multi-small molecule-conjugated PTX inhibited tumor growth most effectively. MCF-7 tumor growth was inhibited at a rate of 57.63% and 54.02% after administration of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX, respectively, which is higher than that of free PTX (about 38.16%). The inhibition rate of the two prodrug (48.65%/44.52%)-treated A549 tumor was about 1.4/1.3 times higher than that of the free PTX-treated tumor (35.23%, Figure 7).


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 vivo therapeutic experiment.Notes: (A) Tumor volumes for MCF-7-bearing mice as a function of time (days). (B) Animal weights of MCF-7-bearing mice as a function of time (days). Data are shown as the mean (n=6). (C) Tumor volumes for A549-bearing mice as a function of time (days). (D) Animal weights of A549-bearing mice as a function of time (days). Data are shown as the mean (n=6). (E) Tissue sections of tumor excised from MCF-7-bearing nude mice 15 days after administration of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX. More than 98% of mice in the groups treated with PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX showed tumor tissue with spotty necrosis, spherical cells, and loose order under higher than normal doses. (Magnification 400×).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.
© Copyright Policy
Related In: Results  -  Collection

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

f7-ijn-10-5571: In vivo therapeutic experiment.Notes: (A) Tumor volumes for MCF-7-bearing mice as a function of time (days). (B) Animal weights of MCF-7-bearing mice as a function of time (days). Data are shown as the mean (n=6). (C) Tumor volumes for A549-bearing mice as a function of time (days). (D) Animal weights of A549-bearing mice as a function of time (days). Data are shown as the mean (n=6). (E) Tissue sections of tumor excised from MCF-7-bearing nude mice 15 days after administration of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX. More than 98% of mice in the groups treated with PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX showed tumor tissue with spotty necrosis, spherical cells, and loose order under higher than normal doses. (Magnification 400×).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.
Mentions: The in vivo antitumor efficacy of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX was evaluated in MCF-7-tumor-bearing mice and A549 tumor-bearing mice by measuring tumor growth rate and body weight. Figure 7A indicates that treatment with PBS produced the fastest tumor growth, while multi-small molecule-conjugated PTX inhibited tumor growth most effectively. MCF-7 tumor growth was inhibited at a rate of 57.63% and 54.02% after administration of FA-FITC-Arg-PTX and FA-5AF-Glu-PTX, respectively, which is higher than that of free PTX (about 38.16%). The inhibition rate of the two prodrug (48.65%/44.52%)-treated A549 tumor was about 1.4/1.3 times higher than that of the free PTX-treated tumor (35.23%, Figure 7).

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