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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

Acute toxicity of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX assessed by LD50.Notes: (A) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-Arg-PTX-FITC (80, 160, 200, 280, and 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-Arg-PTX-FITC was 100% with different dose, LD50 >320 mg/kg. (B) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-5AF-Glu-PTX (80, 160, 200, 280, 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-5AF-Glu-PTX was 100% with different dose, LD50 >320 mg/kg (n=10 per group).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.
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f5-ijn-10-5571: Acute toxicity of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX assessed by LD50.Notes: (A) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-Arg-PTX-FITC (80, 160, 200, 280, and 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-Arg-PTX-FITC was 100% with different dose, LD50 >320 mg/kg. (B) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-5AF-Glu-PTX (80, 160, 200, 280, 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-5AF-Glu-PTX was 100% with different dose, LD50 >320 mg/kg (n=10 per group).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.

Mentions: Surviving animals in the PTX group are indicated with a vertical line on the survival graph (Figure 5). The survival rate of animal in the different dose PTX group (from 15 mg/kg to 45 mg/kg) has decreased from 90% to 0%. Regardless of the dose of FA-FITC-Arg-PTX or FA-5AF-Glu-PTX (from 80 to 320 mg/kg), all groups of animals maintained their original survival rates. No histological difference was observed between the FA-FITC-Arg-PTX and FA-5AF-Glu-PTX group post-injection (data not shown). All results demonstrated that the cytotoxicity of the doses of prodrugs was low to mice.


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)

Acute toxicity of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX assessed by LD50.Notes: (A) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-Arg-PTX-FITC (80, 160, 200, 280, and 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-Arg-PTX-FITC was 100% with different dose, LD50 >320 mg/kg. (B) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-5AF-Glu-PTX (80, 160, 200, 280, 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-5AF-Glu-PTX was 100% with different dose, LD50 >320 mg/kg (n=10 per group).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

f5-ijn-10-5571: Acute toxicity of PTX, FA-FITC-Arg-PTX, and FA-5AF-Glu-PTX assessed by LD50.Notes: (A) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-Arg-PTX-FITC (80, 160, 200, 280, and 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-Arg-PTX-FITC was 100% with different dose, LD50 >320 mg/kg. (B) Compared with PTX (15, 20, 25, 35, and 45 mg/kg), FA-5AF-Glu-PTX (80, 160, 200, 280, 320 mg/kg) increased the survival rate in in normal mice. The survival rate of FA-5AF-Glu-PTX was 100% with different dose, LD50 >320 mg/kg (n=10 per group).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel.
Mentions: Surviving animals in the PTX group are indicated with a vertical line on the survival graph (Figure 5). The survival rate of animal in the different dose PTX group (from 15 mg/kg to 45 mg/kg) has decreased from 90% to 0%. Regardless of the dose of FA-FITC-Arg-PTX or FA-5AF-Glu-PTX (from 80 to 320 mg/kg), all groups of animals maintained their original survival rates. No histological difference was observed between the FA-FITC-Arg-PTX and FA-5AF-Glu-PTX group post-injection (data not shown). All results demonstrated that the cytotoxicity of the doses of prodrugs was low to mice.

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