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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

Characterization of multi-small molecule-conjugated paclitaxel prodrugs.Notes: (A) Absorption peaks of FA-FITC-Arg-PTX prodrug formulation overlaps the peaks of FA, Arg, PTX, and FITC at 365 nm, 220 nm, 227 nm, 375 nm, and 780 nm, respectively. (B) Absorption spectra for the FA-5AF-Glu-PTX formulation. The absorption peaks at 365 nm, 220 nm, 227 nm, and 465 nm represent absorption of FA, Glu, PTX, and 5AF, respectively. (C) Absorption spectra of ICG02-(NH2)Arg-PTX formulation at 220 nm, 227 nm, and 780 nm represent absorption of Arg, FA, and ICG-Der-02, respectively. (D) Absorption peaks of FA-ICG02-Arg-PTX formulation at 365 nm, 220 nm, 227 nm, and 780 nm represent absorption of FA, Arg, PTX, and ICG-Der-02, respectively. (E) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in phosphate-buffered saline. (F) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in human plasma.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; Arg, arginine; Glu, glutamic acid.
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f2-ijn-10-5571: Characterization of multi-small molecule-conjugated paclitaxel prodrugs.Notes: (A) Absorption peaks of FA-FITC-Arg-PTX prodrug formulation overlaps the peaks of FA, Arg, PTX, and FITC at 365 nm, 220 nm, 227 nm, 375 nm, and 780 nm, respectively. (B) Absorption spectra for the FA-5AF-Glu-PTX formulation. The absorption peaks at 365 nm, 220 nm, 227 nm, and 465 nm represent absorption of FA, Glu, PTX, and 5AF, respectively. (C) Absorption spectra of ICG02-(NH2)Arg-PTX formulation at 220 nm, 227 nm, and 780 nm represent absorption of Arg, FA, and ICG-Der-02, respectively. (D) Absorption peaks of FA-ICG02-Arg-PTX formulation at 365 nm, 220 nm, 227 nm, and 780 nm represent absorption of FA, Arg, PTX, and ICG-Der-02, respectively. (E) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in phosphate-buffered saline. (F) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in human plasma.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; Arg, arginine; Glu, glutamic acid.

Mentions: PTX loading in the prodrug formulations was evaluated by the standard curve for HPLC peak area versus PTX content. The regression equation for the standard PTX curve was Y (OD) =65535.65035+17388.99822× (R2=0.99922). The linear range of the standard curve was 0.85–95.18 µg/mL. PTX loading in the two prodrug formulations was 38.70%±0.49% and 32.19%±0.35% (n=5), respectively. To quantify the aqueous solubility of the multi-small molecule-conjugated PTX prodrug formulations, the direct observations were followed in the solubility calculations of the PTX prodrug formulations, FA-FITC-Arg-PTX (6.45±0.15 mg/mL, n=4) and FA-5AF-Glu-PTX (6.41±0.18 mg/mL, n=4) as shown in Figure S3. To investigate the cleavage of the linkers (Arg/Glu) in the products we measured the amount of free PTX released from the compounds after incubation of the products in PBS (pH 7.4) and human plasma, respectively, at 37°C. The free PTX was measured by HPLC, as shown in Figure S4A and B. The release profiles are given in Figure 2E. The FA-FITC-Arg-PTX/FA-5AF-Glu-PTX formulation released PTX more rapidly in human plasma (56.72%/54.84%, 4 hours) and released less PTX in PBS (25.8%/23.3%, 4 hours).


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)

Characterization of multi-small molecule-conjugated paclitaxel prodrugs.Notes: (A) Absorption peaks of FA-FITC-Arg-PTX prodrug formulation overlaps the peaks of FA, Arg, PTX, and FITC at 365 nm, 220 nm, 227 nm, 375 nm, and 780 nm, respectively. (B) Absorption spectra for the FA-5AF-Glu-PTX formulation. The absorption peaks at 365 nm, 220 nm, 227 nm, and 465 nm represent absorption of FA, Glu, PTX, and 5AF, respectively. (C) Absorption spectra of ICG02-(NH2)Arg-PTX formulation at 220 nm, 227 nm, and 780 nm represent absorption of Arg, FA, and ICG-Der-02, respectively. (D) Absorption peaks of FA-ICG02-Arg-PTX formulation at 365 nm, 220 nm, 227 nm, and 780 nm represent absorption of FA, Arg, PTX, and ICG-Der-02, respectively. (E) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in phosphate-buffered saline. (F) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in human plasma.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; Arg, arginine; Glu, glutamic acid.
© Copyright Policy
Related In: Results  -  Collection

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

f2-ijn-10-5571: Characterization of multi-small molecule-conjugated paclitaxel prodrugs.Notes: (A) Absorption peaks of FA-FITC-Arg-PTX prodrug formulation overlaps the peaks of FA, Arg, PTX, and FITC at 365 nm, 220 nm, 227 nm, 375 nm, and 780 nm, respectively. (B) Absorption spectra for the FA-5AF-Glu-PTX formulation. The absorption peaks at 365 nm, 220 nm, 227 nm, and 465 nm represent absorption of FA, Glu, PTX, and 5AF, respectively. (C) Absorption spectra of ICG02-(NH2)Arg-PTX formulation at 220 nm, 227 nm, and 780 nm represent absorption of Arg, FA, and ICG-Der-02, respectively. (D) Absorption peaks of FA-ICG02-Arg-PTX formulation at 365 nm, 220 nm, 227 nm, and 780 nm represent absorption of FA, Arg, PTX, and ICG-Der-02, respectively. (E) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in phosphate-buffered saline. (F) Release of free PTX from FA-FITC-Arg-PTX and FA-5AF-Glu-PTX in human plasma.Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; Arg, arginine; Glu, glutamic acid.
Mentions: PTX loading in the prodrug formulations was evaluated by the standard curve for HPLC peak area versus PTX content. The regression equation for the standard PTX curve was Y (OD) =65535.65035+17388.99822× (R2=0.99922). The linear range of the standard curve was 0.85–95.18 µg/mL. PTX loading in the two prodrug formulations was 38.70%±0.49% and 32.19%±0.35% (n=5), respectively. To quantify the aqueous solubility of the multi-small molecule-conjugated PTX prodrug formulations, the direct observations were followed in the solubility calculations of the PTX prodrug formulations, FA-FITC-Arg-PTX (6.45±0.15 mg/mL, n=4) and FA-5AF-Glu-PTX (6.41±0.18 mg/mL, n=4) as shown in Figure S3. To investigate the cleavage of the linkers (Arg/Glu) in the products we measured the amount of free PTX released from the compounds after incubation of the products in PBS (pH 7.4) and human plasma, respectively, at 37°C. The free PTX was measured by HPLC, as shown in Figure S4A and B. The release profiles are given in Figure 2E. The FA-FITC-Arg-PTX/FA-5AF-Glu-PTX formulation released PTX more rapidly in human plasma (56.72%/54.84%, 4 hours) and released less PTX in PBS (25.8%/23.3%, 4 hours).

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