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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

Dynamic behavior and targeting capability of the PTX prodrug formulations in MDA-MB-231 tumor-bearing mice.Notes: (A) Images of the tumor-bearing mice after administration of ICG02-(NH2)Arg-PTX within 48 hours. (B) Images of the tumor-bearing mice after administration of FA-ICG02-Arg-PTX within 48 hours. (C) The T/N ratio in MDA-MB-231 tumor tissues for ICG02-(NH2)Arg-PTX and FA-ICG02-Arg-PTX prodrug formulations. (D) Based on the targeting ability of PTX prodrugs, we euthanized the mice bearing MDA-MB-231 tumor xenografts at 4 hours post-injection of FA-FITC-Arg-PTX or FA-5AF-Glu-PTX and all tissues were immediately excised for sectioning and were visualized by fluorescence microscopy. *Statistical analysis indicated that there was a significant difference in the T/N ratio in the MDA-MB-231 tumor tissues between the two prodrug formulations (P<0.05). The data are shown as the mean ± standard deviation (n=5 per group).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; T/N, tumor-to-normal tissue; h, hour; m, minutes.
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f6-ijn-10-5571: Dynamic behavior and targeting capability of the PTX prodrug formulations in MDA-MB-231 tumor-bearing mice.Notes: (A) Images of the tumor-bearing mice after administration of ICG02-(NH2)Arg-PTX within 48 hours. (B) Images of the tumor-bearing mice after administration of FA-ICG02-Arg-PTX within 48 hours. (C) The T/N ratio in MDA-MB-231 tumor tissues for ICG02-(NH2)Arg-PTX and FA-ICG02-Arg-PTX prodrug formulations. (D) Based on the targeting ability of PTX prodrugs, we euthanized the mice bearing MDA-MB-231 tumor xenografts at 4 hours post-injection of FA-FITC-Arg-PTX or FA-5AF-Glu-PTX and all tissues were immediately excised for sectioning and were visualized by fluorescence microscopy. *Statistical analysis indicated that there was a significant difference in the T/N ratio in the MDA-MB-231 tumor tissues between the two prodrug formulations (P<0.05). The data are shown as the mean ± standard deviation (n=5 per group).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; T/N, tumor-to-normal tissue; h, hour; m, minutes.

Mentions: MDA-MB-231 cells with relative overexpression of FR-α were used to investigate the dynamics and tumor targeting ability of multi-small molecule-loaded PTX. Representative near-infrared images after administration of ICG02-(NH2)Arg-PTX and FA-ICG02-Arg-PTX are shown in Figure 6A and B. The fluorescent ICG02-(NH2) Arg-PTX initially spread throughout the whole body at about 30 minutes post-injection and gradually appeared in the tumor, as well as the organs of excretion, including the liver, gastrointestinal tract, and bladder. The fluorescent drug in the tumor gradually washed out, with a decrease in signals from the liver, gastrointestinal tract, and bladder. At 24 hours post-injection, the fluorescent probe has mostly cleared from the body (Figure 6A). The FA-ICG02-Arg-PTX initially distributed all over the body and was subsequently cleared via the hepatobiliary and renal pathways (Figure 6B). However, the tumor sites were identifiable 1 hour after injection of the probes. Over time, the drug increasingly accumulated in the tumors and the fluorescence intensity peaked at about 4 hours. The bright fluorescence signal in the tumor tissue gradually disappeared after 4 days (data not shown).


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)

Dynamic behavior and targeting capability of the PTX prodrug formulations in MDA-MB-231 tumor-bearing mice.Notes: (A) Images of the tumor-bearing mice after administration of ICG02-(NH2)Arg-PTX within 48 hours. (B) Images of the tumor-bearing mice after administration of FA-ICG02-Arg-PTX within 48 hours. (C) The T/N ratio in MDA-MB-231 tumor tissues for ICG02-(NH2)Arg-PTX and FA-ICG02-Arg-PTX prodrug formulations. (D) Based on the targeting ability of PTX prodrugs, we euthanized the mice bearing MDA-MB-231 tumor xenografts at 4 hours post-injection of FA-FITC-Arg-PTX or FA-5AF-Glu-PTX and all tissues were immediately excised for sectioning and were visualized by fluorescence microscopy. *Statistical analysis indicated that there was a significant difference in the T/N ratio in the MDA-MB-231 tumor tissues between the two prodrug formulations (P<0.05). The data are shown as the mean ± standard deviation (n=5 per group).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; T/N, tumor-to-normal tissue; h, hour; m, minutes.
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f6-ijn-10-5571: Dynamic behavior and targeting capability of the PTX prodrug formulations in MDA-MB-231 tumor-bearing mice.Notes: (A) Images of the tumor-bearing mice after administration of ICG02-(NH2)Arg-PTX within 48 hours. (B) Images of the tumor-bearing mice after administration of FA-ICG02-Arg-PTX within 48 hours. (C) The T/N ratio in MDA-MB-231 tumor tissues for ICG02-(NH2)Arg-PTX and FA-ICG02-Arg-PTX prodrug formulations. (D) Based on the targeting ability of PTX prodrugs, we euthanized the mice bearing MDA-MB-231 tumor xenografts at 4 hours post-injection of FA-FITC-Arg-PTX or FA-5AF-Glu-PTX and all tissues were immediately excised for sectioning and were visualized by fluorescence microscopy. *Statistical analysis indicated that there was a significant difference in the T/N ratio in the MDA-MB-231 tumor tissues between the two prodrug formulations (P<0.05). The data are shown as the mean ± standard deviation (n=5 per group).Abbreviations: 5AF, 5-aminofluorescein; FA, folic acid; FITC, fluorescein isothiocyanate; PTX, paclitaxel; T/N, tumor-to-normal tissue; h, hour; m, minutes.
Mentions: MDA-MB-231 cells with relative overexpression of FR-α were used to investigate the dynamics and tumor targeting ability of multi-small molecule-loaded PTX. Representative near-infrared images after administration of ICG02-(NH2)Arg-PTX and FA-ICG02-Arg-PTX are shown in Figure 6A and B. The fluorescent ICG02-(NH2) Arg-PTX initially spread throughout the whole body at about 30 minutes post-injection and gradually appeared in the tumor, as well as the organs of excretion, including the liver, gastrointestinal tract, and bladder. The fluorescent drug in the tumor gradually washed out, with a decrease in signals from the liver, gastrointestinal tract, and bladder. At 24 hours post-injection, the fluorescent probe has mostly cleared from the body (Figure 6A). The FA-ICG02-Arg-PTX initially distributed all over the body and was subsequently cleared via the hepatobiliary and renal pathways (Figure 6B). However, the tumor sites were identifiable 1 hour after injection of the probes. Over time, the drug increasingly accumulated in the tumors and the fluorescence intensity peaked at about 4 hours. The bright fluorescence signal in the tumor tissue gradually disappeared after 4 days (data not shown).

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