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Original Research

In situ delivery of thermosensitive gel-mediated 5-fluorouracil microemulsion for the treatment of colorectal cancer

, , , , &
Pages 2855-2867 | Published online: 08 Sep 2016

Figures & data

Table 1 Characteristics of 5FU microemulsion

Figure 1 5FU microemulsion image in TEM.

Note: The 5FU microemulsion particles were visualized under TEM for morphological feature and size distribution (×6,000).
Abbreviations: 5FU, 5-fluorouracil; TEM, transmission electron microscopy.
Figure 1 5FU microemulsion image in TEM.

Table 2 Physicochemical properties of the drug-free thermosensitive gel and TG-5FU-ME

Table 3 Stability of 5FU microemulsion

Table 4 Stability of TG-5FU-ME

Figure 2 Appearance of 5FU microemulsion.

Notes: 5FU microemulsion stored at 20°C±1°C was examined right after the preparation (A, E), as well as after storage for 24 hours (B, F), 72 hours (C, G), and 1 week (D, H). (AD) Naked eye examination; (EH) microscopic examination.
Abbreviation: 5FU, 5-fluorouracil.
Figure 2 Appearance of 5FU microemulsion.

Figure 3 Appearances of TG-5FU-ME.

Notes: Freshly prepared TG-5FU-ME samples were placed at 20°C±1°C for 0 hour (A, A′, F), 1 month (B, B′, G), 2 months (C, C′, H), 3 months (D, D′, I), and 4 months (E, E′, J), followed by naked eye and microscopic examination. (AE) Naked eye examination for the solid form of TG-5FU-ME at RT; (A′E′) naked eye examination for the liquid form sample at temperature below 10°C; (FJ) microscopic examination. 1000× magnification.
Abbreviations: RT, room temperature; TG-5FU-ME, thermosensitive gel-mediated 5FU water-in-oil microemulsion.
Figure 3 Appearances of TG-5FU-ME.

Figure 4 Release profiles of 5FU formulations in vitro.

Notes: Release features of 5FU in 5FU solution, 5FU thermosensitive gel, 5FU microemulsion, and TG-5FU-ME were measured in a dynamic dialysis assay.
Abbreviations: 5FU, 5-fluorouracil; TG-5FU-ME, thermosensitive gel-mediated 5FU water-in-oil microemulsion.
Figure 4 Release profiles of 5FU formulations in vitro.

Figure 5 AP to BL (A→B) and BL to AP (B→A) transport of 5FU.

Notes: Experiments were performed at 37°C for 150 minutes for both directions. The donor chambers were filled with 1.5 mL of a sample solution containing 5FU (200 µM; mean ± SD, n=3). A represents 5FU solution; B represents 5FU micro emulsion; C represents TG-5FU-ME.
Abbreviations: AP, apical; BL, basolateral; 5FU, 5-fluorouracil; SD, standard deviation.
Figure 5 AP to BL (A→B) and BL to AP (B→A) transport of 5FU.

Figure 6 Formulation change affects transportation efficacy of 5FU crossing the Caco-2 cell monolayers.

Notes: The donor chambers were filled with 1.5 mL of a sample solution containing 5FU (200 µM), and the receiver compartments were filled with 2.6 mL of blank HBSS. Samples were taken at receiver side. The determination of 5FU in transport buffer was carried out by HPLC. The apparent permeability coefficient (Papp; cm/s) for 5FU was calculated according to the equation: Papp= (1/AC0) (dQ/dt; mean ± SD, n=3).
Abbreviations: 5FU, 5-fluorouracil; HBSS, Hank’s buffered salt solution; HPLC, high-performance liquid chromatography; TG-5FU-ME, thermosensitive gel-mediated 5FU water-in-oil microemulsion; SD, standard deviation.
Figure 6 Formulation change affects transportation efficacy of 5FU crossing the Caco-2 cell monolayers.

Figure 7 Absorption of 5FU in vitro.

Notes: Caco-2 cells were exposed to 5FU thermosensitive gel, 5FU microemulsion, or TG-5FU-ME (containing 5FU, 200 µM). The percentage of 5FU in AP and BL media and cell monolayer was determined in 2.5 hours (mean ± SD, n=3).
Abbreviations: AP, apical; BL, basolateral; 5FU, 5-fluorouracil; TG-5FU-ME, thermosensitive gel-mediated 5FU water-in-oil microemulsion; SD, standard deviation.
Figure 7 Absorption of 5FU in vitro.

Figure 8 Rectal retention time.

Notes: 5FU microemulsion and TG-5FU-ME with 0.1%Cy7NHS ester were administered into the rectum, 0.5 cm above the anus using a stomach probe needle. (AC) 5FU microemulsion (2 minutes, 5 minutes, 10 minutes after administration); (DF) TG-5FU-ME (2 minutes, 2 hours, 5 hours after administration).
Abbreviations: 5FU, 5-fluorouracil; TG-5FU-ME, thermosensitive gel-mediated 5FU water-in-oil microemulsion; cpx, count per second.
Figure 8 Rectal retention time.

Figure 9 Tissue distribution of 5FU.

Notes: 5FU concentrations in rectal tissue (A), regional lymph node (B), and systemic blood (C) after rectal route administration of 20 mg kg−1 TG-5FU-ME (Image), 5FU microemulsion (Image), or 5FU thermosensitive gel (Image). *P<0.05 (TG-5FU-ME vs thermosensitive gel; mean ± SD, n=3).
Abbreviations: 5FU, 5-fluorouracil; TG-5FU-ME, thermosensitive gel-mediated 5FU water-in-oil microemulsion; SD, standard deviation.
Figure 9 Tissue distribution of 5FU.

Figure 10 The morphology of rectal tissues after exposure to 5FU thermosensitive gel and TG-5FU-ME.

Notes: The rat’s rectal tissue was taken 12 hours after TG-5FU-ME (A) and 5FU thermosensitive gel (B) administration (20 mg kg−1 of 5FU) through rectal route. Tissue slides were examined with H&E staining (×200).
Abbreviations: 5FU, 5-fluorouracil; H&E, hematoxylin and eosin; TG-5FU-ME, thermosensitive gel-mediated 5FU water-in-oil microemulsion.
Figure 10 The morphology of rectal tissues after exposure to 5FU thermosensitive gel and TG-5FU-ME.