Abstract
It has been shown that long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) could act synergistically with 5-fluorouracil (5-FU) to kill cancer cells. To facilitate their simultaneous transport in the bloodstream, we synthesized, for the first time, liposomes (LIPUFU) containing 5-FU in the aqueous core and docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) at a ratio of 1:2 in the lipid bilayer. LIPUFU werestable with uniform size of 154 ± 4 nm, PDI of 0.19 ± 0.03 and zeta potential of -41 ± 2 mV. They contained 557 ± 210 μmol/l DHA, 1467 ± 362 μmol/l EPA, and 9.8 ± 1.1 μmol/l 5-FU. Control liposomes without (LIP) or with only 5-FU (LIFU) or n-3 PUFAs (LIPU) were produced in a similar way. The effects of these different liposomal formulations on the cell cycle, growth, and apoptosis were evaluated in two human colorectal cancer (CRC) cell lines differing in sensitivity to 5-FU, using fluorescence-activated cell sorting analyses. LIPUFU were more cytotoxic than LIP, LIFU, and LIPU in both LS174T (p53+/+, bax−/−) and HT-29 (p53−/0, bax+/+) cell lines. Similar to LIFU, LIPUFU increased the percentage of cells in S phase, apoptosis, and/or necrosis. The cytotoxic potential of LIPUFU was confirmed in vivo by tumor growth inhibition in the chicken chorioallantoic membrane model. These results suggest that LIPUFU could be considered to facilitate the simultaneous transport of 5-FU and n-3 PUFAs to the tumor site, in particular in case of CRC liver metastases.
Highlights
liposomes with 5-FU and n-3 n-3 polyunsaturated fatty acids (PUFAs) (LIPUFU) increased the percentage of necrotic cells in both LS174T (10.3 ± 3.3% vs 5.1 ± 1.0%, P = 0.02) and HT-29 (14.5 ± 0.7% vs 3.1 ± 2.7%, P = 0.004) cells compared to untreated controls
An increase in the percentage of apoptotic cells was only observed in HT-29 cells treated with liposome with 5-FU (LIFU) (4.8 ± 0.7%, P = 0.002) or LIPUFU (3.3 ± 0.5%, P = 0.001) compared to
This limitation was of great concern in the present study because the presence of long-chain n-3 PUFAs into the lipid bilayer had the effect of fluidizing the liposomal membranes
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death [1, 2]. CRC prevention, screening, and treatment are among the main public health concerns. If CRC is diagnosed in the early stages by colonoscopy or sigmoidoscopy, complete cure can be obtained by surgical resection of the tumor with sufficient margins [3]. When the disease has reached stage III/IV and spread to the lymph nodes or distant organs, adjuvant chemotherapy is required to prevent local recurrence and metastatic invasion [2]. The reference drug in CRC treatment is 5-fluorouracil (5FU), an antimetabolite that causes cell cycle arrest in S phase after conversion into fluoronucleotides and misincorporation into RNA and DNA [4]. 5-FU is unstable, with a short biological half-life of 13 ± 7 min [6], and targets indifferently dividing cancer and normal cells, causing serious adverse effects, such as diarrhea (7.1–13.6%), 1530-9932/21/0100-0001/0 # 2021 The Author(s)
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