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. 2020 Mar 27;10(1):5569.
doi: 10.1038/s41598-020-62501-1.

Optimization of Docetaxel Loading Conditions in Liposomes: proposing potential products for metastatic breast carcinoma chemotherapy

Roghayyeh Vakili-Ghartavol  1 , Seyed Mahdi Rezayat  1   2 , Reza Faridi-Majidi  1 , Kayvan Sadri  3 , Mahmoud Reza Jaafari  4   5
Affiliations

Optimization of Docetaxel Loading Conditions in Liposomes: proposing potential products for metastatic breast carcinoma chemotherapy

Roghayyeh Vakili-Ghartavol et al. Sci Rep. .

Abstract

Docetaxel (DTX) was loaded in nanoliposomes based on a new remote loading method using mannitol and acetic acid as hydration buffer. DTX loading conditions were optimized, and the final formulations were prepared according to the best parameters which were HSPC/mPEG2000-DSPE/Chol (F1), HSPC/mPEG2000-DSPE/DPPG/Chol (F2), HSPC/mPEG2000-DSPE/DSPG/Chol (F3), at molar ratios of 85/5/10, 80/5/5/10, 80/5/5/10, respectively. DTX-liposomes were found of desired size (~115 nm) and homogeneity (PDI ≤ 0.2), high drug encapsulation efficacy (34-67%) and DTX concentration, and favorable stability. Passive loaded counterparts liposomes showed three times lower encapsulation efficacy compared to the remote loaded liposomes. The drug release of remote loaded liposomes in plasma 50% was significantly more controlled and less in comparison with their passive loaded counterparts (p < 0.0001). The IC50 values of formulations were determined on MCF-7, 4T1, TUBO, NIH/3T3 cell lines. The biodistribution of iodinated docetaxel as free or liposomal form exhibited significantly greater accumulation of DTX-liposomes in tumors than that of free docetaxel due to the EPR effect. In vivo experiment with BALB/c mice bearing 4T1 or TUBO breast carcinoma tumors also showed that DTX-liposomes could significantly delay tumor growth and prolonged the survival time in comparison with control and Taxotere groups at the similar dose of 8 mg/kg. F1 and F2 formulations were stable and showed good anti-tumor activity and merit further investigation.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Size distribution, TEM images of DTX loaded F1, F2, and F3 nanoliposomes.
Figure 2
Figure 2
The DTX release profile of active loaded nanoliposomes in comparison with passive loaded counterparts in 50% fresh human plasma. Drug release from active loaded nanolipsomes was significantly lower than that of passive loaded nanoliposomes (p < 0.0001). The error bars were obtained from duplicate samples.
Figure 3
Figure 3
In vitro drug release profile of F1, F2 and F3 nanoliposomes at pHs of 5.5, 6.5, and 7.00. At different pHs, F1 and F2 represent a pH independent DTX release (p > 0.05). DTX release from F3 nanolipsomes at both pHs of 5.5 and 6.5 was significantly higher than that of pH 7.00 (p < 0.0001). The error bars were obtained from triplicate samples.
Figure 4
Figure 4
Therapeutic efficacy of DTX loaded liposomes in comparison with control groups (PBS, and Taxotere) in BABL/c models of 4T1 (upper panel) or TUBO (lower panel) mammary carcinoma. A: Body weight, B: Average tumor volume (mm3) in all treated groups and C: Survival of all groups was monitored. (n = 4 or 5, mean ± S.D). In 4T1 breast carcinoma tumor model, F1, F2, and F3 formulations significantly extended mouse survival compared to PBS (p < 0.01, p < 0.0, p < 0.05, respectively). Also, the overall survivals were significantly improved in mice treated with F1 liposomes compare to those received Taxotere (p < 0.05, log-rank).
Figure 5
Figure 5
Biodistribution of prepared nanoliposomes and free iodinated docetaxel formulated in ethanol in (A) tumor of BALB/c mice bearing 4T1 tumor at 12 and 24 h post injection of a single dose of 8 mg/kg docetaxel. Panel (a) shows a ratio of radioiodinated docetaxel amount in tumor to blood at each time point. Data are expressed as mean percentage of injected dose per tissue ((%ID)/g) ± SD (n = 3). Statistically significant differences are shown as follows: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.000.1.
Figure 6
Figure 6
Biodistribution of prepared nanoliposomes and free iodinated docetaxel formulated in ethanol in (B) blood, and (C) liver and spleen of BALB/c mice bearing 4T1 tumor at 12 and 24 h post injection of a single dose of 8 mg/kg docetaxel. Panels (c1) and (c2) show a ratio of radioiodinated docetaxel DTX amount in tumor to liver and spleen (T/NT ratio) at each time point, respectively. Panels (c3) and (c4) show a ratio of radioiodinated docetaxel amount in liver and spleen to blood at each time point, respectively. Data are expressed as mean percentage of injected dose per tissue ((%ID)/g) ± SD (n = 3). Statistically significant differences are shown as follows: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.000.1.
Figure 7
Figure 7
Biodistribution of prepared nanoliposomes and free iodinated docetaxel formulated in ethanol in (D) different organs in BALB/c mice bearing 4T1 tumor at 12 and 24 h post injection of a single dose of 8 mg/kg docetaxel. (D). Panels (d1), (d2), (d3) and (d4) represent a ratio of radioiodinated docetaxel amount in tumor to radioiodinated docetaxel concentration in each organ (T/NT ratio) of each mouse at each time point. Panels (d5), (d6), (d7) and (d8) show a ratio of radioiodinated docetaxel amount in organs to radioiodinated docetaxel concentration in blood of each mouse at each time point. Data are expressed as mean percentage of injected dose per tissue ((%ID)/g) ± SD (n = 3). Statistically significant differences are shown as follows: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.000.1.
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