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

Roghayyeh Vakili-Ghartavol,Mahmoud Reza Jaafari,Reza Faridi-Majidi,Kayvan Sadri,Seyed Mahdi Rezayat

doi:10.1038/s41598-020-62501-1

Roghayyeh Vakili-Ghartavol, Mahmoud Reza Jaafari + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-62501-1

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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.

Highlights

Taxanes have extremely low solubility in water and pharmaceutical concerns caused by their bulky polycyclic structure[1,2]
Using the mice bearing 4T1 or TUBO breast cancer cell lines, which were used in Taxotere development, we assessed the Median survival time (MST), Time to reach end point (TTE), and Tumor growth delay (TGD), Increase life span (ILS), and therapeutic efficacies of liposomal DTX compared to Taxotere and PBS
It could be presumable that some rafts formation in remote loaded liposomes is responsible for good drug incorporation and solution of mannitol and acetic acid might change the fluidity of the bilayer enabling more www.nature.com/scientificreports stable drug incorporation

Summary

Introduction

Taxanes have extremely low solubility in water and pharmaceutical concerns caused by their bulky polycyclic structure[1,2]. Accumulating body of studies on the transport of macromolecules into tumor tissues have demonstrated that blood plasma components, including proteins, macromolecules, nanoparticles, lipidic particles, and other soluble particles could extravasate through leaky tumor vasculature to enter within the interstitial space of tumors and accumulate there due to the inability of lymphatic drainage in tumor tissues. This phenomenon was later termed the EPR effect and paved the way for the passive targeting of tumors using nano sized particles[23,24,25,26,27].

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