Comparative colloidal stability, antitumor efficacy, and immunosuppressive effect of commercial paclitaxel nanoformulations

Hongliang Wang,Yujie Wang,Yuling Liu,Caiyun Qin,Jun Ye,Tong Sun,Hengfeng Liao,Xiaoyan Xu,Qiqi Shen,Yiqun Jin,Xuejun Xia,Renjie Li,Wujun Dong,Yanfang Yang,Lin Li

doi:10.1186/s12951-021-00946-w

Hongliang Wang, Yujie Wang + Show 13 more

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https://doi.org/10.1186/s12951-021-00946-w

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Abstract

BackgroundStandard chemotherapy with taxanes, such as paclitaxel (PTX), remains the mainstay of systemic treatment of triple-negative breast cancer. Nanotechnology-based formulations have gradually replaced PTX injection and are widely used in China. However, no studies have compared the colloidal stability, antitumor efficacy, and safety of commercial PTX nanoformulations. Additionally, the desire to evaluate preclinical antitumor efficacy in human-derived tumor cells led to the widespread application of immunodeficient mouse models that likely contributed to the neglect of nanomedicines-immune system interactions. The present study investigated the colloidal stability, antitumor efficacy and safety, and nanomedicines-host immune system interactions of PTX nanoformulations. A further comparative analysis was performed to evaluate the clinical potential.ResultsCompared with liposome, PTX emulsion and PTX nanoparticle exhibited favorable colloidal stability. PTX emulsion was superior in inducing apoptosis and had a more pronounced inhibitory effect on 4T1-tumor spheroids compared with PTX liposome and PTX nanoparticle. Although PTX emulsion exhibited superior in vitro antitumor effect, no significant differences in the in vivo antitumor efficacy were found among the three types of PTX nanoformulations in an immunocompetent orthotopic 4T1 murine triple-negative breast cancer model. All PTX nanoformulations at maximum tolerated dose (MTD) induced lymphopenia and immunosuppression, as evidenced by the reduction of T cell subpopulations and inhibition of the dendritic cells maturation.ConclusionsThe MTD PTX nanomedicines-induced lymphopenia and immunosuppression may weaken the lymphocyte-mediated antitumor cellular immune response and partly account for the lack of differences in the in vivo antitumor outcomes of PTX nanoformulations. Understanding of what impacts PTX nanomedicines has on the immune system may be critical to improve the design and conduct of translational research of PTX nanomedicines in monotherapy or combination therapy with immunotherapy.Graphic abstract

Highlights

Standard chemotherapy with taxanes, such as paclitaxel (PTX), remains the mainstay of systemic treatment of triple-negative breast cancer
The turbiscan stability index (TSI) of all nanoformulations increased with time, PTX emulsion and PTX nanoparticle maintained relatively lower TSI values as compared with that of PTX liposome (Fig. 3). These results indicate that PTX emulsion and PTX nanoparticle possess favorable colloidal stability, which may be attributed to the surface modification of highly hydrated groups, such as poloxamer 188 or albumin
PTX emulsion exhibited superior in vitro antitumor effect compared to PTX liposome and PTX nanoparticle on 4T1 cells, no significant differences in the in vivo antitumor efficacy were found among the three types of PTX nanoformulations in immunocompetent orthotopic 4T1 murine Triple-negative breast cancer (TNBC) model (Fig. 6)

Summary

Introduction

Standard chemotherapy with taxanes, such as paclitaxel (PTX), remains the mainstay of systemic treatment of triple-negative breast cancer. No studies have compared the colloidal stability, antitumor efficacy, and safety of commercial PTX nanoformulations. The desire to evaluate preclinical antitumor efficacy in humanderived tumor cells led to the widespread application of immunodeficient mouse models that likely contributed to the neglect of nanomedicines-immune system interactions. The present study investigated the colloidal stability, antitumor efficacy and safety, and nanomedicines-host immune system interactions of PTX nanoformulations. Triple-negative breast cancer (TNBC) is the most malignant and aggressive subtype of breast cancer. Chemotherapy is the established mainstay treatment for TNBC [3, 4]. Tumor-targeted delivery of chemotherapeutic agents has become a potential strategy to improve antitumor efficiency and attenuated chemotherapy-associated side effects [5]

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