Induction of enhanced immunogenic cell death through ultrasound-controlled release of doxorubicin by liposome-microbubble complexes

ABSTRACT

Immunogenic cell death (ICD) is a specific kind of cell death that stimulates the immune system to combat cancer cells. Ultrasound (US)-controlled targeted release of drugs by liposome-microbubble complexes is a promising approach due to its non-invasive nature and visibility through ultrasound imaging. However, it is not known whether this approach can enhance ICD induced by drugs, such as doxorubicin. Herein, we prepared a doxorubicin-liposome-microbubble complex (MbDox), and the resultant MbDox was then characterized and tested for US-controlled release of Dox (MbDox+US treatment) to enhance the induction of ICD in LL/2 and CT26 cancer cells and in syngeneic murine models. We found that MbDox+US treatment caused more cellular uptake and nuclear accumulation of Dox in tumor cells, and more accumulation of Dox in tumor tissues. Enhanced induction of ICD occurred both in vitro and in vivo. MbDox+US treatment induced more apoptosis, stronger membrane exposure and the release of ER stress proteins and DAMPs in tumor cells, and increased DC maturation in vitro. In addition, MbDox+US treatment also resulted in stronger therapeutic effects in immunocompetent mice than in immunodeficient mice. Moreover, MbDox+US enhancement of ICD was also evidenced by a higher proportion of activated CD8⁺ T-lymphocytes but lower Treg in tumor tissues. Taken together, our results demonstrate that US-controlled release of ICD inducers into nuclei using liposome-microbubble complexes may be an effective approach to enhance the induction of ICD for tumor treatment.

KEYWORDS:

• immunogenic cell death
• drug carrier
• liposome
• microbubble complexes
• tumor target therapy
• tumor microenvironment

Disclosure of potential conflicts of interest

The authors have declared that no competing interest exists.

Acknowledgment

This work was funded by the National Natural Science Foundation of China (81360482, 81560572, 81673346 and 81460020). We would like to thank LetPub (www.letpub.com) for providing linguistic assistance during the preparation of this manuscript.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (NSFC) (81360482, 81560572, 81673346 and 81460020).