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 and. 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 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.

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…353,354 On the translational side, several preclinical studies reported the generation of nanoparticles or other nanoformulations for the improved delivery of ICD-inducing chemotherapies. 355 Mastria et al (Duke University, Durham, NC, USA) documented that a nanoparticle preparation of doxorubicin, i.e. chimeric polypeptide doxorubicin, efficiently enhances anticancer immunity as it favors tumor infiltration by T cells (including CD8+ T cells) and limits primary tumor growth as well as metastatic spread.…”

Liposomal Formulations to Modulate the Tumour Microenvironment and Antitumour Immune Response

“…The authors found that the liposomal formulation was able to reduce tumour-infiltrating regulatory T-cells, increase cytotoxic T-cell infiltration, and increase the expression of CD80 on mature DCs. Similarly, Huang et al demonstrated that ultrasound-controlled release of doxorubicin from liposome–microbubble complexes was associated with more potent ICD effects [ 193 ]. While current data suggest that improved delivery of chemotherapeutic ICD inducers may augment the immunogenicity of ICD treatments, it would be important to understand how different types of nanoparticles and their immunogenicity potential would impact the effectiveness of ICD-inducing treatments.…”

CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer

“…Accordingly, the death of cancer cells can be immunogenic or non-immunogenic depending on the initiating stimulus (19). Some chemotherapeutics are known to induce the immunogenic cell death (ICD) of cancer cells, including oxaliplatin, mitoxantrone, and doxorubicin (Dox), thereby initiating antitumor immune response activation (20). The effect of ICD inducers has been shown to be adaptive immunity-independent in some spontaneous mammary tumor models, indicating the insu ciency of ICD inducers in the induction of effective antitumor immunity (21).…”