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Synergistic effects of thermosensitive liposomal doxorubicin, mild hyperthermia, and radiotherapy in breast cancer management: an orthotopic mouse model study

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Abstract

Liposome formulations of the cancer drug doxorubicin have been developed to address the severe side effects that result from administration of this drug in a conventional formulation. Among them, thermosensitive liposomal doxorubicin presents enhanced tumor targeting and efficient drug release when combined with mild hyperthermia localized to the tumor site. Exploiting the radiosensitizing benefits of localized thermal therapy, the integration of radiation therapy with the thermally activated liposomal system is posited to amplify the anti-tumor efficacy. This study explored a synergistic therapeutic strategy that combines thermosensitive liposomal doxorubicin, mild hyperthermia, and radiotherapy, using an orthotopic murine model of breast cancer. The protocol of sequential multi-modal treatment, incorporating low-dose chemotherapy and radiotherapy, substantially postponed the progression of primary tumor growth in comparison to the application of monotherapy at elevated dosages. Improvements in unheated distant lesions were also observed. Furthermore, the toxicity associated with the combination treatment was comparable to that of either thermosensitive liposome treatment or radiation alone at low doses. These outcomes underscore the potential of multi-modal therapeutic strategies to refine treatment efficacy while concurrently diminishing adverse effects in the management of breast cancer, providing valuable insight for the future refinement of thermosensitive liposomal doxorubicin applications.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

DPPC:

1,2-dipalmitoyl-sn-glycero-3-phosphocholine

DPPG2 :

1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol

DSPE-mPEG2000 :

N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine

EPR:

Enhanced permeability and retention

HCC:

Hepatocellular carcinoma

HBS:

HEPES buffered saline

HBSS:

Hanks’ balanced salt solution

H&E:

Hematoxylin and eosin

HT:

Mild hyperthermia

MSPC:

1-stearoyl-2-lyso-sn-glycero-3-phosphocholine

RFA:

Radiofrequency ablation

RT:

Radiotherapy

ThermoDXR:

Thermosensitive liposomal doxorubicin

TNBC:

Triple negative breast cancer

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Acknowledgements

This study was supported by a CIHR project grant to C.A. The authors acknowledge the use of equipment in the Centre for Pharmaceutical Oncology (CPO) at the University of Toronto as well as at the STTARR Innovation Centre (University Health Network). Graphical abstract and Fig. 1 were created using Biorender.

Funding

This work was supported by a CIHR project grant to C.A (Grant Number PJT155905).

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Authors and Affiliations

  1. Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada

    Xuehan Wang & Christine Allen

  2. Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada

    Christine Allen

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Xuehan Wang: conceptualization, methodology, investigation, analysis, writing-original draft, writing-revision, and visualization. Christine Allen: conceptualization, writing-review and editing, supervision, funding acquisition.

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Correspondence to Christine Allen.

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Wang, X., Allen, C. Synergistic effects of thermosensitive liposomal doxorubicin, mild hyperthermia, and radiotherapy in breast cancer management: an orthotopic mouse model study. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01654-2

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