Delineating the tumour microenvironment response to a lipid nanoparticle formulation

Jessica Ngai; Presley MacMillan; Benjamin R Kingston; Zachary P Lin; Ben Ouyang; Warren C W Chan

doi:10.1016/j.jconrel.2022.12.021

Delineating the tumour microenvironment response to a lipid nanoparticle formulation

J Control Release. 2023 Jan:353:988-1001. doi: 10.1016/j.jconrel.2022.12.021. Epub 2022 Dec 21.

Authors

Jessica Ngai¹, Presley MacMillan², Benjamin R Kingston³, Zachary P Lin⁴, Ben Ouyang⁵, Warren C W Chan⁶

Affiliations

¹ Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario M5S 3E5, Canada; Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada; Institute of Biomedical Engineering, University of Toronto, Rosebrugh Building, 164 College Street, Toronto, Ontario M5S 3G9, Canada.
² Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
³ Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, 2720 S. Moody Avenue, Portland, OR 97201, United States.
⁴ Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada; Institute of Biomedical Engineering, University of Toronto, Rosebrugh Building, 164 College Street, Toronto, Ontario M5S 3G9, Canada.
⁵ Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada; Institute of Biomedical Engineering, University of Toronto, Rosebrugh Building, 164 College Street, Toronto, Ontario M5S 3G9, Canada; MD/PhD Program, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02111, United States of America.
⁶ Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario M5S 3E5, Canada; Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada; Institute of Biomedical Engineering, University of Toronto, Rosebrugh Building, 164 College Street, Toronto, Ontario M5S 3G9, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada; Department of Material Science and Engineering, University of Toronto, 184 College Street, Toronto, Ontario M5S 3E4, Canada. Electronic address: warren.chan@utoronto.ca.

PMID: 36516899
DOI: 10.1016/j.jconrel.2022.12.021

Abstract

Nanoparticles can reduce cytotoxicity, increase circulation time and increase accumulation in tumours compared to free drug. However, the value of using nanoparticles for carrying small molecules to treat tumours at the cellular level has been poorly established. Here we conducted a cytodistribution analysis on Doxorubicin-treated and Doxil-treated tumours to delineate the differences between the small molecule therapeutic Doxorubicin and its packaged liposomal formulation Doxil. We found that Doxil kills more cancer cells, macrophages and neutrophils in the 4T1 breast cancer tumour model, but there is delayed killing compared to its small molecule counterpart Doxorubicin. The cellular interaction with Doxil has slower uptake kinetics and the particles must be degraded to release the drug and kill the cells. We also found that macrophages and neutrophils in Doxil-treated tumours repopulated faster than cancer cells during the relapse phase. While researchers conventionally use tumour volume and animal survival to determine a therapeutic effect, our results show diverse cell killing and a greater amount of cell death in vivo after Doxil liposomes are administered. We conclude that the fate and behaviour of the nanocarrier influences its effectiveness as a cancer therapy. Further investigations on the interactions between different nanoparticle designs and the tumour microenvironment components will lead to more precise engineering of nanocarriers to selectively kill tumour cells and prolong the therapeutic effect.

Keywords: Cancer; Cytodistribution; Doxil; Doxorubicin; Flow cytometry; Liposomes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Doxorubicin / therapeutic use
Liposomes / therapeutic use
Nanoparticles*
Neoplasms* / drug therapy
Polyethylene Glycols
Tumor Microenvironment

Substances

liposomal doxorubicin
Lipid Nanoparticles
Liposomes
Doxorubicin
Polyethylene Glycols

Abstract

Publication types

MeSH terms

Substances

Grants and funding