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Liposomal Formulation of Hydroxychloroquine Can Inhibit Autophagy In Vivo Dragowska, Wieslawa H.; Singh, Jagbir; Wehbe, Mohamed; Anantha, Malathi; Edwards, Katarina; Gorski, Sharon M.; Bally, Marcel B., 1956-; Leung, Ada W. Y.

Abstract

Background/Objectives: Preclinical studies have shown that the anti-malarial drug hydroxychloroquine (HCQ) improves the anti-cancer effects of various therapeutic agents by impairing autophagy. These findings are difficult to translate in vivo as reaching an effective HCQ concentration at the tumor site for extended times is challenging. Previously, we found that free HCQ in combination with gefitinib (Iressa®, ZD1839) significantly reduced tumor volume in immunocompromised mice bearing gefitinib-resistant JIMT-1 breast cancer xenografts. Here, we sought to evaluate whether a liposomal formulation of HCQ could effectively modulate autophagy in vivo and augment treatment outcomes in the same tumor model. Methods: We developed two liposomal formulations of HCQ: a pH-loaded formulation and a formulation based on copper complexation. The pharmacokinetics of each formulation was evaluated in CD1 mice following intravenous administration. An efficacy study was performed in immunocompromised mice bearing established JIMT-1tumors. Autophagy markers in tumor tissue harvested after four weeks of treatment were assessed by Western blot. Results: The liposomal formulations engendered ~850-fold increases in total drug exposure over time relative to the free drug. Both liposomal and free HCQ in combination with gefitinib provided comparable therapeutic benefits (p > 0.05). An analysis of JIMT-1 tumor tissue indicated that the liposomal HCQ and gefitinib combination augmented the inhibition of autophagy in vivo compared to the free HCQ and gefitinib combination as demonstrated by increased LC3-II and p62/SQSTM1 (p62) protein levels. Conclusions: The results suggest that liposomal HCQ has a greater potential to modulate autophagy in vivo compared to free HCQ; however, this did not translate to better therapeutic effects when used in combination with gefitinib to treat a gefitinib-resistant tumor model.

Item Metadata

Title
Liposomal Formulation of Hydroxychloroquine Can Inhibit Autophagy In Vivo
Creator
Dragowska, Wieslawa H.; Singh, Jagbir; Wehbe, Mohamed; Anantha, Malathi; Edwards, Katarina; Gorski, Sharon M.; Bally, Marcel B., 1956-; Leung, Ada W. Y.
Contributor
BC Cancer Agency; Michael Smith Genome Sciences Centre; Therapeutics Initiative (University of British Columbia)
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2024-12-30
Description
Background/Objectives: Preclinical studies have shown that the anti-malarial drug hydroxychloroquine (HCQ) improves the anti-cancer effects of various therapeutic agents by impairing autophagy. These findings are difficult to translate in vivo as reaching an effective HCQ concentration at the tumor site for extended times is challenging. Previously, we found that free HCQ in combination with gefitinib (Iressa®, ZD1839) significantly reduced tumor volume in immunocompromised mice bearing gefitinib-resistant JIMT-1 breast cancer xenografts. Here, we sought to evaluate whether a liposomal formulation of HCQ could effectively modulate autophagy in vivo and augment treatment outcomes in the same tumor model. Methods: We developed two liposomal formulations of HCQ: a pH-loaded formulation and a formulation based on copper complexation. The pharmacokinetics of each formulation was evaluated in CD1 mice following intravenous administration. An efficacy study was performed in immunocompromised mice bearing established JIMT-1tumors. Autophagy markers in tumor tissue harvested after four weeks of treatment were assessed by Western blot. Results: The liposomal formulations engendered ~850-fold increases in total drug exposure over time relative to the free drug. Both liposomal and free HCQ in combination with gefitinib provided comparable therapeutic benefits (p > 0.05). An analysis of JIMT-1 tumor tissue indicated that the liposomal HCQ and gefitinib combination augmented the inhibition of autophagy in vivo compared to the free HCQ and gefitinib combination as demonstrated by increased LC3-II and p62/SQSTM1 (p62) protein levels. Conclusions: The results suggest that liposomal HCQ has a greater potential to modulate autophagy in vivo compared to free HCQ; however, this did not translate to better therapeutic effects when used in combination with gefitinib to treat a gefitinib-resistant tumor model.
Subject
liposomes; hydroxychloroquine; autophagy; breast cancer; gefitinib
Genre
Article
Type
Text
Language
eng
Date Available
2025-02-03
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0447910
URI
http://hdl.handle.net/2429/90309
Affiliation
Medicine, Faculty of; Pharmaceutical Sciences, Faculty of; Non UBC; Pathology and Laboratory Medicine, Department of
Citation
Pharmaceutics 17 (1): 42 (2025)
Publisher DOI
10.3390/pharmaceutics17010042
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0