Journal article
Liposomal Encapsulation of Chlorambucil with a Terpyridine-Based, Glutathione-Targeted Optical Probe Facilitates Cell Entry and Cancer Cell Death
ACS applied bio materials, Vol.8(1), pp.570-581
01/20/2025
DOI: 10.1021/acsabm.4c01448
PMID: 39686811
Abstract
The nitrogen mustard alkylating agent chlorambucil (CBL) is a critical component of chemotherapeutic regimens used in the treatment of chronic lymphocytic leukemia. The cancer cell-killing actions of CBL are limited by glutathione (GSH) conjugation, a process catalyzed by the GSH transferase hGSTA1-1 that triggers CBL efflux from cells. In the cancer cell microenvironment, intracellular GSH levels are elevated to counterbalance oxidative stress generated due to the high glycolytic demand. As many chemotherapeutic drugs trigger cell death through mechanisms that depend on reactive oxygen species (ROS), antioxidant capacity in cancer cells also represents a barrier to anticancer therapies. Here, we demonstrate that a heightened GSH content in cancer cells can also be exploited for cell-selective drug delivery. We successfully synthesized a malononitrile conjugate terpyridine-based derivative
, which specifically reacts with GSH in the presence of other biologically relevant amino acids including cysteine (Cys) and homocysteine (Hcy). The significant change in the electronic spectra of
in the presence of GSH confirmed GSH detection, which was further corroborated by density functional theory calculations. We next encapsulated CBL into
-containing, anthracene-functionalized, and 10,12-pentacosadiynoic acid (PCDA)- and 1,2-dimyristoyl-
-glycero-3-phosphocholine (DMPC)-based liposomes (
). We established successful CBL encapsulation and release from
-containing liposomes in GSH-enriched cancer cells in vitro. Both
and the
-lacking
control displayed cell-killing activity. However, human triple-negative breast cancer cells MDAMB231, human lung cancer cells A549, and murine leukemic WEHI cells were more sensitive to the cytotoxic effects of
compared to the nonmalignant cells (AC16 and HEK293). Indeed, in these cancer cell lines,
induced greater ROS generation compared to that of
. Together, our results provide initial evidence of the feasibility of exploiting the unique oxidant environment of cancer cells for optimized drug delivery.
Details
- Title: Subtitle
- Liposomal Encapsulation of Chlorambucil with a Terpyridine-Based, Glutathione-Targeted Optical Probe Facilitates Cell Entry and Cancer Cell Death
- Creators
- Mallayasamy Siva - SRM Institute of Science and TechnologyKiran Das - Sanjay Gandhi Post Graduate Institute of Medical SciencesPriya Rana - SRM Institute of Science and TechnologyAbhijit Saha - SRM Institute of Science and TechnologyDebasish Mandal - Thapar Institute of Engineering & TechnologyAtanu Barik - Homi Bhabha National InstituteAdele Stewart - University of IowaBiswanath Maity - Bose InstitutePriyadip Das - SRM Institute of Science and Technology
- Resource Type
- Journal article
- Publication Details
- ACS applied bio materials, Vol.8(1), pp.570-581
- Publisher
- AMER CHEMICAL SOC
- DOI
- 10.1021/acsabm.4c01448
- PMID
- 39686811
- ISSN
- 2576-6422
- eISSN
- 2576-6422
- Grant note
- SRM Institute of Science and Technology: 58/14/14/2021-BRNS/37219 Board of Research in Nuclear Sciences (BRNS), India: 5/4/1-22/CVD/2022-NCD-I Indian Council of Medical Research
P.D. extends gratitude to the Board of Research in Nuclear Sciences (BRNS), India, for financial support (Grant no: 58/14/14/2021-BRNS/37219), as well as to the Interdisciplinary Institute of Indian System of Medicine (IIISM) and Nano Research Centre (NRC) at SRM Institute of Science & Technology. B.M. expresses appreciation to the Indian Council of Medical Research for financial support (Grant no: 5/4/1-22/CVD/2022-NCD-I). We also extend our thanks to SRMIST, CBMR, and Bose Institute for providing the necessary instruments and laboratory facilities to carry out this research.
- Language
- English
- Electronic publication date
- 12/17/2024
- Date published
- 01/20/2025
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984757745602771
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