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Rhodamine B-Conjugated Fluorescent Block Copolymer Micelles for Efficient Chlorambucil Delivery and Intracellular Imaging
[Image: see text] The clinical development of the anticancer drug chlorambucil (CHL) is limited by its low solubility in water, poor bioavailability, and off-target toxicity. Besides, another constraint for monitoring intracellular drug delivery is the non-fluorescent nature of CHL. Nanocarriers bas...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10308396/ https://www.ncbi.nlm.nih.gov/pubmed/37396240 http://dx.doi.org/10.1021/acsomega.3c01514 |
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author | Kulkarni, Bhagyashree Qutub, Somayah Khashab, Niveen M. Hadjichristidis, Nikos |
author_facet | Kulkarni, Bhagyashree Qutub, Somayah Khashab, Niveen M. Hadjichristidis, Nikos |
author_sort | Kulkarni, Bhagyashree |
collection | PubMed |
description | [Image: see text] The clinical development of the anticancer drug chlorambucil (CHL) is limited by its low solubility in water, poor bioavailability, and off-target toxicity. Besides, another constraint for monitoring intracellular drug delivery is the non-fluorescent nature of CHL. Nanocarriers based on block copolymers of poly(ethylene glycol)/poly(ethylene oxide) (PEG/PEO) and poly(ε-caprolactone) (PCL) are an elegant choice for drug delivery applications due to their high biocompatibility and inherent biodegradability properties. Here, we have designed and prepared block copolymer micelles (BCM) containing CHL (BCM-CHL) from a block copolymer having fluorescent probe rhodamine B (RhB) end-groups to achieve efficient drug delivery and intracellular imaging. For this purpose, the previously reported tetraphenylethylene (TPE)-containing poly(ethylene oxide)-b-poly(ε-caprolactone) [TPE-(PEO-b-PCL)(2)] triblock copolymer was conjugated with RhB by a feasible and effective post-polymerization modification method. In addition, the block copolymer was obtained by a facile and efficient synthetic strategy of one-pot block copolymerization. The amphiphilicity of the resulting block copolymer TPE-(PEO-b-PCL-RhB)(2) led to the spontaneous formation of micelles (BCM) in aqueous media and successful encapsulation of the hydrophobic anticancer drug CHL (CHL-BCM). Dynamic light scattering and transmission electron microscopy analyses of BCM and CHL-BCM revealed a favorable size (10–100 nm) for passive targeting of tumor tissues via the enhanced permeability and retention effect. The fluorescence emission spectrum (λ(ex) 315 nm) of BCM demonstrated Förster resonance energy transfer between TPE aggregates (donor) and RhB (acceptor). On the other hand, CHL-BCM revealed TPE monomer emission, which may be attributed to the π–π stacking interaction between TPE and CHL molecules. The in vitro drug release profile showed that CHL-BCM exhibits drug release in a sustained manner over 48 h. A cytotoxicity study proved the biocompatibility of BCM, while CHL-BCM revealed significant toxicity to cervical (HeLa) cancer cells. The inherent fluorescence of RhB in the block copolymer offered an opportunity to directly monitor the cellular uptake of the micelles by confocal laser scanning microscopy imaging. These results demonstrate the potential of these block copolymers as drug nanocarriers and as bioimaging probes for theranostic applications. |
format | Online Article Text |
id | pubmed-10308396 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-103083962023-06-30 Rhodamine B-Conjugated Fluorescent Block Copolymer Micelles for Efficient Chlorambucil Delivery and Intracellular Imaging Kulkarni, Bhagyashree Qutub, Somayah Khashab, Niveen M. Hadjichristidis, Nikos ACS Omega [Image: see text] The clinical development of the anticancer drug chlorambucil (CHL) is limited by its low solubility in water, poor bioavailability, and off-target toxicity. Besides, another constraint for monitoring intracellular drug delivery is the non-fluorescent nature of CHL. Nanocarriers based on block copolymers of poly(ethylene glycol)/poly(ethylene oxide) (PEG/PEO) and poly(ε-caprolactone) (PCL) are an elegant choice for drug delivery applications due to their high biocompatibility and inherent biodegradability properties. Here, we have designed and prepared block copolymer micelles (BCM) containing CHL (BCM-CHL) from a block copolymer having fluorescent probe rhodamine B (RhB) end-groups to achieve efficient drug delivery and intracellular imaging. For this purpose, the previously reported tetraphenylethylene (TPE)-containing poly(ethylene oxide)-b-poly(ε-caprolactone) [TPE-(PEO-b-PCL)(2)] triblock copolymer was conjugated with RhB by a feasible and effective post-polymerization modification method. In addition, the block copolymer was obtained by a facile and efficient synthetic strategy of one-pot block copolymerization. The amphiphilicity of the resulting block copolymer TPE-(PEO-b-PCL-RhB)(2) led to the spontaneous formation of micelles (BCM) in aqueous media and successful encapsulation of the hydrophobic anticancer drug CHL (CHL-BCM). Dynamic light scattering and transmission electron microscopy analyses of BCM and CHL-BCM revealed a favorable size (10–100 nm) for passive targeting of tumor tissues via the enhanced permeability and retention effect. The fluorescence emission spectrum (λ(ex) 315 nm) of BCM demonstrated Förster resonance energy transfer between TPE aggregates (donor) and RhB (acceptor). On the other hand, CHL-BCM revealed TPE monomer emission, which may be attributed to the π–π stacking interaction between TPE and CHL molecules. The in vitro drug release profile showed that CHL-BCM exhibits drug release in a sustained manner over 48 h. A cytotoxicity study proved the biocompatibility of BCM, while CHL-BCM revealed significant toxicity to cervical (HeLa) cancer cells. The inherent fluorescence of RhB in the block copolymer offered an opportunity to directly monitor the cellular uptake of the micelles by confocal laser scanning microscopy imaging. These results demonstrate the potential of these block copolymers as drug nanocarriers and as bioimaging probes for theranostic applications. American Chemical Society 2023-06-14 /pmc/articles/PMC10308396/ /pubmed/37396240 http://dx.doi.org/10.1021/acsomega.3c01514 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Kulkarni, Bhagyashree Qutub, Somayah Khashab, Niveen M. Hadjichristidis, Nikos Rhodamine B-Conjugated Fluorescent Block Copolymer Micelles for Efficient Chlorambucil Delivery and Intracellular Imaging |
title | Rhodamine B-Conjugated Fluorescent Block Copolymer
Micelles for Efficient Chlorambucil Delivery and Intracellular Imaging |
title_full | Rhodamine B-Conjugated Fluorescent Block Copolymer
Micelles for Efficient Chlorambucil Delivery and Intracellular Imaging |
title_fullStr | Rhodamine B-Conjugated Fluorescent Block Copolymer
Micelles for Efficient Chlorambucil Delivery and Intracellular Imaging |
title_full_unstemmed | Rhodamine B-Conjugated Fluorescent Block Copolymer
Micelles for Efficient Chlorambucil Delivery and Intracellular Imaging |
title_short | Rhodamine B-Conjugated Fluorescent Block Copolymer
Micelles for Efficient Chlorambucil Delivery and Intracellular Imaging |
title_sort | rhodamine b-conjugated fluorescent block copolymer
micelles for efficient chlorambucil delivery and intracellular imaging |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10308396/ https://www.ncbi.nlm.nih.gov/pubmed/37396240 http://dx.doi.org/10.1021/acsomega.3c01514 |
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