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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...

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Autores principales: Kulkarni, Bhagyashree, Qutub, Somayah, Khashab, Niveen M., Hadjichristidis, Nikos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
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.
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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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