Morphology Regulation in Redox Destructible Amphiphilic Block Copolymers and Impact on Intracellular Drug Delivery

Bej, Raju; Sarkar, Jayita; Ray, Debes; Aswal, Vinod K.; Ghosh, Suhrit

doi:10.1002/mabi.201800057

Cited by 21 publications

(21 citation statements)

References 76 publications

(34 reference statements)

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“…Having been demonstrated the pHtriggered release of payloads, in the following step, the intracellular drug delivery capability of BPDC2 and the control alternating polymer without drug attachment (see BPC in Scheme S1) and free CBL were investigated by assessing the cytotoxicity in human embryonic kidney cells 293 (HEK 293) and cervical cancer (HeLa) cell lines using MTT assay. 51 Both the normal and cancer cell lines were exposed to various drug concentrations present in the nanoparticles ranging from 0 to 28 μg/mL (polymer concentration: 250 to 1000 μg/mL, 7 μg/mL of CBL in 250 μg/mL polymeric scaffold, the drug loading content is 9.29%) for 24 h at 37 °C. The cytotoxicity results are shown in Figure 6A, where more than 75% cell viability is observed with BPC in both HEK 293 and HeLa cell lines even at a very high dose of 1000 μg/mL, indicating the biocompatibility of nascent polymeric scaffold for drug delivery applications.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Aromatic Nitrogen Mustard-Based Autofluorescent Amphiphilic Brush Copolymer as pH-Responsive Drug Delivery Vehicle

Saha¹,

Choudhury²,

Seal³

et al. 2018

Biomacromolecules

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Delivery of clinically approved nonfluorescent drugs is facing challenges because it is difficult to monitor the intracellular drug delivery without incorporating any integrated fluorescence moiety into the drug carrier. The present investigation reports the synthesis of a pH-responsive autofluorescent polymeric nanoscaffold for the administration of nonfluorescent aromatic nitrogen mustard chlorambucil (CBL) drug into the cancer cells. Copolymerization of poly(ethylene glycol) (PEG) appended styrene and CBL conjugated N-substituted maleimide monomers enables the formation of well-defined luminescent alternating copolymer. These amphiphilic brush copolymers self-organized in aqueous medium into 25–68 nm nanoparticles, where the CBL drug is enclosed into the core of the self-assembled nanoparticles. In vitro studies revealed ∼70% drug was retained under physiological conditions at pH 7.4 and 37 °C. At endolysosomal pH 5.0, 90% of the CBL was released by the pH-induced cleavage of the aliphatic ester linkages connecting CBL to the maleimide unit. Although the nascent nanoparticle (without drug conjugation) is nontoxic, the drug conjugated nanoparticle showed higher toxicity and superior cell killing capability in cervical cancer (HeLa) cells rather than in normal cells. Interestingly, the copolymer without any conventional chromophore exhibited photoluminescence under UV light irradiation due to the presence of “through-space” π–π interaction between the CO group of maleimide unit and the adjacent benzene ring of the styrenic monomer. This property helped us intracellular tracking of CBL conjugated autofluorescent nanocarriers through fluorescence microscope imaging. Finally, the 4-(4-nitrobenzyl)pyridine (NBP) colorimetric assay was executed to examine the ability of CBL-based polymeric nanomaterials toward alkylation of DNA.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Aromatic Nitrogen Mustard-Based Autofluorescent Amphiphilic Brush Copolymer as pH-Responsive Drug Delivery Vehicle

Saha¹,

Choudhury²,

Seal³

et al. 2018

Biomacromolecules

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“…The incorporation of disulfide bonds in the middle/side chain of ABC or in a cross-linker provide redox responsiveness to SAN. Tumor-relevant GSH concentration cleavages these bonds, inducing nanocarrier disassembly and cargo release into cancer cells (Wen et al, 2011;Thambi et al, 2012;Hu et al, 2013;Jia et al, 2014;Li et al, 2014;Sun et al, 2014;Wen and Li, 2014;Che and van Hest, 2016;Thambi et al, 2016;Zou et al, 2016;Hu et al, 2017;Zhao et al, 2017;Bej et al, 2018;Qin et al, 2018;García, 2019b;Kumar et al, 2020;Wei Y. et al, 2020;Zhong et al, 2020).…”

Section: Enzyme-responsive Nanocarriersmentioning

confidence: 99%

Overcoming Biological Barriers With Block Copolymers-Based Self-Assembled Nanocarriers. Recent Advances in Delivery of Anticancer Therapeutics

et al. 2020

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Cancer is one of the most common life-threatening illness and it is the world’s second largest cause of death. Chemotherapeutic anticancer drugs have many disadvantages, which led to the need to develop novel strategies to overcome these shortcomings. Moreover, tumors are heterogenous in nature and there are various biological barriers that assist in treatment reisistance. In this sense, nanotechnology has provided new strategies for delivery of anticancer therapeutics. Recently, delivery platforms for overcoming biological barriers raised by tumor cells and tumor-bearing hosts have been reported. Among them, amphiphilic block copolymers (ABC)-based self-assembled nanocarriers have attracted researchers worldwide owing to their unique properties. In this work, we addressed different biological barriers for effective cancer treatment along with several strategies to overcome them by using ABC‐based self-assembled nanostructures, with special emphasis in those that have the ability to act as responsive nanocarriers to internal or external environmental clues to trigger release of the payload. These nanocarriers have shown promising properties to revolutionize cancer treatment and diagnosis, but there are still challenges for their successful translation to clinical applications.

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“…The tripeptide glutathione (GSH) plays a significant role in controlling the redox state of a cell, and it is well-known that the intracellular GSH concentration (5–10 mM) is significantly higher than that in the extracellular domain , and GSH can reduce a disulfide bond to free thiol. Therefore, disulfide-containing polymers or disulfide-bridged polymer–drug conjugates have been extensively studied for therapeutic delivery application. − We have recently introduced fully bioreducible polydisulfide (PDS) and related amphiphilic polymers and demonstrated their aqueous aggregation and GSH-triggered disassembly. − However, in majority of the examples of amphiphilic polymers including disulfide-containing polymers or our PDS-derived amphiphilic polymers, polyethylene glycol (PEG) serves as the hydrophilic segment and encases the hydrophobic core/membrane of the aqueous aggregate. Albeit having several advantages, PEGylation suffers from hypersensitivity, stress-induced degradation, toxicity of side products, non-biodegradability, the lack of functional groups, and others .…”

Section: Introductionmentioning

confidence: 99%

Polymersome Formation by Amphiphilic Polyglycerol-b-polydisulfide-b-polyglycerol and Glutathione-Triggered Intracellular Drug Delivery

et al. 2020

Self Cite

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This article reports the synthesis, spontaneous selfassembly, highly efficient drug encapsulation, and glutathione (GSH)triggered intracellular sustained drug delivery of an ABA-type amphiphilic triblock copolymer, namely, polyglycerol-b-poly-(disulfide)-b-polyglycerol (PG-b-PDS-b-PG). The bioreducible PDS block with reactive pyridyldisulfide groups present at the chain terminals was attached to thiol-terminated heterotelechelic PG by a thiol− disulfide exchange reaction producing the amphiphilic PG-b-PDS-b-PG. It formed a stable polymersome in aqueous medium with a critical aggregation concentration of 0.02 mg/mL and average hydrodynamic diameter (D h ) of 230 nm and showed highly efficient and stable encapsulation of doxorubicin (Dox) with a remarkably high drug loading efficiency (DLE) and drug loading content (DLC) of 54% and 16%, respectively. Fluorescence spectroscopy studies revealed GSH-triggered drug release and strong dependence of the release kinetics on the GSH concentration due to degradation of the amphiphilic block copolymer and disassembly of the polymersome. MTT assay indicated excellent biocompatibility of the block copolymer as >90% cells (HeLa or MDA-MB-231) were found to be alive after 96 h of incubation with a polymer concentration of up to 1.0 mg/mL, which was further validated by the hemolysis assay. Cytotoxicity assay of the Dox-loaded polymersome exhibited time and dose-dependent sustained killing of HeLa as well as MDA-MB-231 cells wherein after 48 h of incubation >50% cell killing was noticed with a Dox concentration of ∼4.0 and ∼8.7 μg/mL, respectively, while the free Dox showed faster cell killing. Flow cytometry and live cell fluorescence microscopy studies revealed time-dependent cellular uptake of the drug-loaded polymersome followed by diffusion of the drug to the nucleus. Cells with artificially enhanced GSH were killed at a much faster rate indicating that intracellular GSH-triggered disassembly is the key drug release mechanism.

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Morphology Regulation in Redox Destructible Amphiphilic Block Copolymers and Impact on Intracellular Drug Delivery

Cited by 21 publications

References 76 publications

Aromatic Nitrogen Mustard-Based Autofluorescent Amphiphilic Brush Copolymer as pH-Responsive Drug Delivery Vehicle

Aromatic Nitrogen Mustard-Based Autofluorescent Amphiphilic Brush Copolymer as pH-Responsive Drug Delivery Vehicle

Overcoming Biological Barriers With Block Copolymers-Based Self-Assembled Nanocarriers. Recent Advances in Delivery of Anticancer Therapeutics

Polymersome Formation by Amphiphilic Polyglycerol-b-polydisulfide-b-polyglycerol and Glutathione-Triggered Intracellular Drug Delivery

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