Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra-and intracellular environments
In the treatment of lung cancer, there is an urgent need of innovative medicines to optimize pharmacological responses of conventional chemotherapeutics while attenuating side effects. Here, we have exploited some relatively unexplored subtle differences in reduction potential, associated with cance...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English English |
| Published: |
Elsevier
2018
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| Online Access: | https://eprints.nottingham.ac.uk/50374/ |
| _version_ | 1848798235607433216 |
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| author | Conte, Claudia Mastrotto, Francesca Taresco, Vincenzo Tchoryk, Aleksandra Quaglia, Fabiana Stolnik, Snjezana Alexander, Cameron |
| author_facet | Conte, Claudia Mastrotto, Francesca Taresco, Vincenzo Tchoryk, Aleksandra Quaglia, Fabiana Stolnik, Snjezana Alexander, Cameron |
| author_sort | Conte, Claudia |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | In the treatment of lung cancer, there is an urgent need of innovative medicines to optimize pharmacological responses of conventional chemotherapeutics while attenuating side effects. Here, we have exploited some relatively unexplored subtle differences in reduction potential, associated with cancer cell microenvironments in addition to the well-known changes in intracellular redox environment. We report the synthesis and application of novel redox-responsive PLGA (poly(lactic-co-glycolic acid)) -PEG(polyethylene glycol) nanoparticles (RR-NPs) programmed to change surface properties when entering tumor microenvironments, thus enhance cell internalization of the particles and their drug cargo. The new co-polymers, in which PEG and PLGA were linked by ‘anchiomeric effector’ dithiylethanoate esters were synthesized by a combination of ring-opening polymerization and Michael addition reactions and employed to prepare NPs. Non redox-responsive nanoparticles (nRR-NPs) based on related PLGA-PEG copolymers were also prepared as comparators. Spherical NPs of around 120 nm diameter with a low polydispersity index and negative zeta potentials as well as good drug loading of docetaxel were obtained. The NPs showed prolonged stability in relevant simulated biological fluids and a high ability to penetrate an artificial mucus layer due to the presence of the external PEG coating. Stability, FRET and drug release studies in conditions simulating intracellular reductive environments demonstrated a fast disassembly of the external shell of the NPs, thus triggering on-demand drug release.
FACS measurements and confocal microscopy showed increased and faster uptake of RR-NPs in both 2D- and 3D- cell culture models of lung cancer compared to nRR-NPs. In particular, the ‘designed-in’ reductive instability of RR-NPs in conditioned cell media, the fast PEG release in the extracellular compartment, as well as a diminution of uptake rate in control experiments where extracellular thiols were neutralized, suggested a partial extracellular release of the PEG fringe that promoted rapid internalization of the residual NPs into cells.
Taken together, these results provide further evidence of the effectiveness of PEGylated reducible nanocarriers to permeate mucus layer barriers, and establish a new means to enhance cancer cell uptake of drug carriers by extra-and intra-cellular cleavage of protein-and cell-shielding hydrophilic blocks. |
| first_indexed | 2025-11-14T20:16:33Z |
| format | Article |
| id | nottingham-50374 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English English |
| last_indexed | 2025-11-14T20:16:33Z |
| publishDate | 2018 |
| publisher | Elsevier |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-503742019-03-12T04:30:10Z https://eprints.nottingham.ac.uk/50374/ Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra-and intracellular environments Conte, Claudia Mastrotto, Francesca Taresco, Vincenzo Tchoryk, Aleksandra Quaglia, Fabiana Stolnik, Snjezana Alexander, Cameron In the treatment of lung cancer, there is an urgent need of innovative medicines to optimize pharmacological responses of conventional chemotherapeutics while attenuating side effects. Here, we have exploited some relatively unexplored subtle differences in reduction potential, associated with cancer cell microenvironments in addition to the well-known changes in intracellular redox environment. We report the synthesis and application of novel redox-responsive PLGA (poly(lactic-co-glycolic acid)) -PEG(polyethylene glycol) nanoparticles (RR-NPs) programmed to change surface properties when entering tumor microenvironments, thus enhance cell internalization of the particles and their drug cargo. The new co-polymers, in which PEG and PLGA were linked by ‘anchiomeric effector’ dithiylethanoate esters were synthesized by a combination of ring-opening polymerization and Michael addition reactions and employed to prepare NPs. Non redox-responsive nanoparticles (nRR-NPs) based on related PLGA-PEG copolymers were also prepared as comparators. Spherical NPs of around 120 nm diameter with a low polydispersity index and negative zeta potentials as well as good drug loading of docetaxel were obtained. The NPs showed prolonged stability in relevant simulated biological fluids and a high ability to penetrate an artificial mucus layer due to the presence of the external PEG coating. Stability, FRET and drug release studies in conditions simulating intracellular reductive environments demonstrated a fast disassembly of the external shell of the NPs, thus triggering on-demand drug release. FACS measurements and confocal microscopy showed increased and faster uptake of RR-NPs in both 2D- and 3D- cell culture models of lung cancer compared to nRR-NPs. In particular, the ‘designed-in’ reductive instability of RR-NPs in conditioned cell media, the fast PEG release in the extracellular compartment, as well as a diminution of uptake rate in control experiments where extracellular thiols were neutralized, suggested a partial extracellular release of the PEG fringe that promoted rapid internalization of the residual NPs into cells. Taken together, these results provide further evidence of the effectiveness of PEGylated reducible nanocarriers to permeate mucus layer barriers, and establish a new means to enhance cancer cell uptake of drug carriers by extra-and intra-cellular cleavage of protein-and cell-shielding hydrophilic blocks. Elsevier 2018-03-08 Article PeerReviewed application/pdf en cc_by_nc_nd https://eprints.nottingham.ac.uk/50374/1/Conte%20et%20al_RRNPs%20JCR_final_clean.pdf application/pdf en cc_by_nc_nd https://eprints.nottingham.ac.uk/50374/2/ESI_final_clean.pdf Conte, Claudia, Mastrotto, Francesca, Taresco, Vincenzo, Tchoryk, Aleksandra, Quaglia, Fabiana, Stolnik, Snjezana and Alexander, Cameron (2018) Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra-and intracellular environments. Journal of Controlled Release . ISSN 1873-4995 (In Press) |
| spellingShingle | Conte, Claudia Mastrotto, Francesca Taresco, Vincenzo Tchoryk, Aleksandra Quaglia, Fabiana Stolnik, Snjezana Alexander, Cameron Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra-and intracellular environments |
| title | Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra-and intracellular environments |
| title_full | Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra-and intracellular environments |
| title_fullStr | Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra-and intracellular environments |
| title_full_unstemmed | Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra-and intracellular environments |
| title_short | Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra-and intracellular environments |
| title_sort | enhanced uptake in 2d- and 3d- lung cancer cell models of redox responsive pegylated nanoparticles with sensitivity to reducing extra-and intracellular environments |
| url | https://eprints.nottingham.ac.uk/50374/ |