Uittreksel
Biodegradable, semipermeable nanoreactors that are capable of undergoing cellular integration and, subsequently, function as synthetic organelles represent an exciting therapeutic technology. Polymersomal nanoreactors have been investigated as a suitable candidate for the engineering of such a system, with the chemical versatility and structural robustness required for such a demanding application. Although steps have been taken to demonstrate this capacity, there has yet to be a system presented with biochemically robust data showing therapeutic efficacy in primary human cells. The reason for this shortfall is the absence of essential criteria of the polymersomes tested so far; biodegradability, intrinsic semipermeability, and a biomedically relevant setting. Herein, we present enzyme-loaded, biodegradable poly(ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-PCLgTMC) polymersomal nanoreactors, readily fabricated using the biocompatible direct hydration methodology. Physical characterization of PEG-PCLgTMC polymersomes highlights their semipermeable membrane and ability to shield enzymatic cargo. Surface modification with cell-penetrating peptides (CPPs) directs cellular integration of enzyme-loaded PEG-PCLgTMC nanoreactors in a controlled fashion. Using HEK293T cells and human skin fibroblasts we demonstrate that biocompatible catalase nanoreactors successfully perform as a synthetic organelle, imparting activity-dependent antioxidant (reactive-oxygen-species-shielding, ROS-shielding) capacity to cells. Notably, for the first time, patient-derived human-complex-I-deficient primary fibroblasts are effectively protected against the toxicity of exogenous H2O2 by the action of internalized enzyme-loaded nanoreactors, showcasing this system in a therapeutically relevant context.
| Taal | Engels |
|---|---|
| Pagina's | 917-928 |
| Aantal pagina's | 12 |
| Tijdschrift | ACS Central Science |
| Volume | 4 |
| Nummer van het tijdschrift | 7 |
| DOI's | |
| Status | Gepubliceerd - 25 jul 2018 |
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Biodegradable synthetic organelles demonstrate ROS shielding in human-complex-I-deficient fibroblasts. / van Oppen, Lisanne M.P.E.; Abdelmohsen, Loai K.E.A.; van Emst-de Vries, Sjenet E.; Welzen, Pascal L.W.; Wilson, Daniela A.; Smeitink, Jan A.M.; Koopman, Werner J.H.; Brock, Roland; Willems, Peter H.G.M.; Williams, David S.; van Hest, Jan C.M.
In: ACS Central Science, Vol. 4, Nr. 7, 25.07.2018, blz. 917-928.Onderzoeksoutput: Bijdrage aan tijdschrift › Tijdschriftartikel › Academic › peer review
TY - JOUR
T1 - Biodegradable synthetic organelles demonstrate ROS shielding in human-complex-I-deficient fibroblasts
AU - van Oppen,Lisanne M.P.E.
AU - Abdelmohsen,Loai K.E.A.
AU - van Emst-de Vries,Sjenet E.
AU - Welzen,Pascal L.W.
AU - Wilson,Daniela A.
AU - Smeitink,Jan A.M.
AU - Koopman,Werner J.H.
AU - Brock,Roland
AU - Willems,Peter H.G.M.
AU - Williams,David S.
AU - van Hest,Jan C.M.
PY - 2018/7/25
Y1 - 2018/7/25
N2 - Biodegradable, semipermeable nanoreactors that are capable of undergoing cellular integration and, subsequently, function as synthetic organelles represent an exciting therapeutic technology. Polymersomal nanoreactors have been investigated as a suitable candidate for the engineering of such a system, with the chemical versatility and structural robustness required for such a demanding application. Although steps have been taken to demonstrate this capacity, there has yet to be a system presented with biochemically robust data showing therapeutic efficacy in primary human cells. The reason for this shortfall is the absence of essential criteria of the polymersomes tested so far; biodegradability, intrinsic semipermeability, and a biomedically relevant setting. Herein, we present enzyme-loaded, biodegradable poly(ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-PCLgTMC) polymersomal nanoreactors, readily fabricated using the biocompatible direct hydration methodology. Physical characterization of PEG-PCLgTMC polymersomes highlights their semipermeable membrane and ability to shield enzymatic cargo. Surface modification with cell-penetrating peptides (CPPs) directs cellular integration of enzyme-loaded PEG-PCLgTMC nanoreactors in a controlled fashion. Using HEK293T cells and human skin fibroblasts we demonstrate that biocompatible catalase nanoreactors successfully perform as a synthetic organelle, imparting activity-dependent antioxidant (reactive-oxygen-species-shielding, ROS-shielding) capacity to cells. Notably, for the first time, patient-derived human-complex-I-deficient primary fibroblasts are effectively protected against the toxicity of exogenous H2O2 by the action of internalized enzyme-loaded nanoreactors, showcasing this system in a therapeutically relevant context.
AB - Biodegradable, semipermeable nanoreactors that are capable of undergoing cellular integration and, subsequently, function as synthetic organelles represent an exciting therapeutic technology. Polymersomal nanoreactors have been investigated as a suitable candidate for the engineering of such a system, with the chemical versatility and structural robustness required for such a demanding application. Although steps have been taken to demonstrate this capacity, there has yet to be a system presented with biochemically robust data showing therapeutic efficacy in primary human cells. The reason for this shortfall is the absence of essential criteria of the polymersomes tested so far; biodegradability, intrinsic semipermeability, and a biomedically relevant setting. Herein, we present enzyme-loaded, biodegradable poly(ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-PCLgTMC) polymersomal nanoreactors, readily fabricated using the biocompatible direct hydration methodology. Physical characterization of PEG-PCLgTMC polymersomes highlights their semipermeable membrane and ability to shield enzymatic cargo. Surface modification with cell-penetrating peptides (CPPs) directs cellular integration of enzyme-loaded PEG-PCLgTMC nanoreactors in a controlled fashion. Using HEK293T cells and human skin fibroblasts we demonstrate that biocompatible catalase nanoreactors successfully perform as a synthetic organelle, imparting activity-dependent antioxidant (reactive-oxygen-species-shielding, ROS-shielding) capacity to cells. Notably, for the first time, patient-derived human-complex-I-deficient primary fibroblasts are effectively protected against the toxicity of exogenous H2O2 by the action of internalized enzyme-loaded nanoreactors, showcasing this system in a therapeutically relevant context.
UR - http://www.scopus.com/inward/record.url?scp=85050556147&partnerID=8YFLogxK
U2 - 10.1021/acscentsci.8b00336
DO - 10.1021/acscentsci.8b00336
M3 - Article
VL - 4
SP - 917
EP - 928
JO - ACS Central Science
T2 - ACS Central Science
JF - ACS Central Science
SN - 2374-7951
IS - 7
ER -