Native chemical ligation for cross-linking of flower-like micelles

Marzieh Najafi, Neda Kordalivand, Mohammad Amin Moradi, Joep Van Den Dikkenberg, Remco Fokkink, Heiner Friedrich, Nico A.J.M. Sommerdijk, Mathew Hembury, Tina Vermonden

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3 Citaties (Scopus)

Uittreksel

In this study, native chemical ligation (NCL) was used as a selective cross-linking method to form core-cross-linked thermosensitive polymeric micelles for drug delivery applications. To this end, two complementary ABA triblock copolymers having polyethylene glycol (PEG) as midblock were synthesized by atom transfer radical polymerization (ATRP). The thermosensitive poly isopropylacrylamide (PNIPAM) outer blocks of the polymers were copolymerized with either N-(2-hydroxypropyl)methacrylamide-cysteine (HPMA-Cys), P(NIPAM-co-HPMA-Cys)-PEG-P(NIPAM-co-HPMA-Cys) (PNC) or N-(2-hydroxypropyl)methacrylamide-ethylthioglycolate succinic acid (HPMA-ETSA), P(NIPAM-co-HPMA-ETSA)-PEG-P(NIPAM-co-HPMA-ETSA) (PNE). Mixing of these polymers in aqueous solution followed by heating to 50 °C resulted in the formation of thermosensitive flower-like micelles. Subsequently, native chemical ligation in the core of micelles resulted in stabilization of the micelles with a Z-average of 65 nm at body temperature. Decreasing the temperature to 10 °C only affected the size of the micelles (increased to 90 nm) but hardly affected the polydispersity index (PDI) and aggregation number (Nagg) confirming covalent stabilization of the micelles by NCL. CryoTEM images showed micelles with an uniform spherical shape and dark patches close to the corona of micelles were observed in the tomographic view. The dark patches represent more dense areas in the micelles which coincide with the higher content of HPMA-Cys/ETSA close to the PEG chain revealed by the polymerization kinetics study. Notably, this cross-linking method provides the possibility for conjugation of functional molecules either by using the thiol moieties still present after NCL or by simply adjusting the molar ratio between the polymers (resulting in excess cysteine or thioester moieties) during micelle formation. Furthermore, in vitro cell experiments demonstrated that fluorescently labeled micelles were successfully taken up by HeLa cells while cell viability remained high even at high micelle concentrations. These results demonstrate the potential of these micelles for drug delivery applications.

TaalEngels
Pagina's3766-3775
Aantal pagina's10
TijdschriftBiomacromolecules
Volume19
Nummer van het tijdschrift9
DOI's
StatusGepubliceerd - 10 sep 2018

Vingerafdruk

Micelles
Cysteine
Polyethylene glycols
Succinic Acid
Polymers
Drug delivery
Acids
Stabilization
Atom transfer radical polymerization
Polydispersity
N-(2-hydroxypropyl)methacrylamide
Sulfhydryl Compounds
Block copolymers
Agglomeration
Polymerization
Cells

Citeer dit

Najafi, M., Kordalivand, N., Moradi, M. A., Van Den Dikkenberg, J., Fokkink, R., Friedrich, H., ... Vermonden, T. (2018). Native chemical ligation for cross-linking of flower-like micelles. Biomacromolecules, 19(9), 3766-3775. DOI: 10.1021/acs.biomac.8b00908
Najafi, Marzieh ; Kordalivand, Neda ; Moradi, Mohammad Amin ; Van Den Dikkenberg, Joep ; Fokkink, Remco ; Friedrich, Heiner ; Sommerdijk, Nico A.J.M. ; Hembury, Mathew ; Vermonden, Tina. / Native chemical ligation for cross-linking of flower-like micelles. In: Biomacromolecules. 2018 ; Vol. 19, Nr. 9. blz. 3766-3775
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abstract = "In this study, native chemical ligation (NCL) was used as a selective cross-linking method to form core-cross-linked thermosensitive polymeric micelles for drug delivery applications. To this end, two complementary ABA triblock copolymers having polyethylene glycol (PEG) as midblock were synthesized by atom transfer radical polymerization (ATRP). The thermosensitive poly isopropylacrylamide (PNIPAM) outer blocks of the polymers were copolymerized with either N-(2-hydroxypropyl)methacrylamide-cysteine (HPMA-Cys), P(NIPAM-co-HPMA-Cys)-PEG-P(NIPAM-co-HPMA-Cys) (PNC) or N-(2-hydroxypropyl)methacrylamide-ethylthioglycolate succinic acid (HPMA-ETSA), P(NIPAM-co-HPMA-ETSA)-PEG-P(NIPAM-co-HPMA-ETSA) (PNE). Mixing of these polymers in aqueous solution followed by heating to 50 °C resulted in the formation of thermosensitive flower-like micelles. Subsequently, native chemical ligation in the core of micelles resulted in stabilization of the micelles with a Z-average of 65 nm at body temperature. Decreasing the temperature to 10 °C only affected the size of the micelles (increased to 90 nm) but hardly affected the polydispersity index (PDI) and aggregation number (Nagg) confirming covalent stabilization of the micelles by NCL. CryoTEM images showed micelles with an uniform spherical shape and dark patches close to the corona of micelles were observed in the tomographic view. The dark patches represent more dense areas in the micelles which coincide with the higher content of HPMA-Cys/ETSA close to the PEG chain revealed by the polymerization kinetics study. Notably, this cross-linking method provides the possibility for conjugation of functional molecules either by using the thiol moieties still present after NCL or by simply adjusting the molar ratio between the polymers (resulting in excess cysteine or thioester moieties) during micelle formation. Furthermore, in vitro cell experiments demonstrated that fluorescently labeled micelles were successfully taken up by HeLa cells while cell viability remained high even at high micelle concentrations. These results demonstrate the potential of these micelles for drug delivery applications.",
author = "Marzieh Najafi and Neda Kordalivand and Moradi, {Mohammad Amin} and {Van Den Dikkenberg}, Joep and Remco Fokkink and Heiner Friedrich and Sommerdijk, {Nico A.J.M.} and Mathew Hembury and Tina Vermonden",
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Najafi, M, Kordalivand, N, Moradi, MA, Van Den Dikkenberg, J, Fokkink, R, Friedrich, H, Sommerdijk, NAJM, Hembury, M & Vermonden, T 2018, 'Native chemical ligation for cross-linking of flower-like micelles' Biomacromolecules, vol. 19, nr. 9, blz. 3766-3775. DOI: 10.1021/acs.biomac.8b00908

Native chemical ligation for cross-linking of flower-like micelles. / Najafi, Marzieh; Kordalivand, Neda; Moradi, Mohammad Amin; Van Den Dikkenberg, Joep; Fokkink, Remco; Friedrich, Heiner; Sommerdijk, Nico A.J.M.; Hembury, Mathew; Vermonden, Tina.

In: Biomacromolecules, Vol. 19, Nr. 9, 10.09.2018, blz. 3766-3775.

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

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T1 - Native chemical ligation for cross-linking of flower-like micelles

AU - Najafi,Marzieh

AU - Kordalivand,Neda

AU - Moradi,Mohammad Amin

AU - Van Den Dikkenberg,Joep

AU - Fokkink,Remco

AU - Friedrich,Heiner

AU - Sommerdijk,Nico A.J.M.

AU - Hembury,Mathew

AU - Vermonden,Tina

PY - 2018/9/10

Y1 - 2018/9/10

N2 - In this study, native chemical ligation (NCL) was used as a selective cross-linking method to form core-cross-linked thermosensitive polymeric micelles for drug delivery applications. To this end, two complementary ABA triblock copolymers having polyethylene glycol (PEG) as midblock were synthesized by atom transfer radical polymerization (ATRP). The thermosensitive poly isopropylacrylamide (PNIPAM) outer blocks of the polymers were copolymerized with either N-(2-hydroxypropyl)methacrylamide-cysteine (HPMA-Cys), P(NIPAM-co-HPMA-Cys)-PEG-P(NIPAM-co-HPMA-Cys) (PNC) or N-(2-hydroxypropyl)methacrylamide-ethylthioglycolate succinic acid (HPMA-ETSA), P(NIPAM-co-HPMA-ETSA)-PEG-P(NIPAM-co-HPMA-ETSA) (PNE). Mixing of these polymers in aqueous solution followed by heating to 50 °C resulted in the formation of thermosensitive flower-like micelles. Subsequently, native chemical ligation in the core of micelles resulted in stabilization of the micelles with a Z-average of 65 nm at body temperature. Decreasing the temperature to 10 °C only affected the size of the micelles (increased to 90 nm) but hardly affected the polydispersity index (PDI) and aggregation number (Nagg) confirming covalent stabilization of the micelles by NCL. CryoTEM images showed micelles with an uniform spherical shape and dark patches close to the corona of micelles were observed in the tomographic view. The dark patches represent more dense areas in the micelles which coincide with the higher content of HPMA-Cys/ETSA close to the PEG chain revealed by the polymerization kinetics study. Notably, this cross-linking method provides the possibility for conjugation of functional molecules either by using the thiol moieties still present after NCL or by simply adjusting the molar ratio between the polymers (resulting in excess cysteine or thioester moieties) during micelle formation. Furthermore, in vitro cell experiments demonstrated that fluorescently labeled micelles were successfully taken up by HeLa cells while cell viability remained high even at high micelle concentrations. These results demonstrate the potential of these micelles for drug delivery applications.

AB - In this study, native chemical ligation (NCL) was used as a selective cross-linking method to form core-cross-linked thermosensitive polymeric micelles for drug delivery applications. To this end, two complementary ABA triblock copolymers having polyethylene glycol (PEG) as midblock were synthesized by atom transfer radical polymerization (ATRP). The thermosensitive poly isopropylacrylamide (PNIPAM) outer blocks of the polymers were copolymerized with either N-(2-hydroxypropyl)methacrylamide-cysteine (HPMA-Cys), P(NIPAM-co-HPMA-Cys)-PEG-P(NIPAM-co-HPMA-Cys) (PNC) or N-(2-hydroxypropyl)methacrylamide-ethylthioglycolate succinic acid (HPMA-ETSA), P(NIPAM-co-HPMA-ETSA)-PEG-P(NIPAM-co-HPMA-ETSA) (PNE). Mixing of these polymers in aqueous solution followed by heating to 50 °C resulted in the formation of thermosensitive flower-like micelles. Subsequently, native chemical ligation in the core of micelles resulted in stabilization of the micelles with a Z-average of 65 nm at body temperature. Decreasing the temperature to 10 °C only affected the size of the micelles (increased to 90 nm) but hardly affected the polydispersity index (PDI) and aggregation number (Nagg) confirming covalent stabilization of the micelles by NCL. CryoTEM images showed micelles with an uniform spherical shape and dark patches close to the corona of micelles were observed in the tomographic view. The dark patches represent more dense areas in the micelles which coincide with the higher content of HPMA-Cys/ETSA close to the PEG chain revealed by the polymerization kinetics study. Notably, this cross-linking method provides the possibility for conjugation of functional molecules either by using the thiol moieties still present after NCL or by simply adjusting the molar ratio between the polymers (resulting in excess cysteine or thioester moieties) during micelle formation. Furthermore, in vitro cell experiments demonstrated that fluorescently labeled micelles were successfully taken up by HeLa cells while cell viability remained high even at high micelle concentrations. These results demonstrate the potential of these micelles for drug delivery applications.

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U2 - 10.1021/acs.biomac.8b00908

DO - 10.1021/acs.biomac.8b00908

M3 - Article

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JO - Biomacromolecules

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Najafi M, Kordalivand N, Moradi MA, Van Den Dikkenberg J, Fokkink R, Friedrich H et al. Native chemical ligation for cross-linking of flower-like micelles. Biomacromolecules. 2018 sep 10;19(9):3766-3775. Beschikbaar vanaf, DOI: 10.1021/acs.biomac.8b00908