Reversible Morphological Evolution of Responsive Giant Vesicles to Nanospheres by the Self‐Assembly of Crystalline‐b‐Coil Polyphosphazene Block Copolymers

Abstract

The preparation of long-term-stable giant unilamellar vesicles (GUVs, diameter ≥ 1000 nm) and large vesicles (diameter ≥ 500 nm) by self-assembly in THF of the crystalline-b-coil polyphosphazene block copolymers [N=P(OCH2CF3)2 ]n-b-[N=PMePh]m (4 a: n=30, m=20; 4 b: n=90, m=20; 4 c: n=200, m=85), which combine crystalline [N=P(OCH2CF3)2] and amorphous [N=PMePh] blocks, both of which are flexible, is reported. SEM, TEM, and wide-angle X-ray scattering experiments demonstrated that the stability of these GUVs is induced by crystallization of the [N=P(OCH2CF3)2] blocks at the capsule wall of the GUVS, with the [N=PMePh] blocks at the corona. Higher degrees of crystallinity of the capsule wall are found in the bigger vesicles, which suggests that the crystallinity of the [N=P(OCH2CF3)2] block facilitates the formation of large vesicles. The GUVs are responsive to strong acids (HOTf) and, after selective protonation of the [N=PMePh] block, they undergo a morphological evolution to smaller spherical micelles in which the core and corona roles have been inverted. This morphological evolution is totally reversible by neutralization with a base (NEt3), which regenerates the original GUVs. The monitoring of this process by dynamic light scattering allowed a mechanism to to be proposed for this reversible morphological evolution in which the block copolymer 4 a and its protonated form 4 a(+) are intermediates. This opens a route to the design of reversibly responsive polymeric systems in organic solvents. This is the first reversibly responsive vesicle system to operate in organic media.

Formation and Reversible Morphological Transition of Bicontinuous Nanospheres and Toroidal Micelles by the Self‐Assembly of a Crystalline‐b‐Coil Diblock Copolymer

“…Thec omplete lithiation of 1 was checked by treating af reshly prepared solution of 2 with ClSiMe 3 at room temperature (20 8 8C) and confirming the quantitative formation of [(4-trimethylsilyl)phenyl]diphenylphosphane (7;s ee the Supporting Information) and the total absence of 1 by 1 H, 13 C, and 31 PNMR spectroscopy.W hens tyrene (35 equiv) was quickly added to asolution of 2 (1 equiv) in toluene at room temperature,the telechelic polystyrene 3 (PS 35 -PPh 2 , M n = 3915, PDI = 1.1;see the Supporting Information) was obtained after quenching the reaction with ClSiMe 3 .T he chlorination of 3 with C 2 Cl 6 led to PS 35 -PPh 2 Cl 2 (4), which has ÀPPh 2 Cl 2 end groups that initiate the polymerization of Cl 3 P=NSiMe 3 [14] to give the block copolymer [N=PCl 2 ] 35 -PS 35 (5;s ee the Supporting Information). Thec omplete lithiation of 1 was checked by treating af reshly prepared solution of 2 with ClSiMe 3 at room temperature (20 8 8C) and confirming the quantitative formation of [(4-trimethylsilyl)phenyl]diphenylphosphane (7;s ee the Supporting Information) and the total absence of 1 by 1 H, 13 C, and 31 PNMR spectroscopy.W hens tyrene (35 equiv) was quickly added to asolution of 2 (1 equiv) in toluene at room temperature,the telechelic polystyrene 3 (PS 35 -PPh 2 , M n = 3915, PDI = 1.1;see the Supporting Information) was obtained after quenching the reaction with ClSiMe 3 .T he chlorination of 3 with C 2 Cl 6 led to PS 35 -PPh 2 Cl 2 (4), which has ÀPPh 2 Cl 2 end groups that initiate the polymerization of Cl 3 P=NSiMe 3 [14] to give the block copolymer [N=PCl 2 ] 35 -PS 35 (5;s ee the Supporting Information).…”

“…[4] Toroids are also very important in the design of artificial delivery systems for gene therapy. [13] Herein we report an ew and convenient synthesis of the hybrid crystalline-b-coil poly-[bis(trifluoroethoxy)phosphazene]-b-polystyrene (PTFEP-PS) by the use of lithiated initiators functionalized with phosphine groups (Scheme 1). [6] Since pioneering studies on the synthesis of toroidal [7] and bicontinuous nanostructures [8] from the selfassembly of BCPs,very few examples of toroidal (mixed with other morphologies) [9] and bicontinuous [10] micelles derived from BCPs have been reported, mostly from chemically and structurally rather complex combinations of blocks.However, these two morphologies have also been produced purely from simple linear block copolymers, [11] thus demonstrating that structural complexity is not an ecessary condition for their formation.…”

“…[5] On the other hand, micelles with internal bicontinuous structures are considered promising carriers for the simultaneous inclusion of chemically different encapsulated drugs and of interest for their possible catalytic and templating properties. Them acromolecular substitution of the chlorine atoms by À OCH 2 CF 3 groups led to the block copolymer PTFEP 35 -PS 35 (6)c ontaining crystalline [N = P(OCH 2 CF 3 ) 2 ] blocks.This synthetic methodology afforded 6 in similar yield (63 %) and with similar narrow polydispersities (PDI = 1.2; see the Supporting Information) to those of the previous method, [15] but by asignificantly simpler experimental procedure (only the intermediate polymer 3 was isolated and purified (see Scheme S1), whereas the other method requires the isolation of three different polymer intermediates).On the basis of our previous study,inwhich THF was used as as olvent for the crystallization of [N=P(OCH 2 CF 3 ) 2 ] blocks in the capsule wall of giant vesicles, [13] aggregates of 6 were induced by dissolving the block copolymer (1 mg) in THF (3 mL) at room temperature (note that the solubility parameters, d (MPa 1/2 ) = 18.6 (THF), [16] 18.6 (PS), [16] and 19.6 (PTFEP), [17] indicate that THF is ab etter solvent for the PS than for the PTFEP) and subjecting the solution to sonication for 2min at 20 8 8C( see the Supporting Information). [12] Recently,our group has demonstrated the synthesis of reversibly responsive (to changes in pH) giant unilamellar vesicles (GUVs) by the self-assembly of the BCPs [N = P(OCH 2 CF 3 ) 2 ] n -b-[N = PMePh] m containing crystalline [N=P(OCH 2 CF 3 ) 2 ]s egments.…”

“…On the basis of our previous study,inwhich THF was used as as olvent for the crystallization of [N=P(OCH 2 CF 3 ) 2 ] blocks in the capsule wall of giant vesicles, [13] aggregates of 6 were induced by dissolving the block copolymer (1 mg) in THF (3 mL) at room temperature (note that the solubility parameters, d (MPa 1/2 ) = 18.6 (THF), [16] 18.6 (PS), [16] and 19.6 (PTFEP), [17] indicate that THF is ab etter solvent for the PS than for the PTFEP) and subjecting the solution to sonication for 2min at 20 8 8C( see the Supporting Information). The resulting translucent solution of 6 was first investigated by dynamic light scattering (DLS;s ee Figure S8).…”

“…[12] Recently,our group has demonstrated the synthesis of reversibly responsive (to changes in pH) giant unilamellar vesicles (GUVs) by the self-assembly of the BCPs [13] Herein we report an ew and convenient synthesis of the hybrid crystalline-b-coil poly-[bis(trifluoroethoxy)phosphazene]-b-polystyrene (PTFEP-PS) by the use of lithiated initiators functionalized with phosphine groups (Scheme 1). [12] Recently,our group has demonstrated the synthesis of reversibly responsive (to changes in pH) giant unilamellar vesicles (GUVs) by the self-assembly of the BCPs [13] Herein we report an ew and convenient synthesis of the hybrid crystalline-b-coil poly-[bis(trifluoroethoxy)phosphazene]-b-polystyrene (PTFEP-PS) by the use of lithiated initiators functionalized with phosphine groups (Scheme 1).…”