Stimuli-responsive copolymer solution and surface assemblies for biomedical applications

Abstract

Stimuli-responsive polymeric materials is one of the fastest growing fields of the 21st century, with the annual number of papers published more than quadrupling in the last ten years. The responsiveness of polymer solution assemblies and surfaces to biological stimuli (e.g. pH, reduction-oxidation, enzymes, glucose) and externally applied triggers (e.g. temperature, light, solvent quality) shows particular promise for various biomedical applications including drug delivery, tissue engineering, medical diagnostics, and bioseparations. Furthermore, the integration of copolymer architectures into stimuli-responsive materials design enables exquisite control over the locations of responsive sites within self-assembled nanostructures. The combination of new synthesis techniques and well-defined copolymer self-assembly has facilitated substantial developments in stimuli-responsive materials in recent years. In this tutorial review, we discuss several methods that have been employed to synthesize self-assembling and stimuli-responsive copolymers for biomedical applications, and we identify common themes in the response mechanisms among the targeted stimuli. Additionally, we highlight parallels between the chemistries used for generating solution assemblies and those employed for creating copolymer surfaces.

Fig 1

(a) Schematic representation of copolymer architectures used in stimuli-responsive materials, where the response is localized to the units shown as green diamonds. (b) Chemical and physical changes of copolymers in response to a stimulus can grant access to one or multiple response modes (i.e. bond cleavage or conformational/solubility change).

Fig 2

Typical copolymer solution assemblies used in drug delivery applications. Red and blue regions represent the hydrophobic and hydrophilic domains, respectively. Hydrophobic drugs are shown in yellow, and hydrophilic therapeutics are shown in green.

Fig 3

(a) Prior to the application of a stimulus, functional groups (green triangles) are hidden within the collapsed block copolymer brush. Upon application of a stimulus, chain extension exposes the functional groups to the surface. (b) Nanostructure reorientation within a block copolymer thin film in response to a stimulus permits control over surface patterns.

Fig 4

Schematic of responsive KPK morphologies showing the formation of high interfacial curvature micelles at low pH where the K block exists as a random coil, and low interfacial curvature structures (vesicles or disk micelles) at higher pH where the K block adopts an α-helix conformation. Adapted from Ref. . Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA.

Fig 5

Cartoon showing redox-responsive assembly and disassembly of selenium-grafted PEG-b-PAA polymers (selenium shown in red). Adapted from Ref. .

Fig 6

(a) Structure of PS-b-PFS before and after oxidation, where R = CH₃ and R’ = CH₂CH₃. (b) AFM phase image showing selective ferritin (white dots) adsorption onto PFS domains (light domains) in an oxidized PS-b-PFS thin film. Adapted from Ref. . Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA.

Fig 7

DNA-brush copolymer structural rearrangement induced by enzymatic cleavage of a portion of the DNA brush. (left) TEM micrograph of spherical micelles formed in aqueous solutions. (middle) Cartoon representation of the changes in copolymer structure that lead to changes in self-assembly. (right) Cylindrical micelles formed following enzymatic cleavage. Adapted from Ref. . Copyright 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Fig 8

Ionization equilibrium of boronic acids. In aqueous solutions, the neutral, hydrophobic form of boronic acid is in equilibrium with the anionic, hydrophilic form. The balance of this equilibrium depends on the pH of the solution and the pKa of the boronic acid moiety, and increasing the concentration of glucose shifts the equilibrium towards the hydrophilic (water-soluble) forms.

Fig 9

Reversible cell adhesion via the thermal response of PEG copolymers. (a) Cartoon of adhesive state and optical micrograph of cells with spread morphology. (b) Cartoon of cell-repellent state and optical micrograph of cells with rounded morphology. Scale bars correspond to 100 μm. Adapted from Ref. . Copyright 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

Fig 10

Common photo-responsive chemistries.

Fig 11

(a) Synthetic scheme for fabricating copolymer brushes for dual protein patterning. In step 1, PHEMA is grafted to the substrate surface. In step 2, the PHEMA brushes are quaternized, giving them a positive charge. In step 3, the ONB groups are selectively cleaved, exposing negatively charged carboxylic acid groups. (b, c) Selective protein adsorption onto photo-patterned PHEMA surfaces. (b) Fluorescently-labeled proteins [bovine serum albumin (BSA), green, negatively charged; avidin (AV), red, positively charged] attached to the oppositely charged areas of the surface. (c) Non-fluorescent BSA and AV were placed on the surface and immunolabeled with fluorescent antibodies to demonstrate that the adsorbed proteins retained their functionality. Adapted from Ref. .

Fig 12

Hollow nanoparticle templates fabricated by controlling solvent quality during the assembly of a triblock copolymer [PTEPM-b-PS-b-P2VP; PTEPM: poly((3-triethoxysilyl)propyl methacrylate)]. (Step 1) Upon addition of methanol to a solution of unimers in THF, the triblock self-assembles into a micelle with a PS core and a PTEPM/P2VP corona. (Step 2) Addition of acidic water protonates the P2VP block and collapses the PTEPM block onto the PS core where it is subsequently cross-linked. (Step 3) When the micelles are returned to a good solvent, the cross-linked PTEPM block prevents dissociation into unimers, and the PS block is extracted from the core of the micelle, producing a hollow nanoparticle. (Step 4) Subsequent switching between poor and good solvent conditions reversibly collapses the PS block onto the PTEPM shell and protonates the P2VP block. Adapted from Ref. . Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA.

Fig 13

Release profile of a fluorescent dye in response to both a reducing agent (slow response) and short exposures to UV light (fast response). The reducing agent was added at t = 0 min, and the solutions were exposed to UV light at t = 180 min and t = 360 min. (Inset) Schematic representation of block copolymer micelles containing redox-responsive and photo-labile groups. Adapted from Ref. . Copyright 2012 American Chemical Society.

Fig 14

Schematic representation PNIPAM-b-PDMAEA and mCherry protein coacervate micelles formed due to ionic interactions between the positively charged polymer and negatively charged protein. Thin films were cast from these coacervate micelle solutions and stabilized by heating the film above the LCST of the PNIPAM block, allowing for pH-dependent mCherry release. Adapted from Ref. . Copyright 2012 American Chemical Society.