Thermoresponsive Polymer Assemblies: From Molecular Design to Theranostics Application

Abstract

Molecule self-assembly is a ubiquitous phenomenon and a key driving force for constructing nanostructures with diverse morphology and controllable size. Recently, interests in constructing environmentally responsive nanostructures have been growing, due to its diverse stimuli responsiveness. Thermoresponsive polymers as a class of smart materials, undergoes a phase transition by temperature stimuli, resulting assembly of molecules to construct diverse nanostructures with unique morphology and size. Over the past decades, supramolecular assembly in static solutions is well-established, while translating the self-assembly of synthetic molecules from the static controlled conditions to highly complex and dynamic environment of living systems is still challenging. In this review, we provide a brief overview of building blocks for constructing thermoresponsive polymer assemblies particularly those are suitable for in vivo self-assembly. Then we review recent contributions on molecular design and methods for constructing thermoresponsive polymer assemblies in vitro, particularly highlight those are instructive for the subsequent in vivo self-assembly. Furthermore, the tips for successful in vivo construction, self-assembly structure-property relationship, the advantages of in vivo self-assembled thermoresponsive materials for imaging or therapy and material topology-bioeffects relationship are emphasized.

Introduction

The functions and all major natural processes of living cells are regulated by macromolecules that respond to changes in the local environment and through their hierarchical structures and cooperative interactions [1], [2], [3]. There is an ever-increasing and intense interest within the chemical and material sciences to understand, mimic and interface with these biological systems using stimuli-responsive polymers [4], [5], [6]. Of particular interest are thermoresponsive polymers that can undergo conformational or phase transition in response to variations in temperature [7], [8], [9], [10], [11], [12], [13]. Since the first report in 1967 by Scarpa and co-workers [14], thermoresponsive polymers, as smart building blocks, have led to the construction of various topologically controlled structures [15], [16], [17], [18], [19] and advanced in cutting-edge nanotechnology [20], [21], [22] and biomedical applications (e.g. bio-imaging [23], [24], [25] and therapy [26], [27], [28]). In turn, the needs in biomedical applications have given rise to the synthesis of biodegradable thermoresponsive polymers [29], [30], [31] and also the discovery of naturally-derived thermoresponsive polymers [32], [33], [34].

There are two types of thermoresponsive polymers, i.e., lower critical solution temperature (LCST) type and upper critical solution temperature (UCST) type. Due to the abundance of polymers that exhibit LCST behavior, this review article will focus on thermoresponsive polymers that have LCST behavior. At temperature below the phase transition temperature, a LCST-type polymer is completely soluble due to extensive hydrogen bonding interactions with the surrounding water molecules and restricted intra- and intermolecular hydrogen bonding between polymer molecules [9]. Upon heating, the hydrogen bonding between the polymer backbone and the surrounding water molecules become weak, while polymer-polymer interaction interactions dominate, which results in a phase-separation. This process is reversible. The transition temperature of a polymer is one of the most important parameters to take into account when considering applications under a given set of conditions [9], which can be readily tuned by incorporating hydrophilic or hydrophobic modules during the synthesis steps. The detailed description can be found in Sumerlin's work [9]. Several studies have highlighted the abnormal temperatures in tumors and other inflammatory diseases as a direct result of abnormal blood flow, leukocyte infiltration, a high rate of metabolic activity, and a high rate of cell proliferation in diseased tissues [35]. Besides these intrinsic temperature variations, larger temperature changes can be induced artificially at specific locations by applying heat from an external source, which exploits the higher sensitivity of tumor tissues to high temperatures as compared to normal tissues [35]. Both intrinsic tumor temperature variations and externally induced hyperthermic temperature changes offer attractive stimuli for the site specific controlling the assembly or disassembly of the thermoresponsive polymers [35].

Self-assembly of thermoresponsive polymers is so far mainly studied in vitro [5,36,37]. However, in the past few years, an innovative research field has emerged, in which the self-assembling of polymers is orchestrated in vivo to generate fascinating new functional and bioactive materials [38], [39], [40]. This upcoming area is promising to become an important playground in chemical biology and biomedical field. Till now, the design and implementation of precise and controllable assembly in complex physiological conditions and the regulation of biological functions are still facing significant challenges. Due to the property similarity with several intracellular biomolecules [41,42], thermoresponsive polymers are especially suitable for constructing topological-controlled self-assemblies in vivo, and have already displayed exciting performance in bio-imaging and disease therapy [3,6,43].

This review summarizes the main categories of newly discovered thermoresponsive polymers used to engineer topologically controlled self-assembly in vitro and in vivo (Fig. 1). Especially, the tips for in vivo construction of thermoresponsive self-assemblies, the characterization techniques, the advantages of using in vivo constructed thermoresponsive self-assembles for theranostics, and the relationship between the topological structures and bio-effects are highlighted. Finally, we briefly outline our perspectives and discuss the challenges in this area. We envision that this review could further facilitate the design of biomedical materials and provides insights for personal medicine and precise medicine.