Thermoresponsive Polymer Assemblies: From Molecular Design to Theranostics Application
Graphical abstract
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.
Section snippets
Self-assembling units for the construction of thermoresponsive polymer assemblies
Numerous polymers show thermal response phase transition characteristics (Table 1), which can be divided into two categories according to their sources: synthetic polymers and natural polymers. The study of thermoresponsive polymers starts from the discovery of thermal behavior of synthetic polymer poly(N-isopropylacrylamide) (PNIPAAm) in 1967 [14]. Thereafter, numerous thermoresponsive polymers were synthesized [44], [45], [46], [47], [48] and naturally occurring polymers [49], [50], [51], [52]
Molecular design and methods for constructing thermoresponsive polymer assemblies in vitro
The necessity to control and guide the self-assembly of thermoresponsive polymers into specific superstructures stems from the need in materials and biological sciences to better exploit their often-high inherent functionalities for advanced materials [2,[169], [170], [171], [172], [173]]. Structures determine functions [174], [175], [176]. In this section, we review the common approaches to construct topological different thermoresponsive self-assemblies and analyze their properties. We also
In vivo constructed thermoresponsive polymer assemblies and its properties
Supramolecular assembly has succeeded in constructing sophisticated structures in static and simple solutions in vitro [276], [277], [278], [279], [280], [281], [282]. Translating the self-assembly of synthetic molecules from the static controlled conditions in a test tube to the highly complex and dynamic environment of living systems is a non-trivial matter [6,[38], [39], [40],283]. Artificially controlling molecular self-assembly in living systems can not only deepen our understanding of
Conclusions and perspectives
Thermoresponsive building blocks can be assembled into supramolecular materials with precise structure and function, which has great potential for applications in the biomedical field. In this review, we have highlighted the recent progresses made in the field of self-assembled thermoresponsive materials for theranostics application. In last few decades, synthetic thermoresponsive polymers are flourished and helped researchers to understand their phase properties. In recent years, accompanied
CRediT authorship contribution statement
Sheng-Lin Qiao: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Muhetaerjiang Mamuti: Writing – review & editing. Hong-Wei An: . Hao Wang: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing – review & editing.
Declaration of Competing Interest
We declare that there are no competing interests.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Nos. 21374026 and 51573032), the National Science Fund for Distinguished Young Scholars (No. 51725302), Science Fund for Creative Research Groups of the National Natural Science Foundation of China (No. 11621505), CAS Key Research Program for Frontier Sciences (No. QYZDJ-SSW-SLH022), Key Project of Chinese Academy of Sciences in Cooperation with Foreign Enterprises (No. GJHZ1541), and CAS Interdisciplinary Innovation
References (334)
- et al.
Thermo-responsive block copolymers with multiple phase transition temperatures in aqueous solutions
Prog Polym Sci
(2015) - et al.
Temperature responsive bio-compatible polymers based on poly(ethylene oxide) and poly(2-oxazoline)s
Prog Polym Sci
(2012) - et al.
Protein Phase Separation: A New Phase in Cell Biology
Trends Cell Biol
(2018) - et al.
Nanoantagonists with nanophase-segregated surfaces for improved cancer immunotherapy
Biomaterials
(2018) - et al.
Effect of ELP Sequence and Fusion Protein Design on Concentrated Solution Self-Assembly
Biomacromolecules
(2016) Non-linear PEG-based thermoresponsive polymer systems
Prog Polym Sci
(2017)- et al.
Thermoresponsive poly(oligo ethylene glycol acrylates)
Prog Polym Sci
(2014) - et al.
mTOR Regulates Phase Separation of PGL Granules to Modulate Their Autophagic Degradation
Cell
(2018) - et al.
Controllable protein phase separation and modular recruitment to form responsive membraneless organelles
Nat Commun
(2018) - et al.
Intracellular construction of topology-controlled polypeptide nanostructures with diverse biological functions
Nat Commun
(2017)
Engineering responsive polymer building blocks with host-guest molecular recognition for functional applications
Acc Chem Res
Cooperative macromolecular self-assembly toward polymeric assemblies with multiple and bioactive functions
Acc Chem Res
General Approach of Stimuli-Induced Aggregation for Monitoring Tumor Therapy
ACS Nano
To aggregate, or not to aggregate? considerations in the design and application of polymeric thermally-responsive nanoparticles
Chem Soc Rev
Temperature- and light-responsive smart polymer materials
Chem Soc Rev
New directions in thermoresponsive polymers
Chem Soc Rev
Transiently thermoresponsive polymers and their applications in biomedicine
Chem Soc Rev
An Intelligent Transdermal Formulation of ALA-Loaded Copolymer Thermogel with Spontaneous Asymmetry by Using Temperature-Induced Sol–Gel Transition and Gel–Sol (Suspension) Transition on Different Sides
Adv Funct Mater
Slow hydrogen-deuterium exchange in a non-.alpha.-helical polyamide
J Am Chem Soc
Thermo-Switchable Materials Prepared Using the OEGMA-Platform
Adv Mater
Maintenance of amyloid beta peptide homeostasis by artificial chaperones based on mixed-shell polymeric micelles
Angew Chem Int Ed
Multimodal Shape Transformation of Dual-Responsive DNA Block Copolymers
J Am Chem Soc
Thermally triggered self-assembly of folded proteins into vesicles
J Am Chem Soc
Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity
Nat Chem
Magnetic field remotely controlled selective biocatalysis
Nat Catalysis
Thermoresponsive actuation enabled by permittivity switching in an electrostatically anisotropic hydrogel
Nat Mater
Affinity purification of plasmid DNA by temperature-triggered precipitation
Nat Protoc
Intracellular cascade FRET for temperature imaging of living cells with polymeric ratiometric fluorescent thermometers
ACS Appl Mater Interfaces
Dynamic contrast-enhanced photoacoustic imaging using photothermal stimuli-responsive composite nanomodulators
Nat Commun
Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy
Nat Commun
In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity
Nat Biotechnol
Macroscale delivery systems for molecular and cellular payloads
Nat Mater
Stimuli-responsive nanocarriers for drug delivery
Nat Mater
Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release
Chem Rev
Polyphosphoesters: New Trends in Synthesis and Drug Delivery Applications
Macromol Biosci
Temperature-responsive compounds as in situ gelling biomedical materials
Chem Soc Rev
Noncovalent Modulation of the Inverse Temperature Transition and Self-Assembly of Elastin-b-Collagen-like Peptide Bioconjugates
J Am Chem Soc
Intermolecular Structural Change for Thermoswitchable Polymeric Photosensitizer
J Am Chem Soc
Sequence heuristics to encode phase behaviour in intrinsically disordered protein polymers
Nat Mater
Thermoresponsive Polymeric Assemblies and Their Biological Applications
Temperature-Controlled Assembly and Release from Polymer Vesicles of Poly(ethylene oxide)-block- poly(N-isopropylacrylamide)
Adv Mater
Competitive Self-Assembly Kinetics as a Route To Control the Morphology of Core-Crystalline Cylindrical Micelles
J Am Chem Soc
Situ Formation of Nanofibers from Purpurin18-Peptide Conjugates and the Assembly Induced Retention Effect in Tumor Sites
Adv Mater
Controlling cancer cell fate using localized biocatalytic self-assembly of an aromatic carbohydrate amphiphile
J Am Chem Soc
Taurine Boosts Cellular Uptake of Small D-Peptides for Enzyme-Instructed Intracellular Molecular Self-Assembly
J Am Chem Soc
Biomolecular condensates: organizers of cellular biochemistry
Nat Rev Mol Cell Biol
Thermoresponsive nanocomposites from multilayers of nanofibrillated cellulose and specially designed N-isopropylacrylamide based polymers
Soft Matter
Analyte-Reactive Amphiphilic Thermoresponsive Diblock Copolymer Micelles-Based Multifunctional Ratiometric Fluorescent Chemosensors
Macromolecules
Formation of a mesoscopic skin barrier in mesoglobules of thermoresponsive polymers
J Am Chem Soc
Fluorescent water-soluble responsive polymers site-specifically labeled with FRET dyes possessing pH- and thermo-modulated multicolor fluorescence emissions as dual ratiometric probes
J Mate Chem
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