Thermoresponsive Block Copolymers Research Articles

Structural study of two polymer chains of poly(2-methoxyethyl glycidyl ether)-b-poly(2-ethoxyethyl glycidyl ether) thermoresponsive block copolymers using molecular dynamics simulations

Block copolymers are expected to be applied in a wide variety of fields due to the property of self-assembly. Our group has reported that poly(glycidyl ether) block copolymers exhibited complex temperature response in aqueous solution. In this study, we investigated the two chains of the block copolymer structure and configurations at different temperatures by using MD simulation. The results showed that at low temperatures, the polymer structure is linear and can form micelles, but above a certain temperature, the polymer structure changes to a U-shape and the micelle structure would be destroyed, which is responsible for the complex temperature response.

Membrane-Active Thermoresponsive Block Copolymers Containing a Diacylglycerol-Based Segment: RAFT Synthesis, Doxorubicin Encapsulation, and Evaluation of Cytotoxicity against Breast Cancer Cells.

Herein, we report the formation of drug delivery systems from original thermoresponsive block copolymers containing lipid-based segments. Two acrylate monomers derived from palmitic- or oleic-acid-based diacylglycerols (DAGs) were synthesized and polymerized by the reversible addition-fragmentation chain transfer (RAFT) method. Well-defined DAG-based polymers with targeted molar masses and narrow molar mass distributions were next used as macro-chain transfer agents (macro-CTAs) for the polymerization of N-isopropylacrylamide (NIPAAm) or N-vinylcaprolactam (NVCL). The obtained amphiphilic block copolymers were formed into polymeric nanoparticles (PNPs) with and without encapsulated doxorubicin and characterized. Their biological assessment indicated appropriate cytocompatibility with the representatives of normal cells. Furthermore, compared to the free drug, increased cytotoxicity and apoptosis or necrosis induction in breast cancer cells was documented, including a highly aggressive and invasive triple-negative MDA-MB-231 cell line.

Characterization of the physical properties of the thermoresponsive block-copolymer PAGB2000 and numerical assessment of its potentialities in Forward Osmosis desalination

Forward Osmosis is a promising strategy for desalination processes, however some aspects have to be better characterized to make it competitive with other affirmed technologies. One of these aspects is the selection of the draw agent, i.e., a polymeric solution that has to fulfill different requirements to guarantee both high membrane performances and good regeneration process. Previous studies have identified a thermoresponsive copolymer known as PAGB2000 as potential draw agent. However, in the open literature there is no information on the thermo-physical properties required for a fully characterization of the polymer itself, hence, different experimental campaigns have been conducted to quantify: phase behavior, osmotic pressure, density, dynamic viscosity, thermal conductivity, thermal diffusivity and isobaric specific heat capacity. These properties were then used in a computational model to simulate the whole desalination process. Recovery ratio, specific electric consumption and specific thermal consumption were compared with the ones obtained in a previous work, showing that a detailed characterization of the thermo-physical properties is required to get accurate and realistic predictions of the system performance.

Ethylene glycol-based thermoresponsive block copolymer brushes with cell-affinity peptides for thermally controlled interaction with target cells

Tissue engineering has recently attracted attention as a potential remedy for intractable diseases. To be effective, such treatments require cell separation methods that do not modify cellular surfaces. In this study, we developed cell separation materials using ethylene glycol-based thermoresponsive block copolymer brushes and cell-affinity peptides. A poly(2-hydroxyethyl methacrylate-co-propargyl acrylate) (P(HEMA-co-PgA)) brush was grafted onto a glass substrate through atom transfer radical polymerization (ATRP). Subsequently, poly(2-(2-methoxyethoxy)ethyl methacrylate) (PMEO2MA), P(MEO2MA-co-HEMA-co-poly(ethylene glycol) methacrylate [PEGMA]), or P(MEO2MA-co-PEGMA) was grafted onto the P(HEMA-co-PgA) brush-coated substrates through a second ATRP. A Gly-Gly-Gly-Arg-Glu-Asp-Val (GGGREDV) peptide was conjugated to the copolymer brush via a click reaction. The prepared copolymer brushes exhibited thermoresponsive properties. The block copolymer brushes having the P(MEO2MA-co-HEMA-co-PEGMA) and P(MEO2MA-co-PEGMA) segment exhibited effective human umbilical vein endothelial cells (HUVECs) adhesion and normal human dermal fibroblasts (NHDFs) repulsion at 37 °C. By reducing temperature to 20 °C, adherent HUVECs were successfully recovered from the copolymer brushes. Using these copolymer brushes, HUVECs were separated from contaminant NHDFs and smooth muscle cells with these simple changes in temperature. The development of thermoresponsive ethylene glycol-based copolymer brushes with affinity peptides could be a useful cell separation material for tissue engineering applications.

Surface grafted gold nanorods (GNRDs) using thermosensitive copolymers with various transition temperatures: Nanomaterials with potential application for photothermal therapy

A series of diblock copolymers containing a biocompatible polyethylene glycol (PEG) block and a thermoresponsive poly(N-vinyl caprolactam) (PNVCL) based block, were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The cloud point temperature (Tcp) in water of the diblocks was adjusted from 35 to 42 °C by adding N-vinyl pyrrolidone (NVP) units in the thermoresponsive block. The terminal trithiocarbonate group evolving from the RAFT agent used in the synthesis, was modified to thiol to stabilize gold nanorods (GNRDs) via a “grafting-to” approach. Stability of the PEG-b-P(NVCL-co-NVP)@GNRDs nanomaterials was monitored during 8 days; where the localized surface plasmon resonance (LSPR) absorption band did not shifted or showed any broadening. Aqueous dispersed samples were irradiated with near-infrared laser light for 10 min, observing a temperature increase from 25 to 50 °C depending on the laser optical power (between 100 and 500 mW); while no precipitation was observed. For temperatures above the cloud point temperature of the copolymers (Tcp), the formation of aggregates in sizes around 200 nm was observed without precipitation. This study demonstrates that the stabilization of gold nanorods by grafting with the title thermoresponsive block copolymers, and the observed temperature-dependent block-copolymer@GNRD aggregation, has potential uses in drug-delivery applications for photothermal therapy.

Role of the Polymer Microstructure in Controlling Colloidal and Thermo-Responsive Properties of Nano-Objects Prepared Via RAFT Polymerization in a Non-polar Medium.

After having demonstrated their potential in biomedical applications, thermo-responsive block copolymers that are able to self-assemble into nano-objects in response to temperature modifications are becoming more and more appealing in other sectors, such as the oil and gas and lubricant fields. Reversible addition-fragmentation chain transfer (RAFT) polymerization-induced self-assembly has been demonstrated as a valuable strategy for producing nano-objects from modular block copolymers in non-polar media, required for the mentioned applications. Although the influence of the nature and size of the thermo-responsive block of these copolymers on the properties of the nano-objects is extensively studied in the literature, the role of the solvophilic block is often neglected. In this work, we elucidate the role of the main microstructural parameters, including those of the solvophilic portion, of block copolymers produced by RAFT polymerization in the hydrocarbon blend decane/toluene 50:50 v/v on the thermo-responsive behavior and colloidal properties of the resulting nano-objects. Two long-aliphatic chain monomers were employed for the synthesis of four macromolecular chain transfer agents (macroCTAs), with increasing solvophilicity according to the number of units (n) or length of the alkyl side chain (q). Subsequently, the macroCTAs were chain-extended with different repeating units of di(ethylene glycol) methyl ether methacrylate (p), leading to copolymers that are able to self-assemble below a critical temperature. We show that this cloud point can be tuned by acting on n, p, and q. On the other hand, the colloidal stability, expressed in terms of area of the particle covered by each solvophilic segment, is only a function of n and q, which provides a way for controlling the size distribution of the nano-objects and to decouple it from the cloud point.

Directional Self-Assembly of Nanoparticles Coated with Thermoresponsive Block Copolymers and Charged Small Molecules.

Herein, we report the directional stimuli-responsive self-assembly of gold nanoparticles (AuNPs) coated with a thermoresponsive block copolymer (BCP), poly(ethylene glycol)-b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM) and charged small molecules. AuNPs modified with PEG-b-PNIPAM possessing a AuNP/PNIPAM/PEG core/active/shell structure undergo temperature-induced self-assembly into one-dimensional (1D) or two-dimensional (2D) structures in salt solutions, with the morphology varying with the ionic strength of the medium. Salt-free self-assembly is also realized by modulating the surface charge by the codeposition of positively charged small molecules; 1D or 2D assemblies are formed depending on the ratio between the small molecule and PEG-b-PNIPAM, consistent with the trend observed with the bulk salt concentration. A series of charge-controlled self-assembly at various conditions revealed that the temperature-induced BCP-mediated self-assembly reported here provides an effective means for on-demand directional self-assembly of nanoparticles (NPs) with controlled morphology, interparticle distance, and optical properties, and the fixation of high-temperature structures.

Polymeric nanoparticle gel for intracellular mRNA delivery and immunological reprogramming of tumors

Immuno-oncology therapies have been of great interest with the goal of inducing sustained tumor regression, but clinical results have demonstrated the need for improved and widely applicable methods. An antigen-free method of cancer immunotherapy can stimulate the immune system to recruit lymphocytes and produce immunostimulatory factors without prior knowledge of neoantigens, while local delivery reduces the risk of systemic toxicity. To improve the interactions between tumor cells and cytotoxic lymphocytes, a gene delivery nanoparticle platform was engineered to reprogram the tumor microenvironment (TME) in situ to be more immunostimulatory by inducing tumor-associated antigen-presenting cells (tAPCs) to activate cytotoxic lymphocytes against the tumor. Biodegradable, lipophilic poly (beta-amino ester) (PBAE) nanoparticles were synthesized and used to co-deliver mRNA constructs encoding a signal 2 co-stimulatory molecule (4-1BBL) and a signal 3 immuno-stimulatory cytokine (IL-12), along with a nucleic acid-based immunomodulatory adjuvant. Nanoparticles are combined with a thermoresponsive block copolymer for gelation at the injection site for local NP retention at the tumor. The reprogramming nanoparticle gel synergizes with immune checkpoint blockade (ICB) to induce tumor regression and clearance in addition to resistance to tumor rechallenge at a distant site. In vitro and in vivo studies reveal increases in immunostimulatory cytokine production and recruitment of immune cells as a result of the nanoparticles. Intratumoral injection of nanoparticles encapsulating mRNA encoding immunostimulatory agents and adjuvants via an injectable thermoresponsive gel has great translational potential as an immuno-oncology therapy that can be accessible to a wide range of patients.

Proteinosomes via Self-Assembly of Thermoresponsive Miktoarm Polymer Protein Bioconjugates.

To fabricate nanoscale proteinosomes, thermoresponsive miktoarm polymer protein bioconjugates were prepared through highly efficient molecular recognition between the β-cyclodextrin modified BSA (CD-BSA) and the adamantyl group anchored at the junction point of the thermoresponsive block copolymer poly(ethylene glycol)-b-poly(di(ethylene glycol) methyl ether methacrylate) (PEG-b-PDEGMA). PEG-b-PDEGMA was synthesized by the Passerini reaction of benzaldehyde-modified PEG, 2-bromo-2-methylpropionic acid, and 1-isocyanoadamantane, followed by the atom transfer radical polymerization of DEGMA. Two block copolymers with different chain lengths of PDEGMA were prepared, and both self-assembled into polymersomes at a temperature above their lower critical solution temperatures (LCST). The two copolymers can undergo molecular recognition with the CD-BSA and form miktoarm star-like bioconjugates. The bioconjugates self-assembled into ∼160 nm proteinosomes at a temperature above their LCSTs, and the miktoarm star-like structure has a great effect on the formation of the proteinosomes. Most of the secondary structure and esterase activity of BSA in the proteinosomes were maintained. The proteinosomes exhibited low toxicity to the 4T1 cells and could deliver model drug doxorubicin into the 4T1 cells.

Modifying the Properties of Microemulsion Droplets by Addition of Thermoresponsive BAB* Copolymers.

Oil-in-water (O/W) microemulsions (ME) typically feature a low viscosity and exhibit ordinary viscosity reduction as a function of temperature. However, for certain applications, avoiding or even reverting the temperature trend might be required. This can be conceived by adding thermoresponsive (TR) block copolymers that induce network formation as the temperature increases. Accordingly, various ME-polymer mixtures were studied for which three different block copolymer architectures of BAB*-, B2AB*-, and B(AB*)2-types were employed. Here, "B" represents a permanently hydrophobic, "A" a permanently hydrophilic, and "B*" a TR block. For the TR-block, three different poly(acrylamide)s, namely poly(N-n-propylacrylamide) (pNPAm), poly(N,N-diethylacrylamide) (pDEAm), and poly(N-isopropylacrylamide) (pNiPAm), were used, which all exhibit a lower critical solution temperature. For a well-selected ME concentration, these block copolymers lead to a viscosity enhancement with increasing temperature. At a polymer concentration of about 22 g L-1, the most pronounced enhancement was observed for the pNPAm-based systems with factors up to 3, 5, and 8 for BAB*, B2AB*, and B(AB*)2, respectively. This phenomenon is caused by the formation of a transitory network mediated by TR-blocks, as evidenced by the direct correlation between the attraction strength and the viscosity enhancement. For applications requiring a high hydrophobic payload, which is attained via ME droplets, this kind of tailored temperature-dependent viscosity control of surfactant systems should therefore be advantageous.

Thermo-responsive block copolymers: assembly and application

The review focuses on the assembly and application of five thermo-responsive block copolymers containing one or two thermo-responsive blocks, and aims to provide an overview to guide the design of these copolymers and stimulate more applications.

Bilayer-domain formation of thermoresponsive amphiphilic block copolymers in hybrid liposomes for synthetic molecular channels

Maltopentaose-b-PPO copolymer can be incorporated into phospholipid membranes and form bilayer-domains, where they act as synthetic molecular channels.

Thermoresponsive block copolymers of increasing architecture complexity: a review on structure–property relationships

The position of the monomers within the polymer chain and the 3D structure of the polymer affect the thermoresponsive properties.

Solvent-free, photoinduced block copolymer synthesis from polymerizable eutectics by simultaneous PET-RAFT and ring-opening polymerization in air

We report the preparation of thermoresponsive block copolymers via the simultaneous RAFT polymerization and anionic ring-opening polymerization (ROP) of N-isopropylacylamide and ε-caprolactone respectively, in the absence of traditional solvents.

Stimuli‐responsive polypeptoid block copolymers containing o‐nitrobenzyl groups with extremely sharp transition

AbstractBioinspired thermoresponsive polymers have received increasing attention for many applications. Here, we report a series of thermoresponsive polypeptoid block copolymers containing o‐nitrobenzyl groups, that is, poly(ethylene glycol)‐b‐poly[N‐[2‐[N‐(o‐nitrobenzyloxycarbonyl)‐amino]‐ethyl]‐glycine] (PEG‐b‐PN[oNB]G), prepared by ring‐opening polymerization. The polypeptoid block copolymers show reversible lower critical solution temperature (LCST)‐type behavior in water with tunable phase transition properties dependent on the pH values, chemical compositions, and concentrations of the copolymers. The dynamic light scattering results reveal the formation of spherical micelles and temperature‐induced aggregation of PEG‐b‐PN(oNB)G. Notably, the phase transition of the block copolymer solution upon heating appears extremely sharp (∆T < 1°C), superior to bench mark poly(N‐isopropylacrylamide). In addition, we present the removal of photo‐responsive o‐nitrobenzyl groups can result in the increased clouding point and even the loss of phase transition properties, acting as an excellent regulator to tune the LCST behavior. We demonstrate that the hydrogen‐bonding interaction may play a critical part on the LCST behavior. The prepared diblock copolymers show great potential for many applications and its structure–property may shed light on highly designable stimuli‐responsive polymeric materials.

Thermoresponsive Block Copolymer Core-Shell Nanoparticles with Tunable Flow Behavior in Porous Media.

With the purpose of investigating new polymeric materials as potential flow modifiers for their future application in enhanced oil recovery (EOR), a series of amphiphilic poly(di(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) methyl ether methacrylate) [P(DEGMA-co-OEGMA)]-based core-shell nanoparticles were prepared by aqueous reversible addition-fragmentation chain transfer-mediated polymerization-induced self-assembly. The developed nano-objects were shown to be thermoresponsive, demonstrating a reversible lower-critical solution temperature (LCST)-type phase transition with increasing solution temperature. Characterization of their thermoresponsive nature by variable-temperature UV-vis and dynamic light scattering analyses revealed that these particles reversibly aggregate when heated above their LCST and that the critical transition temperature could be accurately tuned by simply altering the molar ratio of core-forming monomers. Sandpack experiments were conducted to evaluate their pore-blocking performance at low flow rates in a porous medium heated at temperatures above their LCST. This analysis revealed that particles aggregated in the sandpack column and caused pore blockage with a significant reduction in the porous medium permeability. The developed aggregates and the increased pressure generated by the blockage were found to remain stable under the injection of brine and were observed to rapidly dissipate upon reducing the temperature below the LCST of each formulation. Further investigation by double-column sandpack analysis showed that the blockage was able to reform when re-heated and tracked the thermal front. Moreover, the rate of blockage formation was observed to be slower when the LCST of the injected particles was higher. Our investigation is expected to pave the way for the design of "smart" and versatile polymer technologies for EOR applications in future studies.

A thermoresponsive cationic block copolymer brush-grafted silica bead interface for temperature-modulated separation of adipose-derived stem cells

Adipose-derived mesenchymal stem cells (ADSCs) have beneficial effects in cell transplantation therapy; these cells are collected from adipose tissue using low-invasive methods. However, to prepare ADSCs for cell therapy, a cell separation method that neither involves modification of the cell surface nor causes loss of cell activity is needed. Here, we aimed to develop ADSC separation columns using thermoresponsive cationic block copolymer brush-grafted beads as packing materials. The block copolymer brush was formed by a bottom cationic segment, poly(N,N-dimethylaminopropylacrylamide) (PDMAPAAm), and an upper thermoresponsive segment, poly(N-isopropylacrylamide) (PNIPAAm), and was grafted in two atom transfer radical polymerization reactions. The copolymer brush-grafted silica beads were packed into a column. An ADSC suspension was introduced into the columns at 37 °C and adsorbed on the copolymer brush-modified beads through electrostatic and hydrophobic interactions with the PDMAPAAm and PNIPAAm segments, respectively. The adsorbed ADSCs eluted from the column by lowering the temperature to 4 °C. In contrast, most Jurkat and vascular endothelial cells eluted at 37 °C, because of the relatively weaker electrostatic interactions with the block copolymer brush compared to ADSCs. Using the prepared column, a mixture of ADSCs and Jurkat cells was separated by changing the column temperature. The recovered ADSCs exhibited cell activity. The developed cell separation column may be useful for isolating ADSCs without cell surface modification, while maintaining cell activity.

Thermo-responsive lipophilic NIPAM-based block copolymers as stabilizers for lipid-based cubic nanoparticles

The design of drug delivery systems (DDS) for the encapsulation of therapeutic agents and the controlled release to the target site of the disease is one of the main goals of nanomedicine. Although already explored in an extensive number of studies over the years, lipid assemblies, and particularly liposomes, are still considered the most promising and interesting candidates as DDS due to their biocompatibility and structural similarity with plasma membranes. Lately, this research area has been extended to include more complex lipid assemblies, such as cubosomes. Cubosomes are an emerging structural platform for the delivery of molecules with pharmaceutical interest, such as drugs, bioactives and contrast agents. Here we report on the application of a thermo-responsive copolymer poly(N,N-dimethylacrylamide)-block-poly(N-isopropylacrylamide) (PDMA-b-PNIPAM), as a thermoresponsive stabilizer of lipid-based nanoparticles for drug-delivery. First, we assessed the affinity of PDMA-b-PNIPAM towards supported and free-standing bilayers; then, we explored the colloidal and thermoresponsive properties of cubic self-assembled DDS composed of glycerol-monooleate (GMO), where PDMA-b-PNIPAM replaces the conventional stabilizer Pluronic F127 (PEOx-PPOy-PEOx), normally used for cubosomes. We prepared dispersions of cubic lipid nanoparticles with two PDMA-b-PNIPAM block copolymers of different molar mass. The colloidal properties were then assessed and compared to those exhibited by standard lipid cubic dispersions stabilized by Pluronic F-127, combining a series of experimental techniques (Quartz Crystal Microbalance with Dissipation monitoring, Dynamic Light Scattering, Small-Angle X-rays Scattering, Cryo-Transmission Electron Microscopy). Interestingly, PDMA-b-PNIPAM stabilized cubosomes display additional benefits with respect to those stabilized by Pluronic, thanks to the combination of a “sponge “ effect for the controlled release of encapsulated molecules and an increased affinity towards lipid bilayer membranes, which is a promising feature to maximize fusion with the target-cellular site.

Strong Anionic/Charge-Neutral Block Copolymers from Cu(0)-Mediated Reversible Deactivation Radical Polymerization.

Despite recent developments in controlled polymerization techniques, the straightforward synthesis of block copolymers that feature both strong anionic and charge-neutral segments remains a difficult endeavor. In particular, solubility issues may arise during the direct synthesis of strong amphiphiles and typical postpolymerization deprotection often requires harsh conditions. To overcome these challenges, we employed Cu(0)-mediated reversible deactivation radical polymerization (Cu(0)-RDRP) on a hydrophobic isobutoxy-protected 3-sulfopropyl acrylate. Cu(0)-RDRP enables the rapid synthesis of the polymer, reaching high conversions and low dispersities while using a single solvent system and low amounts of copper species. These macromolecules are straightforward to characterize and can subsequently be deprotected in a mild yet highly efficient fashion to expose their strongly charged nature. Furthermore, a protected sulfonate segment could be grown from a variety of charge-neutral macroinitiators to produce, after the use of the same deprotection chemistry, a library of amphiphilic, double-hydrophilic as well as thermoresponsive block copolymers (BCPs). The ability of these various BCPs to self-assemble in aqueous media was further studied by dynamic light scattering, ζ-potential measurements as well as atomic force and electron microscopy.

Aggregation Behavior of Nonsymmetrically End-Capped Thermoresponsive Block Copolymers in Aqueous Solutions: Between Polymer Coils and Micellar States

Aggregation Behavior of Nonsymmetrically End-Capped Thermoresponsive Block Copolymers in Aqueous Solutions: Between Polymer Coils and Micellar States