Background: Pentamidine isethionate (PTM) and miltefosine (MF) are clinically relevant antiparasitic agents whose use is limited by toxicity, emerging resistance, and the lack of effective co-delivery strategies. Tetronic® 1307 (T1307), an amphiphilic and thermoresponsive block copolymer, was investigated as a carrier to enable their combination therapy. Methods: PTM and MF were formulated in T1307-based micelles and thermoresponsive gels. The systems were characterized by small-angle neutron scattering (SANS), dynamic light scattering (DLS), and nuclear magnetic resonance spectroscopy (NMR). Antiparasitic activity was evaluated against Leishmania major promastigotes. Results: MF formed stable micelles that efficiently incorporated PTM, generating a "drug-in-drug" architecture. While T1307 alone showed limited PTM loading, MF promoted mixed micelle formation and enhanced PTM incorporation. At physiological temperature and adequate copolymer concentrations, drug-loaded micelles formed thermoreversible gels suitable for topical application. The combined formulations preserved drug activity and exhibited synergistic effects against L. major.Conclusions: T1307 is a promising platform for the co-delivery of PTM and MF, enabling synergistic combination therapy and thermoresponsive gel formation with potential to reduce systemic toxicity and improve treatment administration.

Photoresponsive and UCST-Type thermoresponsive block Copolymer-Based composite micelles for Dual-Stimuli-Triggered selective and programmable release

Tuning interphase behavior of thermo-responsive block polymer assemblies for enhanced filter cake performance

Stable preparation of invivo transplantable periodontal ligament-derived mesenchymal stem cell sheets in thermoresponsive culture dishes with tunable cell detachability.

Synthetic ion channels represent an emerging class of therapeutics. However, most synthetic ion channels are derived from small molecules, whose rapid clearance from the body limits their therapeutic potential. Here, we report macromolecular ion transport systems based on amphiphilic polyether block copolymers. The block copolymers self-assemble into vesicles that are spontaneously incorporated into biological membranes to form polymer-rich domains. The hydrophobic core of the domains, which features ether-oxygen atoms and the presence of water molecules, is analogous to the permeation pathways of natural ion channels such as KcsA. In addition, the inherent thermoresponsive properties of these polymer domains enable on/off switching of ion transport in response to temperature variations, allowing for controlled modulation of cation permeability. Thus, these domains act as macromolecular ion transport systems to disrupt ion homeostasis and trigger apoptosis in cancer cells. The systemic administration of the vesicles in tumor-bearing mice resulted in an accumulation at the tumor sites, inhibiting tumor growth. This work establishes thermoresponsive polyether block copolymers as a versatile and biologically active platform for macromolecular ion transport systems.

Developing smart stimuli-responsive materials with tunable properties is crucial for designing next-generation smart systems. In this regard, block copolymers due to their inherent chemical versatility (chemical versatility in the context of block co-polymers refers to the fact that they can be easily modified at the molecular level according to their application or desirable properties or functions) provide a robust platform for such systems. In this study, we explore how ionic liquid (IL)-modified gold nanoparticles (AuNPs) can be employed to customize the thermal behaviour and morphological characteristics of the thermoresponsive block co-polymer poly(N-isopropylacrylamide)-b-poly(acryloylmorpholine) (PNIPAM-b-PACMO). The AuNPs were modified with two ILs composed of 1-ethyl-3-methylimidazolium ([EMIM]) cations and two different anions-tetrafluoroborate ([BF4]-) and chloride ([Cl]-). Comprehensive spectroscopic and microscopic techniques along with surface characterization techniques (UV-Vis, fluorescence, FTIR, DLS, zeta potential, TEM, SEM and AFM) were employed to analyse the results. The research highlights that Cl-AuNPs interact more strongly with the block co-polymer, increasing its phase transition temperature and stabilizing an extended coil conformation. In contrast, BF4-AuNPs require higher concentrations than 6 nM to induce similar effects. Furthermore, the anion-dependent behavior was highlighted by the unique surface morphologies-vesicular for BF4-AuNPs and rod-like for Cl-AuNPs. Consequently, these structural dissimilarities directly influence crucial properties such as phase transition behavior of the block co-polymer. Altogether, the present study establishes that IL-functionalized AuNPs offer a promising strategy to design block copolymer-nanoparticle composite materials with customizable structures and properties. Thus, this work reveals a tunable, nanoscale coupling between IL-modified AuNPs and block copolymer thermoresponsiveness, providing fundamental insight into designing stimuli-responsive nanocomposites with controlled phase behavior and structure. While the current work is foundational, the insights gained open avenues for designing smart materials with precisely controlled phase behavior, useful in temperature-sensitive coatings, sensors, or actuators, and also in developing nanocarriers where the release or assembly of payloads can be regulated by temperature.

The development of stimuli-responsive drug delivery systems enables targeted delivery and environment-controlled drug release, thereby minimizing off-target effects and systemic toxicity. We prepared and studied tailor-made dual-responsive systems (thermo- and pH-) based on synthetic diblock copolymers consisting of a fully hydrophilic block of poly[N-(1,3-dihydroxypropyl)methacrylamide] (poly(DHPMA)) and a thermoresponsive block of poly[N-(2,2-dimethyl-1,3-dioxan-5-yl)methacrylamide] (poly(DHPMA-acetal)) as drug delivery and smart stimuli-responsive materials. The copolymers were designed for eventual medical application to be fully soluble in aqueous solutions at 25 °C. However, they form well-defined nanoparticles with hydrodynamic diameters of 50-800 nm when heated above the transition temperature of 27-31 °C. This temperature range is carefully tailored to align with the human body's physiological conditions. The formation of the nanoparticles and their subsequent decomposition was studied using dynamic light scattering (DLS), transmission electron microscopy (TEM), isothermal titration calorimetry (ITC), and nuclear magnetic resonance (NMR). 1H NMR studies confirmed that after approximately 20 h of incubation at pH 5, which closely mimics tumor microenvironment, approximately 40% of the acetal groups were hydrolyzed, and the thermoresponsive behavior of the copolymers was lost. This smart polymer response led to disintegration of the supramolecular structures, possibly releasing the therapeutic cargo. By tuning the transition temperature to the values relevant for medical applications, we ensure precise and effective drug release. In addition, our systems did not exhibit any cytotoxicity against any of the three cell lines. Our findings underscore the immense potential of these nanoparticles as eventual advanced drug delivery systems, especially for cancer therapy.

A series of copolymers containing a thermo-responsive biocompatible first block of poly[di(ethylene glycol) methyl ether methacrylate)-co-(oligo(ethylene glycol) methyl ether methacrylate], P(DEGMA-co-OEGMA) were chain-extended to incorporate either poly(N-isopropylacrylamide), PNIPAAm or poly(N-isopropylacrylamide-co-butyl acrylate), P(NIPAAm-co-BA) as second thermo-responsive block using reversible addition-fragmentation chain transfer (RAFT) polymerization. P(DEGMA-co-OEGMA)-b-PNIPAAm copolymers showed two response temperatures at 33 and 43 °C in an aqueous solution forming stable aggregates at 37 °C. In contrast, P(DEGMA-co-OEGMA)-b-P(NIPAAm-co-BA) copolymers showed aggregation below room temperature due to the shift in response temperature provoked by the presence of hydrophobic butyl acrylate (BA) units, and shrinkage upon heating up to body temperature, while maintaining the second response temperature above 40 °C. The terminal trithiocarbonate group of the block copolymers was modified to a thiol functionality and used to stabilize gold nanorods (GNRDs) via the "grafting to" approach. The Localized Surface Plasmon Resonance (LSPR) absorption band of GNRDs with an aspect ratio of 3.9 (length/diameter) was located at 820 nm after surface grafting with block copolymers showing a hydrodynamic diameter of 160 nm at 37 °C. On the other hand, the stability of the P(DEGMA-co-OEGMA)-b-PNIPAAm@GNRDs and P(DEGMA-co-OEGMA)-b-P(NIPAAm-co-BA)@GNRDs nanohybrids was monitored for 8 days; where the LSPR absorption band did not shift or show any broadening. Aqueous dispersed nanohybrids were irradiated with a near-infrared laser (300 mW), where the temperature of the surroundings increased 16 °C after 16 min, where conditions for no precipitation were determined. These tailored temperature-responsive nanohybrids represent interesting candidates to develop drug nanocarriers for photo-thermal therapies.

In this study, we introduce a protein-polymer bioconjugate comprising bovine serum albumin (BSA) and a lipid-based thermoresponsive block copolymer. These amphiphilic BSA-polymer conjugates can autonomously be organized into vesicular compartments for codelivery of glucose oxidase (GOx) and doxorubicin (DOX), demonstrating high drug loading content and remarkable antitumor activity via synergistic cancer therapy combining chemo-starvation strategies. Through the incorporation of a hydrophilic BSA block, the lower critical solution temperature (LCST) of the bioconjugates is tuned to around 40 °C, facilitating their targeted drug delivery to tumor cells. Consequently, these smart protein-polymer conjugates present greater promise compared to traditional drug delivery vehicles, particularly in the realm of anticancer therapy. Moreover, these bioconjugates displayed enhanced intracellular fluorescence intensity with increasing temperature, attributed to the clustering-triggered emission of the nonconventional chromophore moieties within poly(vinylcaprolactam) (PNVCL). The active aggregation-induced emission (AIE) characteristic and excellent biocompatibility suggest an opportunity to further apply these bioconjugates for biosensing and cellular imaging.

Thermoresponsive polymer coatings on cell culture substrates enable noninvasive cell detachment and cell sheet fabrication for biomedical applications. Optimized coatings should support controlled culture and detachment of various cell types and allow chemical modifications, e.g., to introduce specific growth factors for enhanced gene expression. Furthermore, the sterilization and storage stability of the coatings must be assessed for translational attempts. Poly(glycidyl ether) (PGE) brush coatings with short alkoxy side chains provide a versatile platform for cell culture and detachment, but their polyether backbones are susceptible to oxidation and degradation. Thus, we rationally designed potential alternatives with thermoresponsive glycerol-based block copolymers comprising a stable polyacrylate or polymethacrylate backbone and an oligomeric benzophenone (BP)-based anchor. The resulting poly(ethoxy hydroxypropyl acrylate-b-benzophenone acrylate) (pEHPA-b-BP) and poly(ethoxy hydroxypropyl methacrylate-b-benzophenone methacrylate) (pEHPMA-b-BP) block copolymers preserve the short alkoxy-terminated side chains of the PGE derived structure on a stable, but hydrophobic, aliphatic backbone. The amphiphilicity balance is maintained through incorporated hydroxyl groups, which simultaneously can be used for chemical modification. The polymers were tailored into brush coatings on polystyrene surfaces via directed adsorption using the BP oligomer anchor. The resulting coatings with thickness values up to ∼3 nm supported efficient adhesion and proliferation of human fibroblasts despite minimal protein adsorption. The conditions for cell sheet fabrication on pEHPA-b-BP were gentler and more reliable than on pEHPMA-b-BP, which required additional cooling. Hence, the stability of pEHPA-b-BP and PGE coatings was evaluated post gamma and formaldehyde (FO) gas sterilization. Gamma sterilization partially degraded PGE coatings and hindered cell detachment on pEHPA-b-BP. In contrast, FO sterilization only slowed detachment on PGE coatings and had no adverse effects on pEHPA-b-BP, maintaining their efficient performance in cell sheet fabrication.

In this work, we present basic research on developing thermogel carriers containing high amounts of model antibody immunoglobulin G (IgG) with potential use as injectable molecules. The quantities of IgG loaded into the gel were varied to evaluate the possibility of tuning the dose release. The gel materials were based on blends of thermoresponsive and degradable ABA-type block copolymers composed of poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA–PEG–PLGA) or poly(lactide-co-caprolactone)-b-poly(ethylene glycol)-b-(lactide-co-caprolactone) (PLCL–PEG–PLCL). Primarily, the gels with various amounts of IgG were obtained via thermogelation, where the only factor inducing gel formation was the change in temperature. Next, to control the gels’ mechanical properties, degradation rate, and the extent of antibody release, we have tested two approaches. The first one involved the synergistic physical and chemical crosslinking of the copolymers. To achieve this, the hydroxyl groups located at the ends of the PLGA–PEG–PLGA chain were modified into acrylate groups. In this case, the thermogelation was accompanied by chemical crosslinking through the Michael addition reaction. Such an approach increased the dynamic mechanical properties of the gels and simultaneously prolonged their decomposition time. An alternative solution was to suspend crosslinked PEG–polyester nanoparticles loaded with IgG in a PLGA–PEG–PLGA gelling copolymer. We observed that loading IgG into thermogels lowered the gelation temperature (TGEL) value and increased the storage modulus of the gels, as compared with gels without IgG. The prepared gel materials were able to release the IgG from 8 up to 80 days, depending on the gel formulation and on the amount of loaded IgG. The results revealed that additional, chemical crosslinking of the thermogels and also suspension of particles in the polymer matrix substantially extended the duration of IgG release. With proper matching of the gel composition, environmental conditions, and the type and amount of active substances, antibody-containing thermogels can serve as effective IgG delivery materials.

Tunable coffee-ring patterns of sessile suspension droplets through silica particle encapsulation with thermo-responsive block copolymers

Hybrid copper-polyelectrolyte nanoaggregates obtained with smart block copolymers based on 4-[(hydroxyimino)aldehyde]butyl methacrylate (HIABMA) in water and acetonitrile

The unique biophysical and biochemical properties of intrinsically disordered proteins (IDPs) and their recombinant derivatives, intrinsically disordered protein polymers (IDPPs) offer opportunities for producing multistimuli-responsive materials; their sequence-encoded disorder and tendency for phase separation facilitate the development of multifunctional materials. This review highlights the strategies for enhancing the structural diversity of elastin-like polypeptides (ELPs) and resilin-like polypeptides (RLPs), and their self-assembled structures via genetic fusion to ordered motifs such as helical or beta sheet domains. In particular, this review describes approaches that harness the synergistic interplay between order-promoting and thermoresponsive building blocks to design hybrid biomaterials, resulting in well-structured, stimuli-responsive supramolecular materials ordered on the nanoscale.

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

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.

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

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.

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.