Search Results (115)

Oral administration remains the most convenient and favored route for systemic delivery of small-molecule drugs, primarily due to patient compliance and the absence of invasive procedures. Yet, poor aqueous solubility, chemical/enzymatic instability, and limited permeability in the gastrointestinal (GI) tract often result in low bioavailability (BA) of many therapeutic agents. Polymeric micelles formed from the self-assembly of amphiphilic block copolymers have gained considerable attention as a nanotechnology-driven solution to overcome these challenges. Their hydrophobic core–hydrophilic shell structure enables efficient encapsulation of poorly soluble small molecule drugs, providing protection from acidic or enzymatic degradation while potentially enhancing drug transport across the intestinal epithelium. This review examines the design principles, formulation strategies, and in vivo performance of polymeric micelles for oral delivery of small molecule drugs. We discuss strategies to improve micelle stability in the GI environment, including optimization of core hydrophobicity, kinetic stabilization, and corona engineering, and compare polymeric micelles with established alternatives such as self-micro emulsifying drug delivery system (SMEDDS) and amorphous solid dispersions (ASDs) across critical performance parameters. Despite decades of preclinical progress, no oral polymeric micelle formulation has reached regulatory approval, underscoring the persistent challenge of maintaining micellar structural integrity under the dynamic conditions of the GI environment. This review therefore examines not only the promise but also the structural vulnerabilities of oral micelles, proposing a stability-centered framework for interpreting micelle function under GI conditions. Finally, we discuss current translational challenges and suggest directions for future research toward clinical application of oral polymeric micelle systems. Full article

Background: Hepatic fibrosis is characterized by the abnormal activation of hepatic stellate cells (HSCs) and excessive deposition of the extracellular matrix. Currently, effective clinical therapeutic strategies remain limited. Modulating ferroptosis-related pathways in activated HSCs has emerged as a promising therapeutic target for hepatic fibrosis treatment. Methods: An amphiphilic copolymer was synthesized by conjugating COS with ART, which spontaneously self-assembled into micelles; subsequent modification with retinoic acid (RA) yielded RA-functionalized ART–COS copolymer micelles. Curcumin was selected as a model drug to evaluate the potential of the micelles in enhancing intestinal epithelial transport, oral absorption and bioavailability. Meanwhile, in vitro targeting ability, capacity to modulate ferroptosis in HSCs and in vivo therapeutic efficacy were systematically investigated. Results: The RA-functionalized ART–COS micelles significantly enhanced intestinal epithelial drug transport, oral absorption, and bioavailability. In vitro experiments demonstrated that the micelles preferentially accumulate in activated HSCs, inhibit GPX4 expression, and induce excessive ROS production and ferroptosis, thereby effectively attenuating hepatic fibrosis. In vivo studies confirmed that the micelles regulated extracellular matrix metabolism, reduced collagen deposition, suppressed the activation and proliferation of HSCs, and ultimately helped attenuate hepatic fibrosis progression. Conclusions: This study successfully developed RA-functionalized ART–COS copolymer micelles. The micelles improve the accumulation of artesunate in liver tissue and yield favorable anti-fibrotic effects, thereby providing a promising translational strategy for anti-fibrotic therapy. Full article

Rotator cuff tendon injury (RCTI) is aggravated by the pro-inflammatory milieu elicited by TLR4 and TREM1 signaling. Hence, tendon tissue engineering approaches require considerations that address these inflammatory episodes to benefit active regenerative responses. The objective of this study was to engineer and evaluate the immunocompatibility of a tendon-mimetic hydrogel composed of a chitosan–polyvinyl alcohol (PVA) blend incorporated with Collagen-I and to assess LR12 delivery for addressing TREM1-driven inflammation in RCTI management. A chitosan–PVA-HEMA-Acrylic acid (CPHA) hydrogel was synthesized by blending the linear natural polysaccharide chitosan and linear synthetic polymer PVA in an aqueous phase, followed by incorporation and redox chain growth with HEMA using acrylic acid (AA). Interpenetration of Collagen-I in CPHA yielded the CPHA-C hydrogel. CPHA and CPHA-C hydrogels displayed ample surface functional moieties provided by the co-polymers, exhibited excellent porosity as revealed by SEM imaging (28.65 ± 6.85 and 41.56 ± 18.00, respectively, for CPHA and CPHA-C), and were amphiphilic, as evident by contact angle analysis (~70 for CPHA and CPHA-C). Both hydrogels displayed a progressive release profile for the TREM1-inhibitory peptide LR12 for 7 days, whereas the LR12-loaded CPHA hydrogel exhibited increased TREM1 inhibition in LPS-challenged RAW264.7 macrophages. CPHA and CPHA-C hydrogels were immunocompatible and masked the oxidative damage in RAW264.7 macrophages, as evident by decreased levels of mitochondrial superoxide and ROS. Additionally, the CPHA hydrogel displayed an increased TGFβ/TLR4 ratio (0.24), whereas the CPHA-C (−0.52) system showed a decreased ratio upon exposure to tenocytes and macrophages. Overall, the findings highlight the potential of CPHA and CPHA-C hydrogels as candidates for tendon regenerative applications. Full article

Amphiphilic copolymers based on polystyrene and polyglycidol combine the chemical inertness of polystyrene with the biocompatibility of polyglycidol, making them attractive materials for polymeric micelles. While comb-like architectures have been explored to control micellization behavior and biological response, a direct comparison between comb-like and coil-comb topologies in polystyrene–polyglycidol copolymers at identical polyglycidol content remains insufficiently investigated. In this work, amphiphilic comb-like and coil-comb polystyrene–polyglycidol copolymers were synthesized via copper-catalyzed azide–alkyne click chemistry by grafting a monoalkyne-terminated polyglycidol precursor onto azide-functionalized random and block styrene copolymers. The copolymers were characterized by size exclusion chromatography and nuclear magnetic resonance. Polymeric micelles were prepared by nanoprecipitation, and their self-assembly in aqueous solution was investigated by critical micelle concentration determination, dynamic and electrophoretic light scattering, and atomic force microscopy. Both copolymers formed stable aqueous dispersions and exhibited comparable critical micelle concentrations. At identical polyglycidol content, the random copolymer formed a uniform, monomodal micellar population, whereas the block-based coil-comb architecture led to bimodal size distributions, indicating the coexistence of two distinct micellar populations. The investigated systems showed low cytotoxicity and did not induce significant oxidative stress within the studied concentration range. On isolated rat brain sub-cellular fractions (synaptosomes, mitochondria and microsomes), administered alone, the comb-like and coil-comb polystyrene-polyglycidol copolymers did not reveal statistically significant neurotoxic effects. The results demonstrate that macromolecular architecture plays a key role in governing micellar organization and in vitro biological response in polystyrene–polyglycidol copolymers, highlighting their potential as architecture-controlled polymer-based nanocarriers. Full article

Nanogels provide unique opportunities for stabilizing fragile enzymes through soft, hydrated polymer networks. Here, we report the development of a glutathione peroxidase (GPx)-loaded nanogel (GPxNG) engineered via a mild “grafting-to” epoxy–amine coupling strategy to enhance enzyme stability and antioxidant function. An amphiphilic copolymer composed of methacrylated 2,2,6,6-tetramethyl-4-piperidyl (PMA) and glycidyl methacrylate (GMA) was synthesized by controlled reversible addition–fragmentation chain-transfer (RAFT) polymerization using a poly(ethylene glycol) (PEG) macro-chain transfer agent (macro-CTA), yielding well-defined polymer chains with reactive epoxy groups. Covalent conjugation between polymer epoxides and GPx enzyme surface amines generated soft, PEGylated nanogels with high coupling efficiency, uniform particle sizes, and excellent colloidal stability. The engineered nanogels exhibited shear-thinning injectability, robust storage stability, and non-cytotoxic behavior in RAW 264.7 macrophages. Compared with native GPx enzyme, GPxNGs demonstrated significantly enhanced reactive oxygen species (ROS) scavenging activity, including strong inhibition of lipid peroxidation and copper-induced low-density lipoprotein (LDL) oxidation. Importantly, the nanogels preserved GPx enzyme activity after extended storage, freeze–thaw cycles, and repeated catalytic use, whereas the free enzyme rapidly lost function. This protective effect arises from the nanoscale confinement of the GPx enzyme within the flexible PEG-based network, which limits unfolding and aggregation. Overall, this work introduces a simple and biocompatible “grafting-to” nanogel platform capable of stabilizing redox-active enzymes without harsh conditions. The GPx nanogels combine high enzymatic preservation, potent antioxidant activity, and excellent handling properties, highlighting their potential as a therapeutic nanoplatform for mitigating oxidative stress-associated disorders such as atherosclerosis. Full article

The development of hydrophilic biodegradable polymers is crucial for a range of biomedical applications, including targeted drug delivery and prosthetics. Ring-opening polymerization of substituted ε-caprolactone monomers provides an efficient method for the synthesis of polyesters with tailored properties. In this work, a synthetic approach for the preparation of ester- and morpholinoamido-disubstituted ε-caprolactone monomers was developed. Poorly defined polymers were obtained from the monomers, bearing two ester groups due to the competitive transesterification of the pendant substituents. On the other hand, the disubstituted morpholinoamido-ε-caprolactone was polymerized in a controlled manner by ring-opening polymerization, and amorphous homopolymers with a high glass transition temperature (112 °C) and good solubility in water were obtained. Statistical and block copolymers with the unsubstituted ε-caprolactone were also prepared, and DLS analysis of the amphiphilic block copolymers in water shows the presence of self-assembled particles. These results demonstrate the potential of morpholinoamido-functionalized ε-caprolactone derivatives as building blocks for the development of biodegradable polymeric materials for biomedical applications. Full article

Amphiphilic diblock copolymers comprising polyethylene glycol (PEG) and 1-vinyl imidazole (VIM) were synthesized using reversible addition–fragmentation chain transfer (RAFT) polymerization. The study focused on the synthesis of well-defined nanostructures with tunable composition and their functional modification for biomedical applications. The successful polymerization of PEG-b-PVIM diblock copolymers was confirmed via ¹H NMR spectroscopy, and their molecular weights were analyzed using gel permeation chromatography (GPC). The copolymers exhibited pH-responsive behavior, with effective pK values of approximately 4.2. To facilitate radiolabeling and in vivo tracking, a post-polymerization modification enabled the conjugation of a 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) chelator via aminolysis. The final conjugates were purified and characterized, confirming successful functionalization. These findings highlight the potential of PEG_x-b-PVIM_y diblock copolymers for biomedical applications. Full article

Amphiphilic block copolymers are essential for developing advanced polymer nanomaterials with applications in bioimaging, drug delivery, and nanoreactors. In this study, we successfully synthesized functional block copolymer assemblies at high concentrations through redox-initiated reversible addition–fragmentation chain transfer (RAFT) emulsion polymerization of 2-(acetoacetoxy)ethyl methacrylate (AEMA), a β-ketoester functional monomer. Utilizing a redox initiation system at 50 °C, we produced poly(poly(ethylene glycol) methyl ether methacrylate)-b-PAEMA (PPEGMA_n-PAEMA_m). Kinetic studies demonstrated rapid monomer conversion exceeding 95% within 30 min, with distinct polymerization phases driven by micelle formation and monomer depletion. Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) revealed the formation of diverse morphologies, including worm-like, vesicular structures, and spherical micelles, depending on the macro-CTA molecular weight and monomer concentration. Additionally, post-polymerization modification with aggregation-induced emission (AIE) luminogens, such as 1-(4-aminophenyl)-1,2,2-tristyrene (TPE-NH₂), resulted in AIE-active polymer assemblies exhibiting strong fluorescence in aqueous dispersions. These AIE-active polymer assemblies also exhibited good biocompatibility. These findings demonstrate the efficacy of redox-initiated RAFT emulsion polymerization in fabricating functional, scalable block copolymer assemblies with potential applications in the field of life sciences. Full article

Studying membrane proteins in a native environment is crucial to understanding their structural and/or functional studies. Often, widely accepted mimetic systems have limitations that prevent the study of some membrane proteins. Micelles, bicelles, and liposomes are common biomimetic systems but have problems with membrane compatibility, limited lipid composition, and heterogeneity. To overcome these limitations, polymersomes and hybrid vesicles have become popular alternatives. Polymersomes form from amphiphilic triblock or diblock copolymers and are considered more robust than liposomes. Hybrid vesicles are a combination of lipids and block copolymers that form vesicles composed of a mixture of the two. These hybrid vesicles are appealing because they have the native lipid environment of bilayers but also the stability and customizability of polymersomes. Gramicidin A was incorporated into these polymersomes and characterized using continuous wave electron paramagnetic resonance (CW-EPR) and transmission electron microscopy (TEM). EPR spectroscopy is a powerful biophysical technique used to study the structure and dynamic properties of membrane proteins in their native environment. Spectroscopic studies of gramicidin A have been limited to liposomes; in this study, the membrane peptide is studied in both polymersomes and hybrid vesicles using CW-EPR spectroscopy. Lineshape analysis of spin-labeled gramicidin A revealed linewidth broadening, suggesting that the thicker polymersome membranes restrict the motion of the spin label more when compared to liposome membranes. Statement of Significance: Understanding membrane proteins’ structures and functions is critical in the study of many diseases. In order to study them in a native environment, membrane mimetics must be developed that can be suitable for obtaining superior biophysical data quality to characterize structural dynamics while maintaining their native functions and structures. Many currently widely accepted methods have limitations, such as a loss of native structure and function, heterogeneous vesicle formation, restricted lipid types for the vesicle formation for many proteins, and experimental artifacts, which leaves rooms for the development of new biomembrane mimetics. The triblock and diblock polymersomes and hybrid versicles utilized in this study may overcome these limitations and provide the stability and customizability of polymersomes, keeping the biocompatibility and functionality of liposomes for EPR studies of membrane proteins. Full article

A series of novel amphiphilic alternating CPEG copolymers were synthesized through an amine–epoxy click reaction comprising aliphatic amine and polyethylene glycol diglycidyl ether (PEGDE). These polymers were characterized in detail via nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), Fourier-transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA) to confirm the successful synthesis. Due to their amphiphilic structure, these polymers display thermoresponsiveness, with tunable cloud points (Tcps) that are adjustable from 20.8 °C to 46.8 °C by altering the side-chain length of the aliphatic amine, varying the mixing ratios of copolymers, the solution’s pH, and salt additions. This tunable thermoresponsive behavior positions CPEG copolymers as promising candidates for a range of functional material applications. Full article

Folate receptor alpha (FRα) is a glycosylphosphatidylinositol (GPI) membrane-anchored protein containing three N-glycosylated residues at the N47, N139, and N179 termini. These glycosylation sites have been reported to be crucial for the receptor’s structural integrity and its ability to bind and internalize FA. Here, we investigated the role of FRα glycosylation in the binding and internalization efficacy of FA–DABA–SMA in pancreatic PANC-1 cancer cells. There is a strong association of the FA copolymer with FRα with a Pearson coefficient R-value of 0.7179. PANC-1 cancer cells were pretreated with maackia amurensis lectin II (MAL-2), sambucus Nigra lectin (SNA-1), peanut agglutinin (PNA), and wheat germ agglutinin lectin (WGA) at different doses followed by 20 kDa and 350 kDa FA–DABA–SMA loaded with coumarin 153 (C153). Increasing the dosage of MAL2, SNA-1, PNA, and WGA concomitantly and significantly increased the internalization of C153-loaded FA–DABA–SMA in the cells. The half maximal effective lectin concentrations (EC50) to induce cellular internalization into the cytoplasm of the lectins for MAL-2 were 35.88 µg/mL, 3.051 µg/mL for SNA-1, 7.883 µg/mL for PNA, and 0.898 µg/mL for WGA. Live cell imaging of the internalization of 20 kDa and 350 kDa FA copolymers indicated an aggregation of 350 kDa copolymer with FRα in the cytoplasm. In contrast, the 20 kDa FA copolymer remained in the membrane. The data indicate for the first time that the mobile positions of the glycosyl radical groups and the receptor tilt in generating steric hindrance impacted the individual FRα receptors in the binding and internalization of 350 kDa FA–DABA–SMA in cancer cells. Full article

In this study, we describe the preparation of the cationic block copolymer nanocarriers of the proteolytic enzyme serratiopeptidase (SER). Firstly, an amphiphilic poly(2-(dimethylamino)ethyl methacrylate)-b-poly(ε-caprolactone)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA₉-b-PCL₃₅-b-PDMAEMA₉) triblock copolymer was synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Then, cationic micellar nanocarriers consisting of a PCL hydrophobic core and a PDMAEMA hydrophilic shell were formed by the solvent evaporation method. SER was loaded into the polymeric micelles by electrostatic interaction between the positively charged micellar shell and the negatively charged enzyme molecules. The particle size, zeta potential, and colloid stability of complexes as a function of SER concentration were investigated by dynamic and electrophoretic light scattering. It was found that SER retained its proteolytic activity after immobilization in polymeric carriers. Moreover, the complexes have a concentration-dependent enhancing effect on the proliferation and migration of human keratinocyte HaCaT and gingival fibroblast HGF cells. Full article

Polymersomes, self-assembled nanoparticles composed of amphiphilic block copolymers, have emerged as promising versatile nanovesicles with various applications, such as drug delivery, medical imaging, and diagnostics. The integration of click chemistry reactions, specifically the copper [I]-catalysed azide–alkyne cycloaddition (CuAAC), has greatly expanded the functionalisation and bioconjugation capabilities of polymersomes and new drugs, being this synergistic combination explored in this review. It also provides up-to-date examples of previous incorporations of click-compatible moieties (azide and alkyne functional groups) into polymer building blocks, enabling the “click” attachment of various functional groups and ligands, delving into the diverse range of click reactions that have been reported and employed for polymersome copolymer synthesis and the modification of polymersome surfaces, including ligand conjugation and surface modification. Overall, this review explores the current state-of-the-art of the combinatory usage, in recent years, of polymersomes with the click chemistry reaction, highlighting examples of studies of their synthesis and functionalisation strategies. Full article

The synergistic effect of drug and gene delivery is expected to significantly improve cancer therapy. However, it is still challenging to design suitable nanocarriers that are able to load simultaneously anticancer drugs and nucleic acids due to their different physico-chemical properties. In the present work, an amphiphilic block copolymer comprising a biocompatible poly(ethylene glycol) (PEG) block and a multi-alkyne-functional biodegradable polycarbonate (PC) block was modified with a number of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) side chains applying the highly efficient azide–alkyne “click” chemistry reaction. The resulting cationic amphiphilic copolymer with block and graft architecture (MPEG-b-(PC-g-PDMAEMA)) self-associated in aqueous media into nanosized micelles which were loaded with the antioxidant, anti-inflammatory, and anticancer drug quercetin. The drug-loaded nanoparticles were further used to form micelleplexes in aqueous media through electrostatic interactions with DNA. The obtained nanoaggregates—empty and drug-loaded micelles as well as the micelleplexes intended for simultaneous DNA and drug codelivery—were physico-chemically characterized. Additionally, initial in vitro evaluations were performed, indicating the potential application of the novel polymer nanocarriers as drug delivery systems. Full article

In this work, we report on the synthesis and investigation of new hybrid multifunctional iron oxide nanoparticles (IONPs) coated by coumarin-bound copolymer, which combine magneto- or photothermal heating with luminescent thermometry. A series of amphiphilic block copolymers, including Coum-C₁₁-PPhOx₂₇-PMOx₅₉ and Coum-C₁₁-PButOx₈-PMOx₄₂ bearing luminescent and photodimerizable coumarin moiety, as well as coumarin-free PPhOx₂₇-PMOx₅₇, were evaluated for their utility as luminescent thermometers and for encapsulating spherical 26 nm IONPs. The obtained IONP@Coum-C₁₁-PPhOx₂₇-PMOx₅₉ nano-objects are perfectly dispersible in water and able to provide macroscopic heating remotely triggered by an alternating current magnetic field (AMF) with a specific absorption rate (SAR) value of 240 W.g⁻¹ or laser irradiation with a photothermal conversion efficiency of η = 68%. On the other hand, they exhibit temperature-dependent emission of coumarin offering the function of luminescent thermometer, which operates in the visible region between 20 °C and 60 °C in water displaying a maximal relative thermal sensitivity (S_r) of 1.53%·°C⁻¹ at 60 °C. Full article