Amphipathic Polymer Research Articles

Scalable and sustainable remediation of OPD-contaminated aquifer via amphipathic multi-component covalent organic polymers

In-situ injection technology provides a sustainable approach for decontaminating o-phenylenediamine (OPD). However, existing agents often exhibit either exclusive hydrophilicity or hydrophobicity, posing challenges in achieving both effective interception and transport within the aquifer. Herein, a facilely and massively synthesized amphipathic multi-component covalent-organic polymer (SLEL-4) demonstrates appreciable transportability (Lmax > 182.81 cm) and exceptional competitive adsorption ability (four times that of TWEEN 80) for OPD removal. Meanwhile, quantitative analysis expounds the underlying mechanisms. Column and sandbox experiments co-unravel that SLEL-4 effectively remediates actual groundwater contaminated with OPD, achieving sustained efficacy up to 48 h. Impressively, the constructed SLEL-4 deserves recognition as an eco-responsible and cost-optimal option for groundwater treatment according to Life Cycle Assessment (LCA). Overall, this work offers a refreshing perspective on fabricating amphipathic COPs as promising replacements for surfactants in the decontamination of non-aqueous phase liquids (NAPLs), while underscoring the environmental burdens associated with scalable implementation.

Spatially Selective Self-Amplified Imaging of Chemotherapy-Induced Cancer Senescence via Reversal of Impaired Ferritinophagy.

Real-time monitoring of chemotherapy-induced senescence (CIS) in cancer remains a challenging task that would lead to new insights into the adaptive mechanisms of cancer therapy and provide guidance for cancer management. Here, we designed a tailor-made nanoprobe capable of imaging CIS in a sequential activation and self-amplified manner by reversing senescence-related impaired ferritinophagy. It contains an amphipathic polymer as a spatially responsive vehicle, a Fe2+-activable dye as the reporter, and an autophagy inducer as the signal amplifier. Owing to metabolic changes, the nanoprobe preferentially enriches in senescent cancer cells, leading to in situ activation and fluorescence switching of the reporter by labile Fe2+. Meanwhile, the inducer restores ferritinophagy and promotes autophagic degradation of accumulated ferritin, facilitating conversion of ferritin-bound iron into Fe2+ for amplified imaging in senescent cancer cells yet keeping inert in nonsenescent cells. Of note, the accumulation and activation of the nanoprobe and sustained ferritin degradation occur at the same subcellular location, thus minimizing the diffusion process-induced nonspecific responses. The feasibility of this strategy is successfully demonstrated in both living cells and animal models. This work offers a new way for therapeutic evaluation and a basic understanding of the roles of senescence in cancer treatment.

Micro/nano system-mediated local treatment in conjunction with immune checkpoint inhibitor against advanced-Stage malignant melanoma

Tumor relapse and metastasis become a big challenge in treating malignant melanoma because conventional therapeutic options often fail to eradicate the tumor residue after surgical resection, posing huge threat to human health. Herein, a feasible strategy is developed for fighting crafty melanoma pre- and postsurgery. Specifically, nitric oxide (NO)-carried micelles (NOM) are designed by conjugating S-nitrosoglutathione (GSNO) with poly(2-ethyl-2-oxazoline)-b-poly(D, L-lactide) (PEOz-b-PLA) to form amphipathic polymer, which can self-assemble into pH-sensitive micelle to encapsulate chemotherapeutic drug paclitaxel (PTX). By further loading PTX@NOM into the needle tips of dissolvable microneedle (MN) patch, a local synergistic strategy is achieved for combating melanoma via easy insertion. Meanwhile, due to the immunomodulatory ability of NO by inducing the immunogenic cell death (ICD) of tumor cells and polarizing M2-like tumor-associated macrophages (TAMs) into antitumoral M1-like type, the “cold” immune microenvironment of melanoma is effectively remodeled. When combining with aPD-L1-based immune checkpoint blockade therapy, the treatment outcome of aPD-L1 is dramatically boosted, which not only suppresses primary tumor growth, but also inhibits the notorious post-operative melanoma recurrence and metastasis. Overall, this local strategy mediated by nanoparticle-loaded MN patch expands the therapeutic regimen for melanoma treatment in clinic.

CdS/ZnS quantum dots based on an amphipathic polymer platform for fluorescent probe of dopamine with high sensitivity and selectivity

Due to the widespread presence of dopamine in living organisms and its physiological and pharmacological effects, developing rapid and sensitive methods for detecting dopamine has been of great significance. Fluorescent probes are a commonly used and highly sensitive detection method. In this work, based on a self-developed amphipathic polymer template, CdS/ZnS fluorescent quantum dots (QDs) with a maximum absorption wavelength of 500–550 nm were synthesized and characterized. They exhibited stable fluorescence in the pH range from weak acid to alkaline, and fluorescence quenching occurred at pH = 4.5. The QDs could be applied as fluorescent probes for detecting dopamine, with a limit of detection 0.027 mM and high selectivity, unaffected by common metal ions, amino acids, glucose, etc. Compared to the high activity of dopamine being oxidized easily, this fluorescent QDs and its template polymer PEI played a stabilizing role during the testing process. Therefore, this work provides a promising dopamine fluorescent probe with application prospects.

Biotin-modified acid-sensitive micelles for enhancing antitumor effect of paclitaxel

This study was aimed at fabricating tumor targeting and acid-responsive micelles as carriers for paclitaxel (PTX). An amphipathic polymer TOS-Ace-PEG-Bio was designed and synthesized by conjugating α-tocopherol succinate (TOS) with biotinylated polyethylene glycol (PEG-Bio) via acetal bond. The polymer could self-assemble into nanosized micelles and encapsulate PTX. The PTX-loaded micelles possessed appropriate particle size with the mean value of 129.3 ± 0.9 nm. Strong pH dependent PTX release behavior was verified by in vitro drug release study. At cellular level, the PTX-loaded micelles could be selectively internalized by MCF-7 cells. The in vivo study also confirmed their excellent antitumor activity and reduced side effects. Based on these features, the TOS-Ace-PEG-Bio micelles were considered to be promising carriers for delivery of PTX.

Formulation and evaluation of a two-stage targeted liposome coated with hyaluronic acid for improving lung cancer chemotherapy and overcoming multidrug resistance

Multidrug resistance (MDR) has emerged as a prominent challenge contributing to the ineffectiveness of chemotherapy in treating non-small cell lung cancer (NSCLC) patients. Currently, mitochondria of cancer cells are identified as a promising target for overcoming MDR due to their crucial role in intrinsic apoptosis pathway and energy supply centers. Here, a two-stage targeted liposome (HA/TT LP/PTX) was successfully developed via a two-step process: PTX-loaded cationic liposome (TT LP/PTX) were formulated by lipid film hydration & ultrasound technique, followed by further coating with natural anionic polysaccharide hyaluronic acid (HA). TT, an amphipathic polymer conjugate of triphenylphosphine (TPP)-tocopheryl polyethylene glycol succinate (TPGS), was used to modify the liposomes for mitochondrial targeting. The average particle size, zeta potential and encapsulation efficiency (EE%) of HA/TT LP/PTX were found to be 153 nm, −30.3 mV and 92.1% based on the optimal prescription of HA/TT LP/PTX. Compared to cationic liposome, HA-coated liposomes showed improved stability and safety, including biological stability in serum, cytocompatibility, and lower hemolysis percentage. In drug-resistant A549/T cells, HA was shown to improve the cellular uptake of PTX through CD44 receptor-mediated endocytosis and subsequent degradation by hyaluronidase (HAase) in endosomes. Following this, the exposure of TT polymer facilitated the accumulation of PTX within the mitochondria. As a result, the function of mitochondria in A549/T cells was disturbed, leading to an increased ROS level, decreased ATP level, dissipated MMP, and increased G2/M phase arrest. This resulted in a higher apoptotic rate and stronger anticancer efficacy.

Water-Soluble Cationic Eu3+-Metallopolymer with High Quantum Yield and Sensitivity for Intracellular Temperature Sensing.

Lanthanide-based (Ln3+) luminescent materials are ideal candidates for use in fluorescence intracellular temperature sensing. However, it remains a great challenge to obtain a Ln3+-ratiometric fluorescence thermometer with high sensitivity and quantum yield in an aqueous environment. Herein, a cationic Eu3+-metallopolymer was synthesized via the coordination of Eu(TTA)3·2H2O with an AIE active amphipathic polymer backbone that contains APTMA ((3-acrylamidopropyl) trimethylammonium) and NIPAM (N-isopropylacrylamide) units, which can self-assemble into nanoparticles in water solution with APTMA and NIPAM as the hydrophilic shell. This polymer exhibited highly efficient dual-emissive white-light emission (Φ = 34.3%). Particularly, when the temperature rises, the NIPAM units will transform from hydrophilic to hydrophobic in the spherical core of the nanoparticle, while the VTPE units are moved from inside the nanoparticle to the shell, activating its nonradiative transition channel and thereby decreasing its energy transfer to Eu3+ centers, endowing the Eu3+-metallopolymer with an extremely high temperature sensing sensitivity within the physiological temperature range. Finally, the real-time monitoring of the intracellular temperature variation is further conducted.

Preparation of an amphipathic polymer library in a mixture of water/ethanol by photoinduced polymerization and evaluation of the cryoprotective activity

Impact of the polymer structures on the cryoprotective activity was investigated.

Curcumin Nanodiscs Improve Solubility and Serve as Radiological Protectants against Ionizing Radiation Exposures in a Cell-Cycle Dependent Manner.

Curcumin, a natural polyphenol derived from the spice turmeric (Curcuma longa), contains antioxidant, anti-inflammatory, and anti-cancer properties. However, curcumin bioavailability is inherently low due to poor water solubility and rapid metabolism. Here, we further refined for use curcumin incorporated into “biomimetic” nanolipoprotein particles (cNLPs) consisting of a phospholipid bilayer surrounded by apolipoprotein A1 and amphipathic polymer scaffolding moieties. Our cNLP formulation improves the water solubility of curcumin over 30-fold and produces nanoparticles with ~350 µg/mL total loading capacity for downstream in vitro and in vivo applications. We found that cNLPs were well tolerated in AG05965/MRC-5 human primary lung fibroblasts compared to cultures treated with curcumin solubilized in DMSO (curDMSO). Pre-treatment with cNLPs of quiescent G0/G1-phase MRC-5 cultures improved cell survival following 137Cs gamma ray irradiations, although this finding was reversed in asynchronously cycling log-phase cell cultures. These findings may be useful for establishing cNLPs as a method to improve curcumin bioavailability for administration as a radioprotective and/or radiomitigative agent against ionizing radiation (IR) exposures in non-cycling cells or as a radiosensitizing agent for actively dividing cell populations, such as tumors.

Self-engineered lipid peroxidation nano-amplifier for ferroptosis-driven antitumor therapy

Ferroptosis has been extensively explored as a promising therapeutic target for cancer. Most ferroptosis inducers promote the intracellular accumulation of lipid peroxidation by depleting glutathione peroxidase 4 (GPX4). However, GPX4 suppression alone is not sufficient to trigger intracellular lipid peroxidation storm, resulting in inefficient ferroptosis induction and unsatisfactory antitumor effect. Herein, we precisely engineer a lipid peroxidation nano-amplifier based on a facile drug-deliver-drug (DDD) engineering strategy. Interestingly, FIN56 (a GPX4 inhibitor) is found to readily co-assemble with arachidonic acid (AA) into stable nanoparticles without the assistance of any excipients. Then, a disulfide bond-containing amphipathic PEG polymer is decorated on the nano-amplifier for long blood circulation and tumor-specific drug release. Notably, AA could not only be converted into abundant lipid reactive oxygen species (ROS) but also elicit membranous lipid peroxidation in tumor cells, synergistically inducing tumor ferroptosis with FIN56-mediated GPX4 depletion. As expected, the nano-amplifier exhibits potent ferroptosis-driven antitumor activity in 4 T1 breast tumor-bearing mice. This study drives a conceptual step forward in ferroptosis-driven nanotherapeutics, and offers a novel DDD co-delivery paradigm for combination cancer therapy.

Synthesis of sinapic acid modified sodium hyaluronate particles and the one-step processing of multiple Pickering emulsion

In this study, a series of sodium hyaluronate (HA) polymer molecules grafted with different amounts of sinapic acid (SA) groups were synthesized by adjusting the esterification reaction time, and the introduction of SA endows the polymer with both amphipathy and UV absorbability. The amphipathic polymer molecules (HA-SA) tend to self-assemble into polydisperse colloid particles and the particle properties of HA-SA, such as particle size, zeta potential as well as the interfacial activity were studied in detail. The results indicate that the properties of HA-SA particles prepared with different esterification reaction time are quite different due to the different graft amounts of SA. The graft amount of SA increased with the prolongation of esterification reaction time, and the interfacial activity of the obtained HA-SA particles also increased gradually, but an excessively high graft amount would make the polymer too hydrophobic and thus lead to the interfacial activity reduce slightly. By controlling the esterification reaction time within an appropriate range, the prepared particles show significant interfacial activity and are apt to linger on the interface of oil-water to reduce the interfacial tension, which has potential to be a new promising stabilizer of emulsions. Further studies show that, benefiting from the polydispersity of the HA-SA particles, the water-in-oil-in-water (W/O/W) multiple Pickering emulsion can be prepared by one-step homogenization using HA-SA particles as stabilizer. Different from the inorganic particle emulsifiers and their stabilized Pickering emulsions, the particles that self-assembled by HA-SA amphiphilic polymers and their stabilized Pickering emulsions have obvious sensitivity to pH and temperature due to the existence of both COO- and OH- in HA molecule, which provides a new strategy for developing stimulus-responsive Pickering emulsifiers. The excellent moisture retention of HA and the protection of SA against UV radiation make HA-SA particles potentially a high-end cosmetic emulsifier accompanied with moisturizing and sunscreen effects on skin.

Tumor-Microenvironment-Activatable Polymer Nano-Immunomodulator for Precision Cancer Photoimmunotherapy.

Cancer nanomedicine combined with immunotherapy has become a promising strategy for treating cancer in terms of safety and potency; however, precise regulation of the activation of antitumor immunity remains challenging. Herein, a smart semiconducting polymer nano-immunomodulator (SPNI), which responds to the acidic tumor microenvironment (TME), for precision photodynamic immunotherapy of cancer, is reported. The SPNI is self-assembled by a near-infrared (NIR)-absorbing semiconducting polymer and an amphipathic polymer conjugated with a Toll-like receptor 7 (TLR7) agonist via an acid-labile linker. Upon arrival at tumor site, SPNI undergoes hydrolysis and triggers an efficient liberation of TLR7 agonist in response to the acidic TME for dendritic cell activation. Moreover, SPNI exerts photodynamic effects for direct tumor eradication and immunogenic cancer cell death under NIR photoirradiation. The synergistic action of released immunogenic factors and acidic-TME-activated TLR7 agonist can serve as an in situ generated cancer vaccine to evoke strong antitumor activities. Notably, such localized immune activation boosts systemic antitumor immune responses, resulting in enhanced cytotoxic CD8+ T infiltration to inhibit tumor growth and metastasis. Thereby, this work presents a general strategy to devise prodrug of immunotherapeutics for precise regulation of cancer immunotherapy.

Small Protein Enrichment Improves Proteomics Detection of sORF Encoded Polypeptides.

With the rapid growth in the number of sequenced genomes, genome annotation efforts became almost exclusively reliant on automated pipelines. Despite their unquestionable utility, these methods have been shown to underestimate the true complexity of the studied genomes, with small open reading frames (sORFs; ORFs typically considered shorter than 300 nucleotides) and, in consequence, their protein products (sORF encoded polypeptides or SEPs) being the primary example of a poorly annotated and highly underexplored class of genomic elements. With the advent of advanced translatomics such as ribosome profiling, reannotation efforts have progressed a great deal in providing translation evidence for numerous, previously unannotated sORFs. However, proteomics validation of these riboproteogenomics discoveries remains challenging due to their short length and often highly variable physiochemical properties. In this work we evaluate and compare tailored, yet easily adaptable, protein extraction methodologies for their efficacy in the extraction and concomitantly proteomics detection of SEPs expressed in the prokaryotic model pathogen Salmonella typhimurium (S. typhimurium). Further, an optimized protocol for the enrichment and efficient detection of SEPs making use of the of amphipathic polymer amphipol A8-35 and relying on differential peptide vs. protein solubility was developed and compared with global extraction methods making use of chaotropic agents. Given the versatile biological functions SEPs have been shown to exert, this work provides an accessible protocol for proteomics exploration of this fascinating class of small proteins.

Stable Loading and Delivery of Icaritin Using PEG-PCL Micelles for Effective Treatment of Oral Squamous Cell Carcinoma.

Icaritin can inhibit cell proliferation and induce apoptosis in Oral Squamous Cell Carcinoma (OSCC). However, low solubility limits its clinical usage. To improve the efficacy of icaritin treatment, a micelle system was designed for targeted delivery of drugs to OSCC cells. In the present study, the micelles loaded with icaritin were self-assembled from the amphipathic polymer via film dispersion. Nanoparticles were characterized with the transmission electron microscope and dynamic light scattering. The cytotoxicity of icaritin nanoparticles was analyzed by CCK-8, and in vitro target-selective intracellular uptake behaviors were observed using a laser confocal microscope. The micelles were spherical with the mean diameter of 121.2 nm. in vitro studies revealed that icaritin was stablely and slowly released from micelles. Cytotoxicity analysis demonstrated that icartin-loaded micelles exhibited better therapeutic efficacy compared with free icaritin. Cellular uptake and intracellular release results revealed that micelles efficiently delivered icaritin into OSCC cells. These results suggest that encapsulated icaritin in polycaprolactone - polyethylene glycol (PCL-PEG) micelles may provide safe and effective drug delivery in OSCC treatments.

Polymer Nanodiscs and Their Bioanalytical Potential.

Membrane proteins (MPs) play a pivotal role in cellular function and are therefore predominant pharmaceutical targets. Although detailed understanding of MP structure and mechanistic activity is invaluable for rational drug design, challenges are associated with the purification and study of MPs. This review delves into the historical developments that became the prelude to currently available membrane mimetic technologies before shining a spotlight on polymer nanodiscs. These are soluble nanosized particles capable of encompassing MPs embedded in a phospholipid ring. The expanding range of reported amphipathic polymer nanodisc materials is presented and discussed in terms of their tolerance to different solution conditions and their nanodisc properties. Finally, the analytical scope of polymer nanodiscs is considered in both the demonstration of basic nanodisc parameters as well as in the elucidation of structures, lipid-protein interactions, and the functional mechanisms of reconstituted membrane proteins. The final emphasis is given to the unique benefits and applications demonstrated for native nanodiscs accessed through a detergent free process.

Recombinant SARS-CoV-2 envelope protein traffics to the trans-Golgi network following amphipol-mediated delivery into human cells

The severe acute respiratory syndrome coronavirus 2 envelope protein (S2-E) is a conserved membrane protein that is important for coronavirus (CoV) assembly and budding. Here, we describe the recombinant expression and purification of S2-E in amphipol-class amphipathic polymer solutions, which solubilize and stabilize membrane proteins, but do not disrupt membranes. We found that amphipol delivery of S2-E to preformed planar bilayers results in spontaneous membrane integration and formation of viroporin cation channels. Amphipol delivery of the S2-E protein to human cells results in plasma membrane integration, followed by retrograde trafficking to the trans-Golgi network and accumulation in swollen perinuclear lysosomal-associated membrane protein 1–positive vesicles, likely lysosomes. CoV envelope proteins have previously been proposed to manipulate the luminal pH of the trans-Golgi network, which serves as an accumulation station for progeny CoV particles prior to cellular egress via lysosomes. Delivery of S2-E to cells will enable chemical biological approaches for future studies of severe acute respiratory syndrome coronavirus 2 pathogenesis and possibly even development of “Trojan horse” antiviral therapies. Finally, this work also establishes a paradigm for amphipol-mediated delivery of membrane proteins to cells.

Self-assembled micelle responsive to quick NIR light irradiation for fast drug release and highly efficient cancer therapy

Upconversion nanoparticles (UCNPs) have been used for designing near infrared (NIR) light-responsive nanocarriers and controllable drug release. However, the need for long-term NIR light irradiation over hours impaired their application efficiency. Here we develop a self-assembled micelle of amphipathic polymer P-DASA which degrades via quick NIR light irradiation. UCNPs and DOX are also encapsulated in the micelle for quick drug release. P-DASA is composed of hydrophilic polyethylene glycol segment and photo-responsive hydrophobic donor–acceptor Stenhouse adduct (DASA). Only 5-min NIR irradiation causes the hydrophilicity conversion of P-DASA and the complete disruption of micelle with DOX fast release of 83.7% in 30 min to achieve highly efficient therapy. Moreover, the P-glycoprotein mediated DOX efflux is also diminished by concomitantly producing NO intracellularly. This micelle demonstrates impressive in vivo therapeutic effect, and thus provides an avenue for highly efficient cancer therapy.

Nanoparticles based on polymers modified with pH-sensitive molecular switch and low molecular weight heparin carrying Celastrol and ferrocene for breast cancer treatment

Triple negative breast cancer (TNBC) metastasis is still one of the obstacles in clinical treatment, while highly-effective cancer drugs usually cannot be used for their hydrophobicity and comprehensive system toxicity. This study built a kind of pH-sensitive nanoparticles (PP/H NPs) constructed by poly (lactic-co-glycolic acid) modified with β-cyclodextrin (PLGA-β-CD), polyethyleneimine grafted with benzimidazole (PEI-BM) and low molecular weight heparin (LMWH) to delivery Celastrol (Cela) and ferrocene (Fc) for breast cancer therapy. PLGA-β-CD and PEI-BM were synthesized by amidation reaction, the amphipathic polymer nanoparticles with 108.37 ± 1.02 nm were self-assembled in water. After PP/H NPs treatment, the half maximal inhibitory concentration (IC50) decreased by 91% compared with Cela, and ROS level was also elevated. PP/H NPs led to substantial tumor inhibiting rate (TIR, 65.86%), utilized LMWH to strengthen the anti-metastasis effect of PP/H NPs. PP/H NPs took advantage of exogenous chemotherapeutics and endogenous ROS to inhibit tumor growth, and combined with LMWH to hinder breast cancer metastasis.

Formulation of solid dispersion to improve dissolution and oral bioavailability of poorly soluble dexibuprofen

Dexibuprofen (DEXI) belongs to BCS class II drug with poor aqueous solubility resulting in poor bioavailability. To enhance solubility and bioavailability of DEXI, DEXI-loaded solid dispersion (SD) was formulated. DEXI-SDs were prepared by melting method and solvent evaporation method. Amphipathic polymer poloxamer 407 (pol 407) was selected based on solubility and dissolution tests. The ratio of DEXI:pol 407 was optimized as 1:2. The physicochemical properties, dissolution, and oral bioavailability of SD3 and SD6 were evaluated to compare preparation methods. The dissolution rate of DEXI from SD formulations was higher at pH 6.8 and pH 7.2 than at pH 1.2. Following oral administration in rats, the Cmax and AUClast of SD3 and SD6 formulations were significantly higher compared with raw DEXI. In addition, the SD6 formulation showed increased Cmax and AUClast by 1.34- and 1.33-fold, compared with those of SD3 formulation, respectively. These results demonstrated that SD formulation has excellent potential as a formulation for poorly soluble drug DEXI.

A strategy for imaging-guided cocktail cancer therapy using dual-colored polymeric drug carriers with amplified aggregation-induced emission behavior by donor–acceptor/Förster resonance energy transfer adjustment

Abstract