Protein Drug-Loaded Polymeric Nanoparticles

Considerable interest and research have focused on the administration of therapeutic proteins. For delivery of therapeutic proteins, bioavailability and stabilization of protein drugs to maintain therapeutically acceptable levels is an important challenge in clinical trials. To overcome these challenges, polymeric nanoparticles have become one of the best methods for protein delivery. In this review, we summarize the current available polymeric nanoparticles designed for protein delivery, current status, and advantages of protein delivery systems.

Relaxin-encapsulated polymeric metformin nanoparticles remodel tumor immune microenvironment by reducing CAFs for efficient triple-negative breast cancer immunotherapy

Cancer-associated fibroblasts(CAFs)are one of the most abundant stromal cells in the tumor microenvironment which mediate desmoplastic response and are the primary driver for an immunosuppressive microenvironment,leading to the failure of triple-negative breast cancer(TNBC)immunotherapy.Therefore,depleting CAFs may enhance the effect of immunotherapy(such as PD-L1 antibody).Relaxin(RLN)has been demonstrated to significantly improve transforming growth factor-β(TGF-β)induced CAFs activation and tumor immunosuppressive microenvironment.However,the short half-life and systemic vasodilation of RLN limit its in vivo efficacy.Here,plasmid encoding relaxin(pRLN)to locally express RLN was delivered with a new positively charged polymer named polymeric metformin(PolyMet),which could increase gene transfer efficiency significantly and have low toxicity that have been certified by our lab before.In order to improve the stability of pRLN in vivo,this complex was further formed lipid poly-γ-glutamic acid(PGA)/PolyMetpRLN nanoparticle(LPPR).The particle size of LPPR was 205.5±2.9 nm,and the zeta potential was+55.4±1.6 mV.LPPR displayed excellent tumor penetrating efficacy and weaken proliferation of CAFs in 4T1luc/CAFs tumor spheres in vitro.In vivo,it could reverse aberrantly activated CAFs by decreasing the expression of profibrogenic cytokine and remove the physical barrier to reshape the tumor stromal microenvironment,which enabled a 2.2-fold increase in cytotoxic T cell infiltration within the tumor and a decrease in immunosuppressive cells infiltration.Thus,LPPR was observed retarded tumor growth by itself in the 4T1 tumor bearing-mouse,and the reshaped immune microenvironment further led to facilitate antitumor effect when it combined with PD-L1 antibody(aPD-L1).Altogether,this study presented a novel therapeutic approach against tumor stroma using LPPR to achieve a combination regimen with immune checkpoint blockade therapy against the desmoplastic TNBC model.

Voltage-modulated polymer nanopore field-effect transistor for multi-sized nanoparticle detection

Solid-state nanopores offer a range of distinct advantages over biological nanopores,such as structural diversity and greater stability and durability;this makes them highly promising for high-resolution nanoparticle sensing.Biological nanopores can exhibit gating characteristics with stress-responsive switches and can demonstrate specificity toward particular molecules.Drawing inspiration from biological nanopores,this paper introduces a novel polymer nanopore with field-effect characteristics,leveraging a conductive polymer in its construction to showcase intriguing gating behavior.Notably,in this device,the polymer layer serves as the gate,enabling precise control over the source–drain current response inside and outside the pore by simply adjusting the gate voltage.This unique feature allows fine-tuning of the nanopore’s sensitivity to nanoparticles of varying sizes and facilitates its operation in multiple modes.Experimental results reveal that the developed polymer nanopore field-effect transistor demonstrates remarkable selectivity in detecting nanoparticles of various sizes under different applied voltages.The proposed single device demonstrates the exceptional ability to detect multiple types of nanoparticle,showcasing its immense potential for a wide range of applications in biological-particle analysis and medical diagnostics.

Improved Plasmonic Hot‑Electron Capture in Au Nanoparticle/Polymeric Carbon Nitride by Pt Single Atoms for Broad‑Spectrum Photocatalytic H_(2)Evolution

ABSTRACT Rationally designing broad-spectrum photocatalysts to harvest whole visible-light region photons and enhance solar energy conversion is a“holy grail”for researchers,but is still a challenging issue.Herein,based on the common polymeric carbon nitride(PCN),a hybrid co-catalysts system comprising plasmonic Au nanoparticles(NPs)and atomically dispersed Pt single atoms(PtSAs)with different functions was constructed to address this challenge.For the dual co-catalysts decorated PCN(PtSAs–Au_(2.5)/PCN),the PCN is photoexcited to generate electrons under UV and short-wavelength visible light,and the synergetic Au NPs and PtSAs not only accelerate charge separation and transfer though Schottky junctions and metal-support bond but also act as the co-catalysts for H_(2) evolution.Furthermore,the Au NPs absorb long-wavelength visible light owing to its localized surface plasmon resonance,and the adjacent PtSAs trap the plasmonic hot-electrons for H_(2) evolution via direct electron transfer effect.Consequently,the PtSAs–Au_(2.5)/PCN exhibits excellent broad-spectrum photocatalytic H_(2) evolution activity with the H_(2) evolution rate of 8.8 mmol g^(−1) h^(−1) at 420 nm and 264μmol g^(−1) h^(−1) at 550 nm,much higher than that of Au_(2.5)/PCN and PtSAs–PCN,respectively.This work provides a new strategy to design broad-spectrum photocatalysts for energy conversion reaction.

Superparticles Formed by Amphiphilic Tadpole-like Single Chain Polymeric Nanoparticles and Their Application as an Ultrasonic Responsive Drug Carrier

Herein, we report self-assembly of tadpole-like single chain polymeric nanoparticles （TPPs） and the ultrasonic response of the resultant superparticles. The TPPs are with an intramolecularly crosslinked poly（2-（methacryloyloxy）ethyl pent-4-ynoate）-rpoly（hydroxyethyl methacrylate） （PMAEP-r-PHEMA） chain as the ＂head＂ and a poly（2- （dimethylamino）ethyl methacrylate （PDMAEMA） linear chain as the ＂tail＂, and are pre- pared simply and emciently by Glaser-coupling of the pendant alkynes in the PMAEP-r- PHEMA block in the common solvent methanol. The formation of the TPPs was confirmed by gel permeation chromatograph, nuclear magnetic resonance spectroscopy, dynamic light scattering, static dynamic scattering, and transmission electron microscopy. In aqueous solution, the amphiphilic TPPs could self-assemble into regular superparticles, driven by aggregation of the hydrophobic ＂heads＂. Since in the structure there is no chain entanglement and the embedding of PDMAEMA chains disturb close-packing of the ＂heads＂, the superpartieles are responsive to a low-energy ultrasonic vibration, as evidenced by greatly enhanced release of the functional molecules from the superparticles by treatment of a low-energy ultrasound. Therefore, the superparticles should be very promising in the use as the drug carriers that can be manipulated from a long distance, considering that ultrasonic energy can be focused at a small area in a relatively long distance from the ultrasound-radiating source.

POLYMERIC NANOPARTICLES FROM SUPERCRITICAL CO_2 MICROEMULSION POLYMERIZATION

Herein, we reported the microemulsion polymerization in supercritical carbon dioxide. With the aid of an anionic phosphate fluorosurfactant （bis-[2-（F-hexyl）ethyl]phosphate sodium）, water-soluble/CO2-insoluble acryloxyethyltrimethyl ammonium chloride monomer and N,N＇-methylene-bisacrylamide cross-linker were solubilized into CO2 continuous phase via the formation of water-in-CO2 （w/c） microemulsion water pools. Initiated by a CO2-soluble initiator, 2,2＇-azo-bisisobutyronitrile （AIBN）, cross-linked poly（acryloxyethyltrimethyl ammonium chloride） particles were produced and stabilized in these w/c internal water pools. Nano-sized particles with sizes less than 20 nm in diameter and narrow particle size distributions were obtained.

Tuning catalytic selectivity of propane oxidative dehydrogenation via surface polymeric phosphate modification on nickel oxide nanoparticles

Thermal stability has long been recognized as a major limitation for the application of ligand modification in high-temperature reactions. Herein, we demonstrate polymeric phosphate as an efficient and stable ligand to tune the selectivity of propane oxidative dehydrogenation. Beneficial from the weakened affinity of propene, NiO modified with polymeric phosphate shows a selectivity 2–3 times higher than NiO towards the production of propene. The success of this regulation verifies the feasibility of ligand modification in high-temperature gas-phase reactions and shines a light on its applications in other important industrial reactions.

Polymeric nanoparticles developed by vitamin E-modified aliphatic polycarbonate polymer to promote oral absorption of oleanolic acid

Oleanolic acid (OA) exhibited good pharmacological activities in the clinical treatment of hypoglycemia, immune regulation, acute jaundice and chronic toxic hepatitis. However, the oral delivery of OA is greatly limited by its inferior water solubility and poor intestinal mucosa permeability. Herein, we developed a novel polymeric nanoparticle (NP) delivery system based on vitamin E modified aliphatic polycarbonate (mPEG-PCC-VE) to facilitate oral absorption of OA. OA encapsulated mPEG-PCC-VE NPs (OA/mPEG-PCC-VE NPs) showed uniform particle size of about 170 nm with high drug loading capability (8.9%). Furthermore, the polymeric mPEG-PCC-VE NPs, with good colloidal stability and pH-sensitive drug release characteristics, significantly enhanced the in vitro dissolution of OA in the alkaline medium. The in situ single pass intestinal perfusion (SPIP) studies performed on rats demonstrated that the OA/m PEG-PCC-VE NPs showed significantly improved permeability in the whole intestinal tract when compared to OA solution, especially for duodenum and colon. As a result, the in vivo pharmacokinetics study indicated that the bioavailability of OA/m PEG-PCC-VE NPs showed 1.5-fold higher than commercially available OA tablets. These results suggest that mPEGPCC-VE NPs are a promising platform to facilitate the oral delivery of OA.

Evaluation of Cisplatin-Loaded Polymeric Micelles and Hybrid Nanoparticles Containing Poly(Ethylene Oxide)-Block-Poly(Methacrylic Acid) on Tumor Delivery

Particulate carriers such as polymeric micelles (PMs) and liposomes have been investigated to increase drug accumulation in tumors and reduce distribution to healthy tissues. In this study, we prepared PM and hybrid nanoparticles (HNPs) with poly(ethylene oxide)-block-poly(methacrylic acid) (PEO-b-PMAA) for loading cisplatin, and evaluated cisplatin release, cytotoxicity, and biodistribution in mice. PM composed of PEO-b-PMAA and HNPs composed of egg phosphatidylcholine (EPC)/PEO-b-PMAA at molar ratios of 50/2.8 (HNP-P5) and 50/50 (HNP-P50), respectively, were prepared by a nanoprecipitation method. The sizes of PM, HNP-P5, and HNP-P50 after inclusion of cisplatin were approximately 200, 100, and 55 nm, respectively, and their entrapment efficiencies were approximately 44% - 66%. In the drug-release study, HNP-P5 and HNP-P50 showed reduced release of cisplatin compared with PM. Regarding the cytotoxic assay, HNP-P5 exhibited lower cytotoxicity for mouse Lewis lung carcinoma (LLC) and mouse colon carcinoma Colon 26 cells than PM and HNP-P50. In terms of biodistribution, PM could significantly improve blood circulation and tumor accumulation after intravenous injection into Colon 26 tumor-bearing mice compared with free cisplatin, but HNP-P5 and HNP-P50 did not. EPC in HNPs might be destabilized in the circulation, although it could reduce release of cisplatin in in vitro experiments. This study suggested that polymeric micelles composed of PEO-b-PMAA are a better carrier for cisplatin than hybrid nanoparticles composed of PEO-b-PMAA and EPC.

Diffusion of Nanoparticles in Semidilute Polymer Solutions： A Multiparticle Collision Dynamics Study

The diffusion of nanoparticles immersed in semidilute polymer solutions is investigated by a hybrid mesoscopic multiparticle collision dynamics method. Effects of polymer concentration and hydrodynamic interactions among polymer monomers are focused. Extensive simulations show that the dependence of diffusion coefficient D on the polymer concentration c agrees with Phillies equation D-exp （-αc^δ） with a scaling exponent δ≈0.97 which coincides with the experimental one in literature. For increasing nanoparticle size, the scaling prefactor α increases monotonically while the scaling exponent always keeps fixed. Moreover, we also study the diffusion of nanoparticle without hydrodynamic interactions and find that mobility of the nanoparticle slows down, and the scaling exponent is obviously different from the one in experiments, implying that hydrodynamic interactions play a crucial role in the diffusion of a nanoparticle in semidilute polymer solutions.

pH-sensitive Nanoparticles for High Loading and Efficient Delivery of Doxorubicin

An acid-sensitive delivery system based on acylhydrazone bond was developed for high loading and efficient delivery of doxorubicin.Doxorubicin(DOX)was covalently combined with dihydrazide adipate to form acid-sensitive hydrazone bond based on Schiff base reaction,then the intermediate was covalently combined with carboxymethyl chitosan through amide bond to form polymeric prodrugs,and nanoparticles were formed through self-assembling.Moreover,the structural and particle properties of CMCS-ADH-DOX were characterized by ultraviolet visible near infrared spectrophotometry(UV),nuclear magnetic resonance spectroscopy(^(1)H-NMR),fourier transform infrared spectroscopy(FT-IR),dynamic light scattering(DLS),and transmission electron microscopy(TEM).The mean diameter of the self-assembled nanoparticles is 165 nm,while the morphology is a relatively uniform spherical shape.Moreover,these DOXloaded nanoparticles showed pH-triggered drug release behavior.Compared with free DOX,CAD NPs showed lower toxic side effects in L929 cells and similar toxicity in 4T1 cells.The experimental results indicate that the CMCS-ADH-DOX nanoparticles may be used as an acid-sensitive targeted delivery system with good application prospect for cancer.

Ordered Toroid Structures of Nanoparticles in Self-attractive Semiflexible Polymer/Nanoparticle Composites

By employing dynamic Monte Carlo simulations, we investigate a coil-to-toroid transition of self-attractive semiflexible polymers and the spatial distributions of nanoparticles in self- attractive semiflexible polymer/nanoparticle composites. The conformation of self-attractive semiflexible polymers depends on bending energy and self-attractive interactions between monomers in polymer chains. A three-stage process of toroid formation for self-attractive semiflexible chains is shown： several isolated toroids, a loose toroid structure, and a compact toroid structure. Utilizing the compact toroid conformations of self-attractive semiflexible chains, we can control effectively the spatial distributions of nanoparticles in self-attractive semiflexible polymer nanocomposites, and an unconventional toroid structure of nanoparti- cles is observed.

Mussel‑Inspired Redox‑Active and Hydrophilic Conductive Polymer Nanoparticles for Adhesive Hydrogel Bioelectronics

Conductive polymers(CPs)are generally insoluble,and developing hydrophilic CPs is significant to broaden the applications of CPs.In this work,a mussel-inspired strategy was proposed to construct hydrophilic CP nanoparticles(CP NPs),while endowing the CP NPs with redox activity and biocompatibility.This is a universal strategy applicable for a series of CPs,including polyaniline,polypyrrole,and poly(3,4-ethylenedioxythiophene).The catechol/quinone contained sulfonated lignin(LS)was doped into various CPs to form CP/LS NPs with hydrophilicity,conductivity,and redox activity.These CP/LS NPs were used as versatile nanofillers to prepare the conductive hydrogels with long-term adhesiveness.The CP/LS NPs-incorporated hydrogels have a good conductivity because of the uniform distribution of the hydrophilic NPs in the hydrogel network,forming a well-connected electric path.The hydrogel exhibits long-term adhesiveness,which is attributed to the mussel-inspired dynamic redox balance of catechol/quinone groups on the CP/LS NPs.This conductive and adhesive hydrogel shows good electroactivity and biocompatibility and therefore has broad applications in electrostimulation of tissue regeneration and implantable bioelectronics.

A Stable Open-Shell Conjugated Diradical Polymer with Ultra-High Photothermal Conversion Efficiency for NIR-Ⅱ Photo-Immunotherapy of Metastatic Tumor

Massive efforts have been concentrated on the advance of eminent near-infrared(NIR) photothermal materials(PTMs) in the NIR-Ⅱ window(1000–1700 nm), especially organic PTMs because of their intrinsic biological safety compared with inorganic PTMs. However, so far, only a few NIR-Ⅱresponsive organic PTMs was explored, and their photothermal conversion efficiencies(PCEs) still remain relatively low. Herein, donor–acceptor conjugated diradical polymers with open-shell characteristics are explored for synergistically photothermal immunotherapy of metastatic tumors in the NIR-Ⅱ window. By employing side-chain regulation, the conjugated diradical polymer TTB-2 with obvious NIR-Ⅱ absorption was developed, and its nanoparticles realize a record-breaking PCE of 87.7% upon NIR-Ⅱ light illustration. In vitro and in vivo experiments demonstrate that TTB-2 nanoparticles show good tumor photoablation with navigation of photoacoustic imaging in the NIR-Ⅱ window, without any side-effect. Moreover, by combining with PD-1 antibody,the pulmonary metastasis of breast cancer is high-effectively prevented by the efficient photo-immunity effect. Thus, this study explores superior PTMs for cancer metastasis theranostics in the NIR-Ⅱ window, offering a new horizon in developing radical-characteristic NIR-Ⅱ photothermal materials.

Molecularly imprinted polymer based on upconversion nanoparticles for highly selective and sensitive determination of Ochratoxin A

A novel molecularly imprinted polymer (MIP) based on upconversion nanoparticles (UCNPs) was successfully synthesized for determination of Ochratoxin A (OTA). The MIP was developed on the silica-coated UCNPs using N-(1-hydroxy-2-naphthoyl amido)-(L)-phenylalanine (HNA-Phe) as the alternative template. The final composite combined the advantages of the high selectivity of MIP with the high fluorescence intensity of UCNPs which was selective and sensitive to OTA. Under the optimal condition, the fluorescence intensity of UCNPs@SiO2@MIP decreases linearly when the concentration of OTA increases from 0.05 to 1.0 mg/L. The detection limit of OTA with the method was 0.031 mg/L. At three spiked concentration levels (50, 100 and 200 μg/kg), the recovery ranges of OTA in corn, rice and feed are 88.0%–91.6%, 80.2%–91.6% and 89.2%–90.4%, respectively.

RBC Membrane Camouflaged Semiconducting Polymer Nanoparticles for Near-Infrared Photoacoustic Imaging and Photothermal Therapy

Semiconducting conjugated polymer nanoparticles(SPNs)represent an emerging class of phototheranostic materi-als with great promise for cancer treatment.In this report,low-bandgap electron donoracceptor(DA)-conjugated SPNs with sur-face cloaked by red blood cell membrane(RBCM)are developed for highly e ective photoacoustic imaging and photothermal therapy.The resulting RBCM-coated SPN(SPN@RBCM)displays remarkable near-infrared light absorption and good photosta-bility,as well as high photothermal conver-sion e ciency for photoacoustic imaging and photothermal therapy.Particularly,due to the small size(<5 nm),SPN@RBCM has the advantages of deep tumor penetration and rapid clearance from the body with no appreciable toxicity.The RBCM endows the SPNs with prolonged systematic circulation time,less reticuloendothelial system uptake and reduced immune-recognition,hence improving tumor accumulation after intravenous injection,which provides strong photoacoustic signals and exerts excellent photothermal therapeutic e ects.Thus,this work provides a valuable paradigm for safe and highly e cient tumor pho-toacoustic imaging and photothermal therapy for further clinical translation.

Glycyrrhizic Acid-Loaded Poly-ɛ-Caprolactone Nanoparticles Decrease PRRSV Infection in MARC-145 Cells

Porcine reproductive and respiratory syndrome (PRRS) is an economically devastating disease with worldwide distribution caused by Betaarterivirus suid (PRRSV). The virion has great genetic and antigenic variability with a marked increase in virulence. Vaccines tested to date have been of little use in controlling the problems caused by PRRSV, so the present study was conceived to evaluate the antiviral effect of polymeric nanoparticles (PNPs) made with glycyrrhizic acid (GA). Recent work has proven that this nanoparticle system is stable. These nanoparticles have good GA carrying capacity, a size < 250 nm, a spherical morphology, and a wide safety range. The integrity of cell morphology can be maintained for up to 72 h. The antiviral effect of this nanoparticle system was tested in cultures of MARC-145 cells in pre- and coinfection assays with PRRSV to evaluate changes in cell morphology and effects on cell viability. The use of PNPsGA with the real-time quantitative polymerase chain reaction (RT-qPCR) decreased viral infection by 38% in 3 amplification cycles. These results suggest that this system has an antiviral effect against PRRSV under the study conditions established.

Lipase Immobilization onto the Surface of PGMA-b-PDMAEMA-grafted Magnetic Nanoparticles Prepared via Atom Transfer Radical Polymerization

A block copolymer of 2-dimethylaminoethyl methacrylate(DMAEMA) and glycidyl methacrylate(GMA)was grafted onto the surface of magnetic nanoparticles(Fe3O4) via atom transfer radical polymerization.The resultant PGMA-b-PDMAEMA-grafted-Fe3O4 magnetic nanoparticles with amino and epoxy groups were characterized by Fourier transform infrared spectroscopy, powder X-ray diffraction, thermo-gravimetric analysis, and scanning electron microscopy. Lipase from Burkholderia cepacia was successfully immobilized onto the magnetic nanoparticles by physical adsorption and covalent bonding. The immobilization capacity of the magnetic particles is 0.5 mg lipase per mg support, with an activity recovery of up to 43.1% under the optimum immobilization condition. Biochemical characterization shows that the immobilized lipase exhibits improved thermal stability, good tolerance to organic solvents with high lg P, and higher p H stability than the free lipase at p H 9.0. After six consecutive cycles, the residual activity of the immobilized lipase is still over55% of its initial activity.

SYNTHESIS AND CHARACTERIZATION OF STRUCTURALLY WELL-DEFINED POLYMER-INORGANIC HYBRID NANOPARTICLES VIA ATRP

Atom transfer radical polymerization (ATRP) using cuprous chloride/2,2'-bipyridine (bipy) was applied to graft polymerization of styrene on the surface of silica nanoparticles to synthesize polymer-inorganic hybrid nanoparticles, 2-(4Chloromethylphenyl) ethyltriethoxysilane (CTES) was immobilized on the surface of silica nanoparticles through condensation reaction of the silanol groups on silica with triethoxysilane group of CTES. Then ATRP of St was initiated by this surface-modified silica nanoparticles bearing benzyl chloride groups, and formed PSt graft chains on the surface of silica nanoparticles. The thickness of the graft chains increased with reaction time. End group analysis confirmed the occurrence of ATRP. Thermal analysis indicated that thermal stabilization of these resulting hybrid nanoparticles also increases with polymerization conversion. The results above show that this 'grafting from' reaction could be used for the preparation of polymer-inorganic hybrid nanoparticles with controlled structure of the polymer's end groups.

Polymer Nanoparticles Prepared by Supercritical Carbon Dioxide for in Vivo Anti-cancer Drug Delivery

A new approach for producing polymer nanoparticles made of bovine serum albumin-poly(methy methacrylate) conjugate by precipitating in supercritical CO2 is reported. The nanoparticles were loaded with the anti-tumor drug camptothecin. With albumin serving as a nutrient to cells, the drug-encapsulated nanoparticle shows an enhanced ability to kill cancer cells compared to that of the free drug in solution both in vitro and in vivo.