Monomethoxy Poly Research Articles

Inhaled penindolone-loaded nanoparticles outperform oseltamivir for suppression of influenza A virus infection

Influenza A viruses (IAVs) necessitate urgently development of novel treatment approaches due to their high variability and widespread drug resistance. Penindolone (PND), distinct from anti-IAVs drugs on the market, is a promising IAVs inhibitor specifically targeting both HA1 and HA2 subunits of virus hemagglutinin. However, its clinical utility is hindered by poor water solubility and inadequate oral bioavailability. This study was for the first time to propose a practical and potent delivery approach for PND against IAVs. Inhalable PND-loaded nanoparticles (PND-NPs) were obtained through hydrophobic interactions of PND and monomethoxy poly(ethylene glycol)-poly(D, l-lactide) copolymer, realizing efficient loading of PND. The in vitro experiments demonstrated that PND-NPs exhibited lower cytotoxicity and more potent antiviral activity against IAVs than free PND (IC50 2.5 μM vs. 42.9 μM for A/Virginia/ATCC1/2009 and 11 μM vs. 73 μM for A/Puerto Rico/8/3 (PR/8)), thus expanding the therapeutic window. In the PR/8 infected mice model, the local delivery of PND-NPs via aerosolized inhalation demonstrated that PND-NPs, superior to the effects of the clinical drug oseltamivir, effectively reduced viral load and pro-inflammatory cytokines in the lungs, and significantly prolonged the survival time of mice (twice as long as the oseltamivir treatment group). Overall, non-invasive inhalation therapy with PND-NPs holds significant promise for clinical application in the antiviral domain.

Improvement of hydrophilicity and formation of heparin/chitosan coating inhibits stone formation in ureteral stents

Ureteral stents play an important role in draining urine, supporting the ureter, and preventing hydronephrosis and renal failure. Stones on the surface of ureteral stents can lead to local injury, urinary tract obstruction and tumor induction in patients. They are categorized as normal metabolic stones and infected stones according to whether bacterial infection occurs. To inhibit the formation of ureteral stones, monomethoxy poly(ethylene glycol)-poly(trimethyl carbonate) (mPEG-PTMC) is synthesized to improve the surface hydrophilicity of PTMC/PLCL biodegradable elastomers, and heparin/chitosan coatings are formed by layer-by-layer electrostatic self-assembly. The mPEG-PTMC effectively improves surface hydrophilicity without compromising the compatibility of the components. The contact angle is 62.58° when 10 wt% of mPEG-PTMC37 is present. Extracorporeal immersion for 1, 5, and 10 weeks mimicks normal metabolic stones, SEM and ICP-OES show that the increase of hydrophilicity could reduce the adhesion of calcium oxalate stones. The HEP/CTS coating also significantly reduces the coverage of calcium oxalate on the surface of the sample, and the calcium concentration decreases by 68.5 %. Equipped with an extracorporeal dynamic urinary circulatory system to simulate the production of infected stones after bacterial infection, after seven days, mPEG-PTMC37 halved the stone surface coverage. Compared to PTMC/PLCL elastomer, mPEG-PTMC37, mPEG-PTMC28 and HTP/CTS coatings inhibit 38.72 %, 15.55 %, 39.60 % of Ca and 65.06 %, 57.47 %, 70.11 % of Mg, respectively. In addition, the heparin/chitosan coatings reduce the surface adhesion of Staphylococcus by 69.9 %. The cell experiments show the materials all have good biocompatibility. It makes a useful exploration for developing a new kind of ureteral stents.

Regulatable endothermic behavior of one-chain-tethered sliding graft copolymers as novel solid-solid phase change materials

Sliding graft copolymer (SGC) is a polyrotaxane (PR) composed of a poly(ethyelene glycol) (PEG) axle and α-cyclodextrins (α-CDs) substituted with polymer graft-chains. We have previously reported a sharp-endothermic phase transition of SGCs, which was expected due to the high mobility of graft chains by the mechanical linkage of PRs. To examine this hypothesis, SGCs with well-defined structures were prepared. PRs consisting of monoazidated α-CD and PEG were grafted with monomethoxy poly(ethylene glycos)s (mPEGs) via click chemistry. The SGC bearing shortest graft chains (mPEG750) did not exhibit endotherm, whereas those with side chains of mPEG2000 and mPEG4000 underwent endothermic phase transition. However, values of the transition temperatures and those of melting enthalpies were lower than those of unmodified mPEGs. Unlike our previous report, the SGCs synthesized here contained densely-packed α-CDs, which were capable of rotational movement but not translational movement. The endothermic peak observed for the present SGC is relatively broader than that observed for our previous SGC, which suggests that the mobility of α-CDs were critical to induce sharp-endothermic phase transition.

Systemic and Local Administration of a Dual-siRNA Complex Efficiently Inhibits Tumor Growth and Bone Invasion in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) accounts for nearly 90% of oral and oropharyngeal cancer cases and is characterized by high mortality and poor prognosis. RNA-based gene therapies have been developed as an emerging option for cancer treatment, but it has not been widely explored in OSCC. In this work, we developed an efficient siRNA cationic micelle DOTAP-mPEG-PCL (DMP) by self-assembling the cationic lipid DOTAP and monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) polymer. We tested the characteristics and transformation efficiency of this micelle and combined DMP with siRNA targeting STAT3 and TGF-β to evaluate the antitumor effect and bone invasion interfering in vitro and in vivo. The average size of the DMP was 28.27 ± 1.62 nm with an average zeta potential of 54.60 ± 0.29 mV. The DMP/siRNA complex showed high delivery efficiency, with rates of 97.47 ± 0.42% for HSC-3. In vitro, the DMP/siSTAT3 complex exhibited an obvious cell growth inhibition effect detected by MTT assay (an average cell viability of 25.1%) and clonogenic assay (an average inhibition rate of 51.9%). Besides, the supernatant from HSC-3 transfected by DMP/siTGF-β complexes was found to interfere with osteoclast differentiation in vitro. Irrespective of local or systemic administration, DMP/siSTAT3+siTGF-β showed antitumor effects and bone invasion inhibition in the OSCC mice mandibular invasion model according to tumor volume assays and Micro-CT scanning. The complex constructed by DMP cationic micelles and siSTAT3+siTGF-β represents a potential RNA-based gene therapy delivery system for OSCC.

A Copolymer of Monomethoxy Poly(ethylene glycol)‐Polycaprolactone as Form‐Stable Phase Change Materials for Thermal Energy Storage

AbstractIn this work, a series of monomethoxy poly(ethylene glycol)‐polycaprolactone (mPEG‐PCL) copolymers with different mass percentages of mPEG was chemically synthesized as form‐stable phase change materials (FSPCMs) for thermal energy storage (TES) application for the first time. Their chemical structures, surface morphology, and thermal properties were studied in terms of nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). 1H NMR, gel permeation chromatography (GPC), and FTIR results confirmed the successful ring‐opening polymerization of ϵ‐caprolactone with mPEG macromonomer, and the respective average molecular weight of the copolymers was obtained in the range of 9704–17346 g mol−1. DSC analysis results revealed that the copolymers have a phase change temperature and latent heat in the range of 52.8–57.9 °C and 88.8–114.4 J g−1 respectively and TGA analysis showed that they are thermally stable up to 150 °C. Leakage test results showed that the copolymers (mPEG)x‐(PCL)y displayed excellent form stability with minimal leakage while thermal cycling revealed good thermal reliability. In addition, the copolymers successfully demonstrated their ability to store and release heat for a prolonged period, making them suitable for TES applications like heating water storage tanks.

Space Station-like Composite Nanoparticles for Co-Delivery of Multiple Natural Compounds from Chinese Medicine and Hydrogen in Combating Sensorineural Hearing Loss.

Ototoxic drugs such as aminoglycoside antibiotics and cisplatin (CDDP) can cause sensorineural hearing loss (SNHL), which is closely related to oxidative stress and the acidification of the inner ear microenvironment. Effective treatment of SNHL often requires multifaceted approach due to the complex pathology, and drug combination therapy is expected to be at the forefront of modern hearing loss treatment. Here, space-station-like composite nanoparticles (CCC@mPP NPs) with pH/oxidation dual responsiveness and multidrug simultaneous delivery capability were constructed and then loaded with various drugs including panax notoginseng saponins (PNS), tanshinone IIA (TSIIA), and ammonia borane (AB) to provide robust protection against SNHL. Molecular dynamics simulation revealed that carboxymethyl chitosan/calcium carbonate-chitosan (CCC) NPs and monomethoxy poly(ethylene glycol)-PLGA (mPP) NPs can rendezvous and dock primarily by hydrogen bonding, and electrostatic forces may be involved. Moreover, CCC@mPP NPs crossed the round window membrane (RWM) and entered the inner ear through endocytosis and paracellular pathway. The docking state was basically maintained during this process, which created favorable conditions for multidrug delivery. This nanosystem was highly sensitive to pH and reactive oxygen species (ROS) changes, as evidenced by the restricted release of payload at alkaline condition (pH 7.4) without ROS, while significantly promoting the release in acidic condition (pH 5.0 and 6.0) with ROS. TSIIA/PNS/AB-loaded CCC@mPP NPs almost completely preserved the hair cells and remained the hearing threshold shift within normal limits in aminoglycoside- or CDDP-treated guinea pigs. Further experiments demonstrated that the protective mechanisms of TSIIA/PNS/AB-loaded CCC@mPP NPs involved direct and indirect scavenging of excessive ROS, and reduced release of pro-inflammatory cytokines. Both in vitro and in vivo experiments showed the high biocompatibility of the composite NPs, even after long-term administration. Collectively, this work suggests that composite NPs is an ideal multi-drug-delivery vehicle and open new avenues for inner ear disease therapies.

PEGylated Erlotinib HCl Injectable Nanoformulation for Improved Bioavailability.

The present study was undertaken to synthesize PEGylated monomethoxy poly (ethylene glycol)-poly (ε-Caprolactone) (mPEG-PCL) block copolymer and formulate Erlotinib HCl-loaded mPEG-PCL nanoparticles for enhancing the bioavailability of the drug. Using the ring-opening polymerization technique, PEGylated mPEG-PCL block copolymer was synthesized, and the structure of the copolymer was characterized using FTIR, 1H-NMR, and DSC techniques. The solvent evaporation approach was used to effectively encapsulate Erlotinib HCl within block copolymeric nanoparticles. Erlotinib HCl-loaded mPEG-PCL nanoparticles had a mean particle size of 146.5 ± 2.37 nm and a zeta potential of -27.8 ± 2.77mV. The nanoparticles had a percent entrapment efficiency of 80.78 ± 0.09%. The in vitro drug release of Erlotinib HCl-loaded copolymeric nanoparticles showed a slow and sustained release behavior which could be maintained for up to 72 h. The Korsmeyer-Peppas fitting findings indicated that the drug release process followed a non-Fickian diffusion mechanism. The pharmacokinetic (PK) behavior of the developed nanoformulation was studied in albino Wistar rats, and the relative bioavailability of the optimized NP formulation given by intravenous route was found to be 187.33%. The PK data suggested that Erlotinib HCl-loaded mPEG-PCL copolymeric nanoparticles can dramatically alter the PK behavior of Erlotinib HCl and greatly improve the drug's bioavailability by as much as three times when compared to the oral formulation. As a result, it was established that the block copolymeric nanoparticles have promise for the effective encapsulation of Erlotinib HCL for an injectable formulation with increased bioavailability.

PH- and Temperature-responsive Hydrogels Based on Tertiary Amine-modified Polypeptides for Stimuli-responsive Drug Delivery.

pH- and temperature-responsive hydrogels have attracted considerable attention due to their responsiveness to dual physiologically-relevant stimuli. In this study, we developed stimuli-responsive hydrogels based on monomethoxy poly(ethylene glycol) (mPEG)-polypeptide block copolymers containing various tertiary amine pendants (EEP-TAs). The EEP-TAs were synthesized via ring-opening copolymerization of α-amino acid N-carboxyanhydrides, and further modified post-polymerization with click chemistry. The EEP-TAs exhibited an α-helix-to-β-sheet transition when the pH was increased from 4.0 to 7.4. At elevated polymer concentrations, aqueous solutions of the EEP-TAs underwent thermo-induced sol-gel phase transitions, which were dependent on the pH. The hydrogels almost fully degraded within 3 weeks in the subcutaneous layer of mice and exhibited good histocompatibility in vivo. Additionally, doxorubicin (DOX)-loaded hydrogels exhibited pH-responsive drug release profiles in vitro, which were composed of rapid release at acidic pH and more sustained release at neutral pH. Thus, these polypeptide hydrogels hold potential as depots for environment-responsive delivery of therapeutic agents.

Novel Monomethoxy Poly(Ethylene Glycol) Modified Hydroxylated Tung Oil for Drug Delivery.

Novel monomethoxy poly(ethylene glycol) (mPEG) modified hydroxylated tung oil (HTO), denoted as mPEG-HTO-mPEG, was designed and synthesized for drug delivery. mPEG-HTO-mPEG consists of a hydroxylated tung oil center joined by two mPEG blocks via a urethane linkage. The properties of mPEG-HTO-mPEG were affected by the length of the mPEG chain. Three mPEG with different molecular weights were used to prepare mPEG-HTO-mPEG. The obtained three mPEG-HTO-mPEG polymers were characterized by nuclear magnetic resonance (NMR), Fourier transformation infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and gel permeation chromatography (GPC), respectively. Furthermore, the particle sizes of mPEG-HTO-mPEG micelles were evaluated by dynamic light scattering (DLS) and transmission electron microscope (TEM). A critical aggregation concentration (CAC) ranged from 7.28 to 11.73 mg/L depending on the chain length of mPEG. The drug loading and release behaviors of mPEG-HTO-mPEG were investigated using prednisone acetate as a model drug, and results indicated that hydrophobic prednisone acetate could be effectively loaded into mPEG-HTO-mPEG micelles and exhibited a long-term sustained release. Moreover, compared with HTO, mPEG-HTO-mPEG had no obvious cytotoxicity to HeLa and L929 cells. Therefore, monomethoxy poly(ethylene glycol) modified hydroxylated tung oil mPEG-HTO-mPEG may be a promising drug carrier.

Acid/reduction dual-sensitive amphiphilic graft polyurethane with folic acid and detachable poly(ethylene glycol) as anticancer drug delivery carrier

In order to not only improve the stability of nanomicelles in blood circulation but also promote the cellular uptake in tumors and rapidly release the encapsulated drugs in tumor cells, a kind of acid/reduction dual-sensitive amphiphilic graft polyurethane with folic acid and detachable poly(ethylene glycol) (FA-PUSS-gimi-mPEG) was synthesized by grafting folic acid and monomethoxy poly(ethylene glycol) to the polyurethane side chain. FA-PUSS-gimi-mPEG could self-assemble in aqueous solution to form negatively charged nanomicelles, which endowed them good stability under normal physiological condition. Using ultraviolet-visible spectrometer (UV–vis) and dynamic light scattering (DLS), it was found that the hydrophilic poly(ethylene glycol) layer of FA-PUSS-gimi-mPEG micelles could be detached due to the cleavage of benzoic-imine bond under slightly acidic condition, which resulted in reversing the charge of the micellar surface and exposing folic acid to the micellar surface. FA-PUSS-gimi-mPEG micelles could load doxorubicin (DOX), moreover the drug release rate was faster at pH 5.0 and 10 mM glutathione (GSH) than that under normal physiological condition. The results of cell experiments further demonstrated that FA-PUSS-gimi-mPEG micelles had acid/reduction dual-sensitive property. The changes in the structure of FA-PUSS-gimi-mPEG micelles could enhance the cellular uptake under acid condition and the micelles could accelerate the drug release in tumor cells due to the presence of disulfide bonds in the polymer. Therefore, FA-PUSS-gimi-mPEG micelles could efficiently deliver anticancer drug into tumor cells and enhance the inhibition of cellular proliferation through multi-effect synergy.

Poly(trimethylene carbonate)‐b‐poly(ethylene glycol) diblock copolymer micelles for hydrophobic drug delivery: The effect of hydrophilic/hydrophobic segment length on micellar properties and drug loading

AbstractThe encapsulation and release of hydrophobic drugs from polymersomes are of great importance in drug delivery. A significant challenge is to enhance the encapsulation capacity of finding better drug‐polymer compatibility. Herrin, poly(trimethylene carbonate)‐b‐poly(ethylene glycol) (PTMC‐PEG) diblock copolymers were successfully synthesized by ring opening polymerization of trimethylene carbonate using monomethoxy poly(ethylene glycol) (mPEG) as macro‐initiator and stannous octoate as catalyst. The resulting diblock copolymer were characterized by 1H NMR, FTIR, GPC, and DSC techniques. Blank and paclitaxel (PTX) loaded micelles was prepared by co‐solvent evaporation method and characterized by transmission electron microscope (TEM) and dynamic light scattering (DLS). The influence of hydrophilic/hydrophobic segment length to drug loading and release was explored. All micelles have the sustained hydrophobic drug release properties of the micelles. Moreover, the cytotoxicity of micelles was evaluated by MTT and live‐dead cell staining assay using L929 cell lines, showing the good biocompatibility. Therefore, PTMC‐PEG micelles could be a suitable material for the loading and releasing of hydrophobic drugs.

Self‐Assembly and Transport Behaviour of Non‐ionic Fluorinated and Alkylated Amphiphiles for Drug Delivery

AbstractA newer series of AB2 typed non‐ionic amphiphiles have been synthesized using p‐hydroxybenzoate as a central core, which is further functionalized with two hydrophilic units, i. e. D‐lactose/poly(glycerol) dendron [G2.0]/monomethoxy poly(ethyleneglycol) and a hydrophobic alkyl/fluoroalkyl moiety. The aggregation behaviour of the synthesised amphiphiles in aqueous medium was studied using fluorescence spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM) and were found to form nano‐sized aggregates. The potential of these amphiphiles to act as nanocarrier was studied using model hydrophobic probe Nile red and nimodipine by recording their UV‐visible and fluorescence spectroscopic data. For comparison purpose, analogous AB type amphiphiles were also synthesized and their transport ability analysed. A study of cell viability in HeLa cells revealed that all synthesized amphiphiles are well tolerated at the concentrations studied. The immobilized hydrolase Novozym‐435 was used to release the encapsulated dye from the inner hydrophobic core of micellar structures of synthesized amphiphiles in vitro.

A promising strategy for synergistic cancer therapy by integrating a photosensitizer into a hypoxia-activated prodrug

Herein, we fabricate a multifunctional molecular prodrug BAC where the chemotherapeutical agent camptothecin (CPT) is linked with a boron dipyrromethene (BODIPY)-based photosensitizer by an azobenzene chain which is sensitive to over-expressed azoreductase in hypoxic tumor cells. This prodrug was further loaded into biodegradable monomethoxy poly(ethylene glycol)-b-poly(caprolactone) (mPEG-b-PCL) to improve its solubility and tumor accumulation. The formed BAC nanoparticles (BAC NPs) can destroy aerobic tumor cells with relatively short distance from blood vessels by photodynamic therapy (PDT) under illumination. The PDT action inevitably leads to consumption of O2, and subsequently acute hypoxia which can induce cleavage of azobenzene linkage to boost release of CPT killing the other hypoxic interior tumor cells survived from PDT. Both in vitro and in vivo studies have verified that BAC NPs possess remarkable antitumor activity by a synergistic action of PDT and chemotherapy.

Enhanced Oral Absorption and Liver Distribution of Polymeric Nanoparticles through Traveling the Enterohepatic Circulation Pathways of Bile Acid.

The intestinal epithelium is known to be a main hindrance to oral delivery of nanoparticles. Even though surface ligand modification can enhance cellular uptake of nanoparticles, the "easy entry and hard across" was frequently observed for many active targeting nanoparticles. Here, we fabricated polymeric nanoparticles relayed by bile acid transporters with monomethoxy poly(ethylene glycol)-poly(D,l-lactide) and deoxycholic acid-conjugated poly(2-ethyl-2-oxazoline)-poly(D,l-lactide) based on structural characteristics of intestine epithelium and the absorption characteristics of endogenous substances. As anticipated, deoxycholic acid-modified polymeric nanoparticles featuring good stability in simulated gastrointestinal fluid could notably promote the internalization of their payload by Caco-2 cells through mediation of apical sodium-dependent bile acid transporter (ASBT) and transmembrane transport of the nanoparticles across Caco-2 cell monolayers via relay-guide of ASBT, ileal bile acid-binding protein, and the heteromeric organic solute transporter (OSTα-OSTβ) along with multidrug resistance-associated protein 3 (MRP3) evidenced by competitive inhibition and fluorescence immunoassay, which was further visually confirmed by the stronger fluorescence from C6-labeled nanoparticles inside enterocytes and the basal side of the intestinal epithelium of mice. The transcellular transport of deoxycholic acid-modified nanoparticles in an intact form was mediated by caveolin/lipid rafts and clathrin with intracellular trafficking trace of endosome-lysosome-ER-Golgi apparatus and bile acid transport route. Furthermore, the increased uptake by HepG2 cells compared with unmodified nanoparticles evidenced the target ability of deoxycholic acid-modified nanoparticles to the liver, which was further supported by ex vivo imaging of excised major organs of mice. Thus, this study provided a feasible and potential strategy to further enhance transepithelial transport efficiency and liver-targeted ability of nanoparticles by means of the specific enterohepatic circulation pathways of bile acid.

BTN-PEG-PCL nanoparticles for targeted delivery of curcumin: In vitro and in Ovo assessment

The major challenge of curcumin (CUR) therapy is the low bioavailability in the tumor cells, which could be solved by targeting and manipulating nanoparticles (NPs) in the drug delivery systems (DDS) through enhancement of CUR uptake. In our study, ligand-targeted micelle NPs including BTN-poly ethylene glycol-polycaprolactone(PCL) (BTNcment-PEG-PCL) and mono methoxy poly (ethylene glycol)-poly (caprolactone) (mPEG-PCL) diblock co-polymers series were synthesized by way of a single-step nano-precipitation method and characterized by H NMR, FT-IR, DSC, DLS, TEM, and GPC techniques. Following CUR-loading on the NP series, cytotoxicity and cellular uptake of CUR-BTN-PEG-PCL and CUR-mPEG-PCL on human breast adenocarcinoma (MCF-7), Human embryonic kidney (HEK293), and human umbilical vein endothelial (HUVEC) cell lines were evaluated by MTT assay and microscope fluorescence, respectively. Then, in vitro studies of targeted and untargeted NPs for the cell cycle and apoptosis assessment using flow cytometry have shown that CUR in CUR-BTN-PEG-PCL as a novel and targeted nanocarrier increases the cell population of Sub G1 and apoptosis. Moreover, in Ovo chick chorioallantoic membrane (CAM) assay demonstrated that CUR-BTN-PEG-PCL has notably decreased tumor cell proliferation and angiogenesis due to enhanced CUR bioavailability for the site-specific tumor. In conclusion, BTN-PEG–PCL NPs as a novel and efficiently targeted nanocarrier predominantly improved CUR potential for cancer therapy.

Hypoxia-responsive hyaluronic acid nanogels with improved endo/lysosomal escape ability for tumor-targeted cytochrome c delivery

An ideal protein therapeutic effect depends on the protein drug-carrying nanocarrier to achieve high loading efficiency, excellent systemic stability, specific tumor targeting, rapid endo/lysosomal escape, and controlled protein release behavior. Herein, novel and interesting hypoxia-responsive nanogels with improved endo/lysosomal escape ability are reported in this work for tumor-targeted protein delivery. These nanogels can encapsulate a cationic protein, cytochrome C (CC), inside their cores with good stability in various media and thus protect the protein from degradation during blood circulation. In this nanogel system, monomethoxy poly(ethylene glycol) (mPEG) is conjugated to hyaluronic acid (HA) and serves as an outer shell for improving stability of the nanostructure, and the anionic HA is employed for encapsulation of cationic CC through multiphysical interactions with a high loading efficiency. The nanogel system is crosslinked using a hypoxia-responsive crosslinker for subsequent triggered release of CC. Due to presence of the hypoxia-responsive crosslinker, more than 80% of the loaded CC can be released within 24 h under hypoxic conditions. The in vitro experimental results demonstrate that these nanogels can effectively deliver CC into cancer cells via CD44-mediated tumor targeting, subsequently enable rapid endo/lysosomal escape, and trigger CC release under hypoxic conditions. In addition, cytotoxicity test confirms that the CC-loaded nanogels exhibit much higher cytotoxicity to cancer cells at hypoxic condition than that at normoxic condition, which indicates that this nano-platform is a promising candidate for tumor-targeting protein delivery and efficient cancer therapy.

Thermosensitive core-rigid micelles of monomethoxy poly(ethylene glycol)-deoxy cholic acid

BackgroundThermosensitive micelles with rigid cores that exhibit a reversible lower critical solution temperature at 30–35 °C can be applied for drug delivery.MethodHydrophilic monomethoxy poly(ethylene glycol) was conjugated to hydrophobic deoxycholic acid to prepare monomethoxy poly(ethylene glycol)-deoxycholic acid (mPEG-DC). Micelle formation and thermosensitive solution behavior were studied using various methods, including hydrophobic dye solubilization, transmission electron microscopy, dynamic light scattering, turbidity measurement, microcalorimetry, and 1H-NMR spectroscopy. Drug release from the thermosensitive micelles was demonstrated using estradiol, a model drug.ResultsThe mPEG-DC formed micelles with a critical micelle concentration of 0.05 wt.% and an average size of 15 nm. Aqueous mPEG-DC solutions exhibit a lower critical solution temperature (LCST) that is independent of concentration and reversible over heating and cooling cycles. The LCST transition is an entropically driven process involving dehydration of the PEG shell. The thermosensitive mPEG-DC micelles with rigid DC cores were applied as an estradiol delivery system in which estradiol was released, without initial burst, over the 16 days in a diffusion-controlled manner.ConclusionsThis study suggests that mPEG-DCs form thermosensitive micelles with rigid cores that can function as an excellent diffusion-controlled hydrophobic drug delivery system without initial burst release.Graphical Thermosensitive core-rigid micelles of monomethoxy poly(ethylene glycol)-deoxy cholic acid

Investigation of domain structures in monomethoxy poly(ethylene glycol)‐b‐poly(caprolactone) grafted poly(acrylic acid) by NMR diffusion studies

AbstractAssociating polymers developed by grafting a block copolymer of monomethoxy poly(ethylene glycol)‐b‐poly(caprolactone) (MPEG‐b‐PCL) onto poly(acrylic acid) undergo an irreversible sol–gel transition on heating. The influence of various physicochemical parameters on the thermoresponsive behaviour was examined by rheology and NMR studies. Pulsed field gradient NMR diffusion studies were performed to probe the mechanism of thermally induced gelation. Analysis of the diffusion data reveals the presence of loosely and strongly associated structures which respond differently to variation in temperature. It is observed that the polymer solution, which is visibly homogeneous, is heterogeneous on a mesoscopic scale with a distribution of domains. Detailed investigation of the thermally induced sol–gel transition shows that the mechanism of gelation involves irreversible alterations in the domain structure and size. © 2022 Society of Industrial Chemistry.

Single Micelle Vectors based on Lipid/Block Copolymer Compositions as mRNA Formulations for Efficient Cancer Immunogene Therapy.

Immunogene therapy provides a new strategy for the treatment of colorectal cancer. Compared to plasmid DNA, mRNA possesses several advantages as a therapeutic nucleic acid material and shows high potential in cancer therapy. Although efforts have been made to conquer the limited efficiency of mRNA delivery, most of the current mRNA vectors possess complex structures or compositions, which introduces additional toxicity and hinders their further clinical application. Hence, it is highly necessary to develop potent mRNA delivery systems with simple structures. Here, we report efficient mRNA delivery using the biodegradable micelle delivery system of DMP (DOTAP-mPEG-PCL). Biodegradable DMP micelles were simply prepared by the self-assembly of cationic lipid DOTAP and the diblock polymer monomethoxy poly(ethylene glycol)-poly(ε-caprolactone). With an average size of only 30 nm, we proved that these single-structured cationic micelles are highly potent in condensing and protecting mRNA molecules, with a delivery efficiency of 60.59% on C26 mouse colon cancer cells. The micelles triggered specific internalization pathways and were fully degraded in vivo. After binding with IL-22BP (interleukin-22 binding protein)-encoding mRNA, a strongly elevated IL-22BP mRNA level was detected in C26 cells. After intraperitoneal and intratumoral injection of the DMP/mIL-22BP complex, strong inhibition effects on C26 colon cancer models were observed, with high therapeutic efficiency and safety when systemically administrated. These data suggest that the DMP micelle is an advanced single-structured mRNA delivery system with high safety.

Crucial Impact of Residue Chirality on the Gelation Process and Biodegradability of Thermoresponsive Polypeptide Hydrogels.

Thermosensitive polypeptide hydrogels have gained considerable attention in potential biomedical applications, of which the polymer structure may be tuned by residue chirality. In this study, polypeptide-based block copolymers with different chiralities were synthesized by ring-opening polymerization of γ-ethyl-l-glutamate N-carboxyanhydride and/or γ-ethyl-d-glutamate N-carboxyanhydride using amino-terminated monomethoxy poly(ethylene glycol) as a macroinitiator. All mPEG-polypeptide copolymers underwent sol-gel transition with an increase in temperature. The block copolymers with mixed enantiomeric residues of γ-ethyl-l-glutamate (ELG) and γ-ethyl-d-glutamate (EDG) in the polypeptide blocks exhibited lower critical gelation concentrations and lower critical gelation temperatures compared with those composed of pure ELG or EDG residues. We established that the difference in gelation properties between the copolymers was derived from the distinction of the secondary structures. We further demonstrated the influence of polypeptide chirality on the degradability and biocompatibility of hydrogels in vivo. Our findings provide insights into the design of hydrogels having tailored secondary conformation, gelation property, and biodegradability.