PEG Shell Research Articles

Cisplatin-loaded polymer/magnetite composite nanoparticles as multifunctional therapeutic nanomedicine

Multifunctional nanocarriers with multilayer core-shell architecture were prepared by coating superparamagnetic Fe3O4 nanoparticles with diblock copolymer folate-poly(ethylene glycol)-b-poly(glycerol monomethacrylate) (FA-PEG-b-PGMA), and triblock copolymer methoxy poly(ethylene glycol)-b-poly(2-(dimethylamino) ethyl methacrylate)-b-poly(glycerol monomethacrylate) (MPEG-b-PDMA-b-PGMA). The PGMA segment was attached to the surfaces of Fe3O4 nanoparticles, and the outer PEG shell imparted biocompatibility. In addition, folate was conjugated onto the surfaces of the nanocarriers. Cisplatin was then loaded into the nanocarrier by coordination between the Pt atom in cisplatin and the amine groups in the inner shell of the multilayer architecture. The loaded cisplatin showed pH-responsive release: slower release at pH 7.4 (i.e. mimicking the blood environment) and faster release at more acidic pH (i.e. mimicking endosome/lysosome conditions). All of the cisplatin-loaded nanoparticles showed concentration-dependent cytotoxicity in HeLa cells. However, the folate-conjugated cisplatin-loaded carriers exhibited higher cytotoxicity in HeLa cells than non-folate conjugated cisplatin-loaded carriers.

Biodegradable depsipeptide–PDO–PEG-based block copolymer micelles as nanocarriers for controlled release of doxorubicin

Nowadays, biodegradable amphiphilic block copolymers with stable performance and adjustable structure have attracted the interests of researchers in the field of drug delivery. In this work, the triblock copolymer, P(SBMD-co-PDO)-b-PEG-b-P(SBMD-co-PDO), was successfully synthesized by ring-opening polymerization of 3(S)-sec-butyl-morpholine-2,5-dione (SBMD) and p-dioxanone (PDO) with poly(ethylene glycol) (PEG) as the initiator. In phosphate buffered solution (PBS), these copolymers could self-assemble into nano-sized micelles that have a hydrophobic P(SBMD-co-PDO) core surrounded by a hydrophilic PEG shell. Because of the strong hydrogen bonding and hydrophobic interactions, doxorubicin (DOX) was loaded into the micelles with high loading capacity (LC, up to 28.4%) and encapsulation efficiency (EE, up to 62.5%). The drug-loaded micelles showed sustained-release of DOX along with the hydrolytic degradation of the micelles in PBS. Therefore, these amphiphilic triblock copolymers have potential as drug matrix for controlled release.

Redox-responsive biodegradable PEGylated nanographene oxide for efficiently chemo-photothermal therapy: A comparative study with non-biodegradable PEGylated nanographene oxide

Nanographene oxide (NGO) with a non-sheddable poly(ethylene glycol) (PEG) coating has been used for chemo-photothermal therapy. However, the drug release of PEGylated NGO (NGO-PEG) with an amine bond is adversely affected by the diffusion barrier effect of PEG shells. Here, we developed a simple new method for the preparation of biodegradable PEGylated NGO conjugates (NGO-SS-PEG) with cleavable disulfide bonds for rapid drug release and more efficiently chemo-photothermal therapy. The glutathione (GSH)-induced and photothermal-mediated intracellular release of doxorubicin (DOX) from NGO-SS-PEG was studied in A549 cells using confocal laser scanning microscopy and flow cytometry analysis. In vivo cytotoxicity experiments were performed on chemo-photothermal therapy. Furthermore, we presented a comparative study of intracellular drug release and biological efficacy between NGO-SS-PEG/DOX and NGO-PEG/DOX. The results demonstrated that the rapid drug release from the NGO-SS-PEG conjugates with sheddable PEG was triggered upon the stimulus of high GSH levels inside A549 cells. Interesting, the DOX release mediated by the photothermal effect from the NGO-SS-PEG conjugates was found to be more obvious than that for NGO-PEG. Additionally, NGO-SS-PEG showed a higher efficacy than NGO-PEG for anti-tumor therapy compared with NGO-PEG. Thus, NGO-SS-PEG can improve therapeutic efficacy and is an attractive drug nanocarrier.

Hydrogen-bonded and reduction-responsive micelles loading atorvastatin for therapy of breast cancer metastasis

Metastasis is one of the major obstacles for the successful therapy of breast cancer. Although increased candidate drugs targeting cancer metastasis are tested, their clinical translation is limited by either serve toxicity or low efficacy. In present work, a nano-drug delivery system loading atorvastatin calcium (Ator) was developed for the efficient suppression of the metastasis of breast cancer. The nano-drug delivery system was constructed by a amphiphilic copolymer of methoxy polyethylene glycol-s-s-vitamin E succinate (mPEG-s-s-VES, PSV), which was consisted of a hydrophilic mPEG1k segment and a hydrophobic VES head, which were conjugated with a linker bearing amide and disulfide groups simultaneously. Self-assembly of PSV and Ator formed Ator-loaded PSV micelles (ASM) with good colloidal stability, high drug loading content (up to 50%) and great encapsulation efficiency (99.09 ± 0.28%). In cellular level, it was found that the ASM could efficiently release the Ator payload into cytosol due to detachment of PEG shell at high intracellular glutathione condition. ASM could significantly inhibit the migration and invasion of 4T1 breast cancer cells with inhibitory rates of 79.2% and 88.5%, respectively. In a 4T1 orthotropic mammary tumor metastatic cancer model, it was demonstrated that ASM could completely blocked the lung and liver metastasis of breast cancer with minimal toxicity owing to enhanced Ator accumulation in tumor and lung as compared with that of free Ator. The down-regulations of metastasis-promoting MMP-9, Twist and uPA proteins were demonstrated as the main underlying mechanism. As a result, ASM could be a promising drug delivery system for the efficient therapy of breast cancer metastasis.

Folding graft copolymer with pendant drug segments for co-delivery of anticancer drugs

A graft copolymer with pendant drug segments can fold into nanostructures in a protein folding-like manner. The graft copolymer is constructed by directly polymerizing γ-camptothecin-glutamate N-carboxyanhydride (Glu(CPT)-NCA) on multiple sites of poly(ethylene glycol) (PEG)-based main chain via the ring open polymerization (ROP). The “purely” conjugated anticancer agent camptothecin (CPT) is hydrophobic and serves as the principal driving force during the folding process. When exposed to water, the obtained copolymer, together with doxorubicin (Dox), another anticancer agent, can fold into monodispersed nanocarriers (with a diameter of around 50 nm) for dual-drug delivery. Equipped with a PEG shell, the nanocarriers displayed good stability and can be internalized by a variety of cancer cell lines via the lipid raft and clathrin-mediated endocytotic pathway without premature leakage, which showed a high synergetic activity of CPT and Dox toward various cancer cells. In vivo study validated that the nanocarriers exhibited strong accumulation in tumor sites and showed a prominent anticancer activity against the lung cancer xenograft mice model compared with free drugs.

Redox-responsive nanoparticles with Aggregation-Induced Emission (AIE) characteristic for fluorescence imaging.

The redox environment between intracellular compartments and extracellular matrix is significantly different, and the cellular redox homeostasis determines many physiological functions. Here, redox-responsive nanoparticles with aggregation-induced emission (AIE) characteristic for fluorescence imaging are developed by encapsulation of fluorophore with redox "turn-on" AIE characteristic, TPE-MI, into the micelles of poly(ethylene glycol) (PEG)- and cholesterol (CE)-conjugated disulfide containing poly(amido amine)s. The redox-responsive fluorescence profiles of the nanoparticles are investigated after reaction with glutathione (GSH). The encapsulation of TPE-MI in micelles leads to a higher efficiency and red shift in emission, and the fluorescence intensity of the nanoparticles increases with the concentration of GSH. Confocal microscopy imaging shows that the nanoparticles can provide obvious contrast between the intracellular compartments and the extracellular matrix in MCF-7 and HepG2 cells. So the nanoparticles with PEG shells and low cytotoxicity are promising to provide fluorescence bioimaging with a high contrast and for differentiation of cellular redox environment.

Magnetic nanoparticles with a pH-sheddable layer for antitumor drug delivery

A dually responsive nanocarrier with a multilayer core–shell architecture was prepared based on Fe3O4@SiO2 nanoparticles successively coated with poly(benzyl L-aspartate) (PBLA) and poly(ethylene glycol) (PEG) for the purpose of tumor specific drug delivery applications. In this system, PEG chains are connected to the surface via pH-sensitive benzoic-imine bonds and serve as a pH-sheddable hydrophilic corona. Meanwhile, the PBLA segments serve as a hydrophobic middle layer used to load the drugs via hydrophobic interactions. The Fe3O4@SiO2 nanoparticle functions as a superparamagnetic core used to direct the drug loaded nanocarrier to the target pathological site. The obtained materials were characterized with FT-IR, 1H NMR, dynamic light scattering, zeta-potential, TEM, TGA, and hysteresis loop analysis. An anticancer drug doxorubicin (DOX) was selected as the model drug loaded into the nanocarrier, which was relatively stable under physiological conditions due to its neutral hydrophilic shell, and could quickly release the drug in response to increased acidity via shedding of the PEG shells through cleavage of the intermediate benzoic-imine bonds. Meanwhile, the neutral shell shedding would reveal a positively charged nanoparticle surface that is readily taken up by tumor cells. These pH- and magnetic-responsive nanoparticles showed significant potential for use in the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy.

SiRNA delivery from triblock copolymer micelles with spatially-ordered compartments of PEG shell, siRNA-loaded intermediate layer, and hydrophobic core

Hydrophobized block copolymers have widely been developed for construction of polymeric micelles for stable delivery of nucleic acids as well as anticancer drugs. Herein, we elaborated an A-B-C type of triblock copolymer featuring shell-forming A-segment, nucleic acid-loading B-segment, and stable core-forming C-segment, directed toward construction of a three-layered polymeric micelle as a small interfering RNA (siRNA) vehicle. The triblock copolymer was prepared with nonionic and hydrophilic poly(ethylene glycol) (PEG), cationic poly(l-lysine) (PLys), and poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)] bearing a hydrophobic dimethoxy nitrobenzyl ester (DN) moiety in the side chain [PEG-PLys-PAsp(DET-DN)]. The resulting triblock copolymers spontaneously formed sub-100 nm-sized polymeric micelles with a hydrophobic PAsp(DET-DN) core as well as PEG shell in an aqueous solution. This micelle was able to incorporate siRNA into the intermediate PLys layer, associated with slightly reduced size and a narrow size distribution. The triblock copolymer micelles (TCMs) stably encapsulated siRNA in serum-containing medium, whereas randomly hydrophobized triblock copolymer [PEG-PLys(DN)-PAsp(DET-DN)] control micelles (RCMs) gradually released siRNA with time and non-PEGylated diblock copolymer [PLys-PAsp(DET-DN)] control micelles (DCMs) immediately formed large aggregates. The TCMs thus induced appreciably stronger sequence-specific gene silencing in cultured cancer cells, compared to those control micelles. The siRNA delivery with TCMs was further examined in terms of cellular uptake and intracellular trafficking. The flow cytometric analysis revealed that the cellular uptake of TCMs was more efficient than that of RCMs, but less efficient than that of DCMs. The intracellular trafficking study using confocal laser scanning microscopy combined with fluorescence resonance energy transfer (FRET) revealed that the TCMs could readily release the siRNA payload within cells, which was in contrast to the DCMs exhibiting much slower release profile. This result indicates that PEG shell contributed to the smooth release of siRNA from TCMs within the cells, presumably due to avoiding irreversible aggregate formation. The obtained results demonstrated that the design of separately functionalized polymer segments expanded the performance of polymeric micelles for successful siRNA delivery.

PEGylation of αα-Hb using succinimidyl propionic acid PEG 5K: Conjugation chemistry and PEG shell structure dictate respectively the oxygen affinity and resuscitation fluid like properties of PEG αα-Hbs

PEGylation of intramolecularly crosslinked Hb has been studied here to overcome the limitation of dissociation of Hb tetramers. New hexa and deca PEGylated low oxygen affinity PEG-ααHbs have been generated. Influence of PEG conjugation chemistry and the PEG shell structure on the functional properties as well as PEGylation induced plasma expander like properties of the protein has been delineated. The results have established that in the design of PEG-Hbs as oxygen therapeutics, the influence of conjugation chemistry and the PEG shell structure on the oxygen affinity of Hb needs to be optimized independently besides optimizing the PEG shell structure for inducing resuscitation fluid like properties.

Stimuli‐Triggered Growth and Removal of a Bioreducible Nanoshell on Nanoparticles

A new and easy method of stimuli-triggered growth and removal of a bioreducible nanoshell on nanoparticles is reported. The results show that pH or temperature could induce the aggregation of disulfide-contained branched polymers at the surface of nanoparticles; subsequently, the aggregated polymers could undergo intermolecular disulfide exchange to cross-link the aggregated polymers, forming a bioreducible polymer shell around nanoparticles. When these nanoparticles with a polymer shell are treated with glutathione (GSH) or d,l-dithiothreitol (DTT), the polymer shell could be easily removed from the nanoparticles. The potential application of this method is demonstrated by easily growing and removing a bioreducible shell from liposomes, and improvement of in vivo gene transfection activity of liposomes with a bioreducible PEG shell.

Targeted gene delivery by polyplex micelles with crowded PEG palisade and cRGD moiety for systemic treatment of pancreatic tumors

Adequate retention in systemic circulation is the preliminary requirement for systemic gene delivery to afford high bioavailability into the targeted site. Polyplex micelle formulated through self-assembly of oppositely-charged poly(ethylene glycol) (PEG)-polycation block copolymer and plasmid DNA has gained tempting perspective upon its advantageous core–shell architecture, where outer hydrophilic PEG shell offers superior stealth behaviors. Aiming to promote these potential characters toward systemic applications, we strategically introduced hydrophobic cholesteryl moiety at the ω-terminus of block copolymer, anticipating to promote not only the stability of polyplex structure but also the tethered PEG crowdedness. Moreover, Mw of PEG in the PEGylated polyplex micelle was elongated up to 20 kDa for expecting further enhancement in PEG crowdedness. Furthermore, cyclic RGD peptide as ligand molecule to integrin receptors was installed at the distal end of PEG in order for facilitating targeted delivery to the tumor site as well as promoting cellular uptake and intracellular trafficking behaviors. Thus constructed cRGD conjugated polyplex micelle with the elevated PEG shielding was challenged to a modeled intractable pancreatic cancer in mice, achieving potent tumor growth suppression by efficient gene expression of antiangiogenic protein (sFlt-1) at the tumor site.

A facile synthetic approach to a biodegradable polydisulfide MRI contrast agent.

A polydisulfide MRI contrast agent was obtained by grafting diethylenetriaminepentaacetic (DTPA) to disulfide-containing poly(amido amine)s-graft-poly(ethylene glycol) (PEG) followed by Gd(iii) complexation. Self-assembly of the MRI contrast agent obtained occurs in aqueous solution forming nanosized micelles with PEG shells and ionic complex cores. The chemistry and structures of the MRI contrast agent and assembly were characterized using NMR, GPC and DLS. Thiol-induced degradation of the backbone and the assembly of the MRI contrast agent were investigated using GPC and DLS, respectively, and easy degradation was observed. Poly(BAC-AMPD)-g-PEG-g-Gd-DTPA also shows a low cytotoxicity and a high r1 value, so it is promising to provide better MRI imaging with fewer side effects.

Thermo- and pH-responsive copolymers based on PLGA-PEG-PLGA and poly(l-histidine): Synthesis and in vitro characterization of copolymer micelles

A series of novel thermo- and pH-responsive block copolymers of PHis-PLGA-PEG-PLGA-PHis composed of poly(ethylene glycol) (PEG), poly(d,l-lactide-co-glycolide) (PLGA) and poly(l-histidine) (PHis) were synthesized and used for the construction of stimuli-responsive copolymer micelles. The starting polymers of PLGA-PEG-PLGA and PHis were synthesized by ring-opening polymerization of dl-lactide and glycolide with PEG as an initiator and l-histidine N-carboxylanhydride with isopropylamine as an initiator, respectively. The final copolymer was obtained by the coupling reaction of PHis with PLGA-PEG-PLGA. The copolymer micelles were constructed to have an inner core consisting of two hydrophobic blocks (PLGA and deprotonated PHis) and an outer hydrophilic PEG shell. The temperature- and pH-induced structure changes of the micelles were characterized by an alteration in particle size, a decrease in pyrene florescence intensity, and a variation of 1H NMR spectra in D2O. It was speculated that the hydrophobic–hydrophilic transitions of PEG and PHis in response to temperature and pH variations accounted for the destabilization of micelles. In vitro release profiles, cell cytotoxicity and intracellular location studies further confirmed the temperature- and pH-responsive properties of the copolymer micelles. These results demonstrate the potential of the developed copolymers to be stimuli-responsive carriers for targeted delivery of anti-cancer drugs.

Block copolymer-templated mineralization for pH-responsive robust nanocarriers of 5-fluorouracil

We describe a novel synthetic method to prepare calcium carbonate (CaCO3)-mineralized nanoparticles for the intracellular delivery of an anticancer drug, 5-fluorouracil (5-FU). The 5-FU-loaded mineralized nanoparticles (FU-CaCO3-MNPs) were prepared by block copolymer (poly(ethylene glycol)-b-poly(L-aspartic acid) (PEG-PAsp))-templated mineralization in the presence of calcium cations (Ca2+), carbonate anions (CO32−), and negatively charged 5-FU. The mineralization produced hybrid nanoparticles consisting of 5-FU-loaded CaCO3 cores and PEG shells. The mineralized CaCO3 cores of the nanoparticles could stably hold loaded 5-FU by maintaining the structural robustness, and the outer corona of PEG provided colloidal stability to the nanoparticles in serum solutions. The 5-FU release from the FU-CaCO3-MNPs at physiological pH (pH 7.4) was efficiently inhibited, whereas at an endosomal pH (pH 5.0), the 5-FU release was facilitated. Fluorescence microscopic analysis showed that FU-CaCO3-MNPs were taken up by the MCF-7 breast cancer cells, and transferred into acidic endosomes to dissolve the CaCO3 core. Finally, the 5-FU release was facilitated to inhibit the proliferation of cancer cells. These mineralized hybrid nanoparticles may serve as a useful candidate for enhanced intracellular delivery of many ionic anticancer drugs.

Graft Copolymer Nanoparticles with pH and Reduction Dual-Induced Disassemblable Property for Enhanced Intracellular Curcumin Release

Nanoparticle (NP)-assisted drug delivery systems with disassemblable behaviors in response to intracellular microenvironment are urgently demanded in systemic cancer chemotherapy for enhanced intracellular drug release. Curcumin (CUR), an effective and safe anticancer agent, was limited by its water insolubility and poor bioavailability. Herein, pH and reduction dual-induced disassemblable NPs for high loading efficiency and improved intracellular release of CUR were developed based on an acid degradable cyclic benzylidene acetal groups (CBAs)-functionalized poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate)-g-SS-poly(ethylene glycol) (PTTMA-g-SS-PEG) graft copolymer, which was readily prepared via RAFT copolymerization and coupling reaction. The NPs self-assembled from PTTMA-g-SS-PEG copolymers were stable at physiological pH, and quickly disassembled in mildly acidic and reductive environments because of the hydrolysis of CBAs in hydrophobic PTTMA core and the cleavage of disulfide-linked detachable PEG shell. PTTMA-g-SS-PEG NPs exhibited excellent CUR loading capacity with drug loading content up to 19.2% and entrapment efficiency of 96.0%. Within 20 h in vitro, less than 15.0% of CUR was released from the CUR-loaded NPs in normal physiological conditions, whereas 94.3% was released in the presence of reductive agent and mildly acidic conditions analogous to the microenvironment in endosome/lysosome and cytoplasm. Confocal fluorescence microscopies revealed that the CUR-loaded PTTMA-g-SS-PEG NPs exhibited more efficiently intracellular CUR release for EC-109 cells than that of CUR-loaded reduction-unresponsive PTTMA-g-PEG NPs and free CUR. In vitro cytotoxicity studies displayed blank PTTMA-g-SS-PEG NPs showed low toxicity at concentrations up to 1.0 mg/mL, whereas CUR-loaded PTTMA-g-SS-PEG NPs demonstrated more efficient growth inhibition toward EC-109 and HepG-2 cells than reduction-unresponsive controls and free CUR. Therefore, the above results indicated that pH and reduction dual-induced disassemblable PTTMA-g-SS-PEG NPs may have emerged as superior nanocarriers for active loading and promoted intracellular drug delivery in systemic cancer chemotherapy.

Thiocarbmoylation Chemistry Based Pegylation Of αα Fumaryl-Hb Is Unique As It Does Not Induce An Increase In Oxygen Affinity: High Oxygen Affinity Pegylated Crosslinked Hbs Are Better As Oxygen Therapeutics

BackgroundPEGylated Hbs have emerged as a novel class of nohypertensive, oxygen carrying low viscosity nitric oxide producing resuscitation fluids. The limitations of PEGylation of Hb are that it induces a weakening of its interdimeric interactions and increases oxygen affinity. Besides, the influence of oxygen affinity of PEG-Hb on the tissue oxygen is still a unknown zone in the blood substitute field. In this study, we prepared two PEGylated intramolecularly crosslinked Hb and compared their performance in the extreme hemodilution model. MethodsHb-PEG adducts were prepared by incubation of PEG reagents with Hb to conjugate PEG chains to the amino groups on the surface of Hb molecule. The unreacted PEG was removed by tangential flow filtration against PBS using Minim (PAL Co.) at 4 °C. The oxygen equilibrium curves of Hb-PEG solutions were obtained using a Hemox analyzer (TCS Scientific, New Hope, PA). Extreme hemodilution: By progressive hemodilution, the hamster's systemic Hct is reduced to 18% with a non- O2 carrying colloid plasma expander (dextran 70). It is at the critical transition of Hb where O2 carrying capacity becomes limited that the study materials are introduced. This final hemodilution step is performed with the study material until an 11% hematocrit is reached, a control being generated using dextran 70. O2 delivery to the microcirculation and O2 extraction to the tissue were determined by measured by the Phosphorescence Decay (PD) Technique. ResultsThe extension arm facilitate (EAF) PEGylation as well direct PEGylation using either reductive alkylation chemistry or acylation chemistry based PEGylation of αα fumaryl-Hb generates PEG Hbs with an higher oxygen affinity (∼20 mm Hg), as compared to the oxygen affinity of 30 mm Hg for αα fumaryl-Hb. The thiocarbmoylation chemistry based PEGylation of αα-fumaryl Hb using isothiocyanate phenyl PEG 5K (ITP-PEG5K) has been investigated here. TetraPEGylated αα fumaryl-Hb [(TCP-PEG5K)4 αα-Hb] generated by thiocarbmoylation chemistry generates thiourethane linkage and exhibits an oxygen affinity (34 mm Hg), which is slightly lower than that of parent molecule (30 mm Hg). The tetraPEGylation by ITP PEG exhibits very high site selectivity to the four α-amino groups, which is the same as the reductive PEGylation. The reductive PEGylation results in a significant increase in the oxygen affinity of αα-fumaryl Hb (15 mm Hg). The oxygen affinity of (TCP-PEG 5K)4 ββ-Hb is around 8 mm Hg, which is comparable to that of ββ-Hb. Thus PEG-chains on the amino termini of crosslinked Hb with thiourethane linkage is distinct as it does not increase the oxygen affinity of crosslinjed Hb. Despite the low P50 of (TCP-PEG5K)4 αα-Hb, it neutralized the in vivo hypertensive activity of αα-fumaryl Hb. Besides, the tissue oxygenation by (TCP-PEG5K)4 αα-Hb is 3.5 mmHg, and is lower than that for affinity reductive PEGylated Hb, 5.4 mmHg. Conclusions(i) Conjugation chemistry dictates the influence on the oxygen affinity of PEGylated crosslinked Hbs and not the PEG shell, (ii) The number and amount of PEG-chains in the PEG-shell dictates the plasma expander like properties of PEG Hb; (iii) PEGylation mediated attenuation of the hypertensive activity of Hb is not a correlate of its oxygen affinity; and (iv) The tissue oxygenation PEGylated αα Hb is not correlated with oxygen affinity. Accordingly, the choice of the oxygen affinity for PEG-Hb and chemistry of PEGylation for its application as an oxygen therapeutic will be dictated by the overall efficacy of tissue oxygenation expected for a PEG Hb solution in a given clinical setting. We speculate that (TCP-PEG5KK)4 ββ-Hb will achieve a tissue oxygenation better or comparable to PEG5K2 Hb, the molecule that has given the best tissue oxygenation as an oxygen therapeutic in extreme hemodilution model so far. Disclosures:No relevant conflicts of interest to declare.

Complex Micelles with Glucose-Responsive Shells for Self-Regulated Release of Glibenclamide

Complex micelles with a hydrophobic poly(ϵ-caprolactone) (PCL) core and a mixed P(Asp-co-AspPBA)/PEG shell were prepared through co-assembly of two block copolymers PCL-b- P(Asp-co-AspPBA) and PEG-b-PCL in basic aqueous solutions. The P(Asp-co-AspPBA) chains (Asp = aspartic acid; AspPBA = aspartamidophenylboronic acid) collapsed and formed a shell layer around the PCL core at neutral pH while the soluble PEG chains stabilised the micelles. The collapsed P(Asp-co-AspPBA) polymer becomes soluble under higher glucose concentration and collapses onto the PCL core reversibly at lower glucose concentration. Self-regulated release of glibenclamide from the complex micelles was achieved based on the reversible change of P(Asp-co-AspPBA) chain mobility in response to the change of glucose concentration. As a result, polymeric micelles with glucose-responsive on-off switches were successfully developed.

Dissipative Particle Dynamics Studies of Doxorubicin-Loaded Micelles Assembled from Four-Arm Star Triblock Polymers 4AS-PCL-b-PDEAEMA-b-PPEGMA and their pH-Release Mechanism

Dissipative particle dynamics (DPD) simulation was applied to investigate the microstructures of the micelles self-assembled from pH-sensitive four-arm star triblock poly(ε-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (4AS-PCL-b-PDEAEMA-b-PPEGMA). In the optimized system, the micelles have a core-mesosphere-shell three-layer structure. The drug-loading process and its distribution at different formulations in the micelles were studied. The results show that DOX molecules distributed in the core and the interface between the core and the mesosphere, suggesting the potential encapsulation capacity of DOX molecules. More drugs were loaded in the micelles with the increase in DOX, and the size of micelles became larger. However, some openings start to generate on the PEG shell when the DOX reaches a certain concentration. By changing the pH values of the system, different morphologies of the micelles were acquired after the pH-sensitive blocks PDEAEMA were protonated, the mechanism of which was also analyzed through correlating functions. The results indicated that the sudden increase in solubility parameter of the pH-sensitive blocks and the swelling of the micelles were the key factors on the change of morphologies. Furthermore, with the decrease in pH value, the number and size of the cracks on the surface of the micelles were larger, which may have a direct effect on the drug release. In conclusion, 4AS-PCL-b-PDEAEMA-b-PPEGMA has great promising applications in delivering hydrophobic anticancer drugs for improved cancer therapy.

Poly(ethylene glycol) Conjugation Stabilizes the Secondary Structure of α-Helices by Reducing Peptide Solvent Accessible Surface Area

We investigate the effect of poly(ethylene glycol) (PEG) side-chain conjugation on the conformational behavior of an α-helix using molecular dynamics simulations in explicit solvents of varying hydrophobicity. Our simulations illustrate an increase in peptide helicity with increasing PEG molecular weight in the range ~400 to 1800 Da. The data with varying PEG contour lengths as well as constant force pulling simulations that allow control over the end-to-end length of PEG indicate a strong inverse correlation between peptide helicity and solvent accessible surface area (SASA). A residue-based mapping analysis reveals that the formation of a protecting PEG shell around peptide helix in water is facilitated by two distinct mechanisms that depend on the solvent environment. First, cationic residues such as lysine interact favorably with PEG due to strong polar interactions with PEG oxygen atoms. Additionally, we find that hydrophobic residues interact strongly with PEG to reduce their SASA in polar solvents by polymer shielding. Our simulations illustrate that these two mechanisms that involve side-chain chemistry and solvent polarity govern the preferred conformation of PEG on the helix surface and thus the stability of peptide secondary structure. These findings elucidate the molecular mechanisms underpinning recent experimental findings on the stability and conformational dynamics of protein-PEG conjugates.

Surface Chemistry Architecture of Silica Nanoparticles Determine the Efficiency of in Vivo Fluorescence Lymph Node Mapping

Near-infrared (NIR) imaging of the lymphatic system offers a sensitive, versatile, and accurate lymph node mapping to locate the first, potentially metastatic, draining nodes in the operating room. Many luminescent nanoprobes have received great attention in this field, and the design of nontoxic and bright nanosystems is of crucial importance. Fluorescent NIR-emitting dye doped silica nanoparticles represent valuable platforms to fulfill these scopes, providing sufficient brightness, resistance to photobleaching, and hydrophilic nontoxic materials. Here, we synthesized these highly stable core-shell nanoparticles with a programmable surface charge positioning and determined the effect of these physicochemical properties on their in vivo behavior. In addition, we characterized their fluorescence kinetic profile in the right axillary lymph node (RALN) mapping. We found that nanoparticles with negative charges hidden by a PEG shell are more appropriate than those with external negative charges in the mapping of lymph nodes. We also demonstrated the efficient excretion of these nanostructures by the hepatobiliary route and their nontoxicity in mice up to 3 months postinjection. These results indicate the potential future development of these fluorescent nanosystems for LN mapping.