Complementary Supramolecular Functionalization Enhances Antifouling Surfaces: A Ureidopyrimidinone-Functionalized Phosphorylcholine Polymer.

Fibrosis of implants remains a significant challenge in the use of biomedical devices and tissue engineering materials. Antifouling coatings, including synthetic zwitterionic coatings, have been developed to prevent fouling and cell adhesion to several implantable biomaterials. While many of these coatings need covalent attachment, a conceptually simpler approach is to use a spontaneous self-assembly event to anchor the coating to a surface. This could simplify material processing through highly specific molecular recognition. Herein, we investigate the ability to utilize directional supramolecular interactions to anchor an antifouling coating to a polymer surface containing a complementary supramolecular unit. A library of controlled copolymerization of ureidopyrimidinone methacrylate (UPyMA) and 2-methacryloyloxyethyl phosphorylcholine (MPC) was prepared and their UPy composition was assessed. The MPC-UPy copolymers were characterized by 1H NMR, Fourier transform infrared (FTIR), and gel permeation chromatography (GPC) and found to exhibit similar mol % of UPy as compared to feed ratios and low dispersities. The copolymers were then coated on an UPy elastomer and the surfaces were assessed for hydrophilicity, protein absorption, and cell adhesion. By challenging the coatings, we found that the antifouling properties of the MPC-UPy copolymers with more UPy mol % lasted longer than the MPC homopolymer or low UPy mol % copolymers. As a result, the bioantifouling nature could be tuned to exhibit spatio-temporal control, namely, the longevity of a coating increased with UPy composition. In addition, these coatings showed nontoxicity and biocompatibility, indicating their potential use in biomaterials as antifouling coatings. Surface modification employing supramolecular interactions provided an approach that merges the simplicity and scalability of nonspecific coating methodology with the specific anchoring capacity found when using conventional covalent grafting with longevity that could be engineered by the supramolecular composition itself.

Phosphorus-Containing Polymers as Sensitive Biocompatible Probes for 31P Magnetic Resonance.

The visualization of organs and tissues using 31P magnetic resonance (MR) imaging represents an immense challenge. This is largely due to the lack of sensitive biocompatible probes required to deliver a high-intensity MR signal that can be distinguished from the natural biological background. Synthetic water-soluble phosphorus-containing polymers appear to be suitable materials for this purpose due to their adjustable chain architecture, low toxicity, and favorable pharmacokinetics. In this work, we carried out a controlled synthesis, and compared the MR properties, of several probes consisting of highly hydrophilic phosphopolymers differing in composition, structure, and molecular weight. Based on our phantom experiments, all probes with a molecular weight of ~3-400 kg·mol-1, including linear polymers based on poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), poly(ethyl ethylenephosphate) (PEEP), and poly[bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)]phosphazene (PMEEEP) as well as star-shaped copolymers composed of PMPC arms grafted onto poly(amidoamine) dendrimer (PAMAM-g-PMPC) or cyclotriphosphazene-derived cores (CTP-g-PMPC), were readily detected using a 4.7 T MR scanner. The highest signal-to-noise ratio was achieved by the linear polymers PMPC (210) and PMEEEP (62) followed by the star polymers CTP-g-PMPC (56) and PAMAM-g-PMPC (44). The 31P T1 and T2 relaxation times for these phosphopolymers were also favorable, ranging between 1078 and 2368 and 30 and 171 ms, respectively. We contend that select phosphopolymers are suitable for use as sensitive 31P MR probes for biomedical applications.

Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani.

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH2O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

In vivo evaluation of anti-Leishmania activity of alkyltriazoles and alkylphosphocholines by oral route.

The failures in the treatment of leishmaniasis is an increasing problem around the world, especially related to resistance. Thus, we describe the synthesis and in vivo anti-Leishmania activity of alkylphosphocholine and alkyltriazoles; besides, their likely action mechanisms stem from some eventual inhibition of parasite enzymes using computational tools. These compounds were tested in an in vivo hamster model infected with Leishmania Leishmania infantum chagasi. Fifty days after parasite inoculation, the two compounds 12-azidedodecylphosphocholine (3) and 3-(1-(12-fluorododecyl)-1H-1,2,3-triazol-1-yl)propano-1-ol (9), were separately administered once a day as oral suspensions (25 and 12.5 mg/kg/day, respectively) during ten days, and their efficacy was compared to the reference compound pentavalent antimonial Glucantime (GLU). Compound 3 significantly reduced the number of parasites in the spleen (4.93 × 102 amastigotes/g) and liver (4.52 × 103 amastigotes/g). Compound 9 reduced the number of amastigotes in the spleen to 1.30 × 104 and 1.36 × 103 amastigotes/g in the liver. GLU was the most effective overall treatment (7.50 × 101 and 2.28 × 102 amastigotes/g in the spleen and liver, respectively). The high activity levels of these compounds in vivo may stem from their high in vitro leishmanicidal activity and lipophilicity. The in silico absorption, distribution, metabolism, and excretion studies also showed some anti-Leishmania potential. Compound 9 had more lipophilic characteristics than those of compound 3. In silico studies of the nine enzymes of compounds 3 and 9 showed significant evidence of interactions with nicotimidase and tyrosine aminotransferase, demonstrating possible inhibition enzymes present in L. (L.) infantum chagasi. These compounds could be a promising template for developing a new class of leishmanicidal agents, by oral route, and deserve further investigation to explore different therapeutic regimens.

Identification of Antifungal Bisphosphocholines from Medicinal Gentiana Species.

Gentiana species including G. crassicaulis, G. macrophylla, G. dahurica, and G. straminea are used in traditional Chinese medicine as "Qinjiao" for the treatment of rheumatism, hepatitis, and pain. Four antifungal bisphosphocholines [irlbacholine (2) and three new analogues, gentianalines A-C (1, 3, and 4)] were identified from G. crassicaulis by a bioassay-guided fractionation and structure elucidation approach. Subsequent chemical analysis of 56 "Qinjiao" samples (45 from G. crassicaulis, five from G. macrophylla, three from G. dahurica, and three from G. straminea) showed that bisphosphocholines were present in all four Gentiana species, with irlbacholine as the major compound ranging from 2.0 to 6.2 mg per gram of dried material. Irlbacholine exhibited potent in vitro antifungal activity against Cryptococcus neoformans, Aspergillus fumigatus, Candida albicans, and Candida glabrata with minimum inhibitory concentration (MIC) values of 0.63, 1.25, 10.0, and 5.0 µg/mL, respectively. Identification of the bisphosphocholines, a rare class of antifungal natural products, in these medicinal plants provides scientific evidence to complement their medicinal use. The bisphosphocholines carrying a long aliphatic chain possess amphiphilic molecule-like properties with a tendency of retention in both normal and reversed-phase silica gel column chromatography and thereby may be neglected in natural products discovery. This report may stimulate interest in this class of compounds, which warrant the further study of other biological activities as well.

Structure of human GABAB receptor in an inactive state.

The human GABAB receptor-a member of the class C family of G-protein-coupled receptors (GPCRs)-mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2-6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9-14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique 'intersubunit latch' within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity.

Bifunctional Phosphorylcholine-Modified Adsorbent with Enhanced Selectivity and Antibacterial Property for Recovering Uranium from Seawater.

The recovery of uranium from seawater is of great concern because of the growing demand for nuclear energy. Though amidoxime-functionalized adsorbents as the most promising adsorbents have been widely used for this purpose, their low selectivity and vulnerability to biofouling have limited their application in real marine environments. Herein, a new bifunctional phosphorylcholine-modified adsorbent (PVC-PC) is disclosed. The PVC-PC fiber is found to be suitable for use in the pH range of seawater and metals that commonly coexist with uranium, such as alkali and alkaline earth metals, transition metals, and lanthanide metals, have no obvious effect on its uranium adsorption capacity. PVC-PC shows better selectivity and adsorption capacity than the commonly used amidoxime-functionalized adsorbent. Furthermore, PVC-PC fiber exhibits excellent antibacterial properties which could reduce the effects of biofouling caused by marine microorganisms. Because of its good selectivity and antibacterial property, phosphorylcholine-based material shows great potential as a new generation adsorbent for uranium recovery from seawater.

Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.

Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 µM for Leishmania infantum, 3.4 µM for L. donovani, 6.7 µM for L. major), Trypanosoma cruzi (EC50 7.5 µM) and T. brucei (EC50 0.8 µM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.

Glucosamine sulphate-loaded distearoyl phosphocholine liposomes for osteoarthritis treatment: combination of sustained drug release and improved lubrication.

Osteoarthritis (OA) is a chronic joint disease resulting from joint inflammation and damage. In this study, we employed a boundary lubricant known as a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) liposome for loading of an anti-inflammatory drug d-glucosamine sulphate (GAS) to construct a treatment strategy allowing for sustained anti-inflammation and reduced damage. This kind of drug-loaded nanocarrier integrates the anti-inflammatory effect of the GAS and the lubrication ability of DSPC liposomes without the involvement of complex synthesis processes leading to easier popularization. Our experimental results indicated that the GAS-loaded DSPC liposomes could release GAS in a sustained manner while providing good lubrication in pure water (H2O) and phosphate buffered saline (PBS). Moreover, the GAS-loaded DSPC liposomes prepared at a 2 : 8 molar ratio in PBS exhibited a greater entrapment efficiency, lower GAS release rate and smaller friction coefficient as compared to those prepared in H2O. The superiority of the drug release and lubrication ability achieved with the GAS-loaded DSPC liposomes in PBS were elucidated on the basis of salt-induced enhancement in liposomal stability and hydration lubrication by the hydrated salt ions. Such GAS release accelerated the viability and proliferation of primary mouse chondrocytes while also providing the anti-inflammatory and chondroprotective potential for tumor necrosis factor (TNF-α) induced chondrocyte degeneration through the down-regulation of pro-inflammatory cytokines, pain related gene and catabolic proteases, as well as the up-regulation of anabolic components. We envision that the GAS-loaded DSPC liposomes could represent a promising new strategy for clinical treatment of OA in the future.

Novel anti-biofouling bioactive calcium silicate-based cement containing 2-methacryloyloxyethyl phosphorylcholine.

Calcium silicate-based cements (CSCs) are commonly used for endodontic procedures; however, their antibacterial effects are limited. The objective of this study was to develop a 2-methacryloyloxyethyl phosphorylcholine (MPC)-incorporated CSC with improved antibacterial properties, while maintaining the original advantageous features of CSC. MPC was incorporated into a commercial CSC (Endocem MTA) at 0 wt% (control), 1.5%, 3.0 wt%, 5.0 wt%, 7.5 wt%, and 10 wt%. The setting time, compressive strength, water sorption, and glycerol contact angle were measured. Protein absorption was measured and bacterial adhesion on the surface was evaluated using Enterococcus faecalis. The bactericidal effect was examined by the disc diffusion test. Mineralization ability was assessed based on calcium ion deposition, as assessed by alizarin red staining, after immersion into Hank's balanced salt solution for 7 days. High concentrations of MPC in CSC (7.5 wt% and 10 wt%) increased the setting time, reduced compressive strength, and reduced wettability. MPC (3 wt%) had greater protein repellent and anti-biofouling effects than those of control and test materials (P < 0.001). However, no bactericidal effect was observed for any control or test materials. There was greater calcium ion deposition on the surface of MPC-supplemented CSC than on the control (P < 0.001). The addition of 3 wt% MPC polymer to CSC confers protein-repellent properties and reduced bacterial attachment, with the potential for improved mineralization.

Plant-derived phosphocholine facilitates cellular uptake of anti-pulmonary fibrotic HJT-sRNA-m7.

Pulmonary fibrosis, a progressive chronic disease with a high mortality rate, has limited treatment options. Currently, lung transplantation remains the only effective treatment. Here we report that a small RNA, HJT-sRNA-m7, from a Chinese herbal medicine Hong Jing Tian (HJT, RHODIOHAE CRENULATAE RADIX ET RHIZOMA, Rhodiola crenulata) can effectively reduce the expressions of fibrotic hallmark genes and proteins both in alveolar in vitro and in mouse lung tissues in vivo. We also discovered over one hundred oil-soluble chemicals from HJT decoctions, most of which are found in lipid extracts from other Chinese herbals decoctions, including Pu Gong Ying (PGY, TARAXACI HERBA, Taraxacum mongolicum), Chuan Xin Lian (CXL, changed to "ANDROGRAPHIS HERBA, Andrographis paniculata"), and Jin Yin Hua (JYH, lonicera japonica or Honeysuckle). We identified the active component in these decoctions as two forms of phosphocholines, PC (18:0/18:2) and PC (16:0/18:2). These PCs potentially could form liposomes with small RNAs to enter human alveolar and gastric cells. Our experimental results suggest an unprecendent lipid complex route through which botanic small RNA can enter human bodies. Our results provide an innovative treatment strategy for oral delivery of siRNAs as therapeutic medication.

Bioinspired Polydopamine/Polyzwitterion Coatings for Underwater Anti-Oil and -Freezing Surfaces.

Zwitterionic polymers are continually suggested as promising alternatives to tune the surface/interface properties of materials in many fields because of their unique molecular structures. Tremendous efforts have been devoted to immobilizing zwitterionic polymers (polyzwitterions, PZIs) on the material surfaces. However, these efforts usually suffer from cumbersome and time-consuming procedures. Herein we report a one-step strategy to facilely achieve the bioinspired polydopamine/polyzwitterion (PDA/PZI) coatings on various substrates. It requires only 30 min to form PDA/PZI coatings by mixing oxidant, dopamine, and zwitterionic monomers, including carboxybetaine methacrylate (CBMA), sulfobetaine methacrylate (SBMA), and 2-methacryloxyethyl phosphorylcholine (MPC). These bioinspired coatings display multifunctional properties such as underwater antioil-adhesion and antifreezing thanks to their high hydrophilicity and underwater superoleophobicity. The coatings even show the antiadhesion property for crude oil with high viscosity. Therefore, the PDA/PZI-coated meshes are efficient for separating both light oil and crude oil from oil/water mixtures. All these results demonstrate that the one-step strategy is a facile approach to design and exploit the bioinspired PDA/PZI coatings for diverse applications.

Phosphocholine-Modified Lipooligosaccharides of Haemophilus influenzae Inhibit ATP-Induced IL-1ß Release by Pulmonary Epithelial Cells.

Phosphocholine-modified bacterial cell wall components are virulence factors enabling immune evasion and permanent colonization of the mammalian host, by mechanisms that are poorly understood. Recently, we demonstrated that free phosphocholine (PC) and PC-modified lipooligosaccharides (PC-LOS) from Haemophilus influenzae, an opportunistic pathogen of the upper and lower airways, function as unconventional nicotinic agonists and efficiently inhibit the ATP-induced release of monocytic IL-1ß. We hypothesize that H. influenzae PC-LOS exert similar effects on pulmonary epithelial cells and on the complex lung tissue. The human lung carcinoma-derived epithelial cell lines A549 and Calu-3 were primed with lipopolysaccharide from Escherichia coli followed by stimulation with ATP in the presence or absence of PC or PC-LOS or LOS devoid of PC. The involvement of nicotinic acetylcholine receptors was tested using specific antagonists. We demonstrate that PC and PC-LOS efficiently inhibit ATP-mediated IL-1ß release by A549 and Calu-3 cells via nicotinic acetylcholine receptors containing subunits α7, α9, and/or α10. Primed precision-cut lung slices behaved similarly. We conclude that H. influenzae hijacked an endogenous anti-inflammatory cholinergic control mechanism of the lung to evade innate immune responses of the host. These findings may pave the way towards a host-centered antibiotic treatment of chronic airway infections with H. influenzae.

Intranasal glucagon for hypoglycaemia in diabetic patients. An old dream is becoming reality?

In 1983 it was shown that glucagon administered intranasally (IN) was absorbed through the nasal mucosa and increased blood glucose in healthy subjects. Shortly thereafter, it was shown that IN glucagon counteracts with hypoglycaemia in insulin-treated diabetic patients. In spite of this evidence, IN glucagon was not developed by any pharmaceutical company before 2010, when renewed interest led to intensive evaluation of a possible remedy for hypoglycaemia in insulin-treated diabetic adults and children. IN glucagon is now being developed as a needle-free device that delivers glucagon powder for treatment of severe hypoglycaemia; the ease of using this device stands in stark contrast to the difficulties encountered in use of the current intramuscular glucagon emergency kits. Studies have demonstrated the efficacy, safety and ease-of-use of this IN glucagon preparation, and suggest IN glucagon as a promising alternative to injectable glucagon for treating severe hypoglycaemia in children and adults who use insulin. This would meet the unmet medical need for an easily administered glucagon preparation.

Wear resistance of poly(2-methacryloyloxyethyl phosphorylcholine)-grafted carbon fiber reinforced poly(ether ether ketone) liners against metal and ceramic femoral heads.

Younger, active patients who undergo total hip arthroplasty (THA) have increasing needs for wider range of motion and improved stability of the joint. Therefore, bearing materials having not only higher wear resistance but also mechanical strength are required. Carbon fiber-reinforced poly(ether ether ketone) (CFR-PEEK) is known as a super engineering plastic that has great mechanical strength. In this study, we focused on poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-grafted CFR-PEEK and investigated the effects of PMPC grafting and the femoral heads materials on the wear properties of CFR-PEEK liners. Compared with untreated CFR-PEEK, the PMPC-grafted CFR-PEEK surface revealed higher wettability and lower friction properties under aqueous circumstances. In the hip simulator wear test, wear particles generated from the PMPC-grafted CFR-PEEK liners were fewer than those of the untreated CFR-PEEK liners. There were no significant differences in the size and the morphology of the wear particles between the differences of PMPC-grafting and the counter femoral heads. Zirconia-toughened alumina (ZTA) femoral heads had significantly smoother surfaces compared to cobalt-chromium-molybdenum alloy femoral heads after the hip simulator test. Thus, we conclude that the bearing combination of the PMPC-grafted CFR-PEEK liner and ZTA head is expected to be a lifelong bearing interface in THA. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1028-1037, 2018.

Zwitterionic gold nanorods: low toxicity and high photothermal efficacy for cancer therapy.

Novel "zwitterionic" gold nanorods (Au NRs) were constructed through a facile ligand exchange process between cetyltrimethylammonium bromide (CTAB)-Au NRs and the zwitterionic block polymer {poly(2-methacryloyloxyethyl phosohorylcholine)-b-poly(lipoic methacrylate) (pMPC-b-pLA)}. In vitro, they exhibited low dark cytotoxicity and a high therapeutic efficacy to cancer cells. Their blood circulation half-life in vivo (t1/2, ∼10 h) was 20-fold longer than that of CTAB-Au NRs (t1/2, <30 min). After intravenous administration, they accumulated in tumour sites via an enhanced permeability and retention (EPR) effect and enabled destruction of human xenograft tumours in mice after exposure of the tumour location to NIR laser irradiation at 808 nm. These studies showed that the "zwitterionic" Au NRs had low toxicity and high photothermal efficacy both in vitro and in vivo due to the suprahydrophilic, biocompatible zwitterionic polymer coating layer. They may have the potential to be a promising NIR PTT agent in the biomedical field.

A hydrated phospholipid polymer-grafted layer prevents lipid-related oxidative degradation of cross-linked polyethylene.

The surface and substrate of a cross-linked polyethylene (CLPE) liner are designed to achieve resistance against oxidative degradation in the construction of hip joint replacements. In this study, we aimed to evaluate the oxidative degradation caused by lipid absorption of a highly hydrophilic nanometer-scaled thickness layer prepared by grafting a poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) layer and a high-dose gamma-ray irradiated CLPE with vitamin E blending (HD-CLPE[VE]). The HD-CLPE(VE) and PMPC-grafted HD-CLPE(VE) exhibited extremely high oxidation resistance regardless of lipid absorption, even though residual-free radical levels were detectable. The water wettability of the PMPC-grafted CLPE and PMPC-grafted HD-CLPE(VE) surfaces was considerably greater than that of untreated surfaces. The hydrated PMPC-grafted layer also exhibited extremely low solubility for squalene. Lipids such as squalene and cholesterol esters diminished the oxidation resistance of CLPE despite the vitamin E improvement. Notably, the PMPC-grafted surface was resistant to lipid absorption and diffusion as well as subsequent lipid-related oxidative degradation, likely because of the presence of the hydrated PMPC-grafted layer. Together, these results provide preliminary evidence that the resistance against lipid absorption and diffusion of a hydrated PMPC-grafted layer might positively affect the extent of resistance to the in vivo oxidation of orthopedic implants.

Iron Chelation Nanoparticles with Delayed Saturation as an Effective Therapy for Parkinson Disease.

Iron accumulation in substantia nigra pars compacta (SNpc) has been proved to be a prominent pathophysiological feature of Parkinson's diseases (PD), which can induce the death of dopaminergic (DA) neurons, up-regulation of reactive oxygen species (ROS), and further loss of motor control. In recent years, iron chelation therapy has been demonstrated to be an effective treatment for PD, which has shown significant improvements in clinical trials. However, the current iron chelators are suboptimal due to their short circulation time, side effects, and lack of proper protection from chelation with ions in blood circulation. In this work, we designed and constructed iron chelation therapeutic nanoparticles protected by a zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) to delay the saturation of iron chelators in blood circulation and prolong the in vivo lifetime, with HIV-1 trans-activating transcriptor (TAT) served as a shuttle to enhance the blood-brain barrier (BBB) permeability. We explored and investigated whether the Parkinsonian neurodegeneration and the corresponding symptoms in behaviors and physiologies could be prevented or reversed both in vitro and in vivo. The results demonstrated that iron chelator loaded therapeutic nanoparticles could reverse functional deficits in Parkinsonian mice not only physiologically but also behaviorally. On the contrary, both untreated PD mice and non-TAT anchored nanoparticle treated PD mice showed similar loss in DA neurons and difficulties in behaviors. Therefore, with protection of zwitterionic polymer and prolonged in vivo lifetime, iron chelator loaded nanoparticles with delayed saturation provide a PD phenotype reversion therapy and significantly improve the living quality of the Parkinsonian mice.

IR-780 Loaded Phospholipid Mimicking Homopolymeric Micelles for Near-IR Imaging and Photothermal Therapy of Pancreatic Cancer.

IR-780 iodide, a near-infrared (near-IR) fluorescent dye, can be utilized as an effective theranostic agent for both imaging and photothermal therapy. However, its lipophilicity limits its further biomedical applications. Herein, we synthesized a phospholipid mimicking amphiphilic homopolymer poly(12-(methacryloyloxy)dodecyl phosphorylcholine) (PMDPC) via reversible addition-fragmentation chain transfer (RAFT) polymerization. The amphiphilic homopolymer PMDPC can be self-assembled into micelles and used for the encapsulation of IR-780. The IR-780 loaded micelles (PMDPC-IR-780) exhibited low cytotoxicity in the dark, whereas remarkable photothermal cytotoxicity to pancreatic cancer cells (BxPC-3) was observed upon near-IR laser irradiation. We further investigated in vivo biodistribution of PMDPC-IR-780 micelles. Higher accumulation of PMDPC-IR-780 than that of free IR-780 in tumor tissue was verified, which might be ascribed to the enhanced permeability and retention (EPR) effect and long circulation time benefiting from the zwitterionic phosphorylcholine surface. Therefore, the IR-780 loaded phospholipid mimicking homopolymeric micelles could have great potential for cancer theranostics.

Clickable and Antifouling Platform of Poly[(propargyl methacrylate)-ran-(2-methacryloyloxyethyl phosphorylcholine)] for Biosensing Applications.

A functional copolymer platform, namely, poly[(propargyl methacrylate)-ran-(2-methacryloyloxyethyl phosphorylcholine)] (PPgMAMPC), was synthesized by reversible addition-fragmentation chain-transfer polymerization. In principle, the alkyne moiety of propargyl methacrylate (PgMA) should serve as an active site for binding azide-containing molecules via a click reaction, i.e., Cu-catalyzed azide/alkyne cycloaddition (CuAAC), and 2-methacryloyloxyethyl phosphorylcholine (MPC), the hydrophilic monomeric unit, should enable the copolymer to suppress nonspecific adsorption. The copolymers were characterized using Fourier transform infrared (FTIR) and (1)H NMR spectroscopies. Thiol-terminated, PPgMAMPC-SH, obtained by aminolysis of PPgMAMPC, was immobilized on a gold-coated substrate using a "grafting to" approach via self-assembly. Azide-containing species, namely, biotin and peptide nucleic acid (PNA), were then immobilized on the alkyne-containing copolymeric platform via CuAAC. The potential use of surface-attached PPgMAMPC in biosensing applications was shown by detection of specific target molecules, i.e., streptavidin (SA) and DNA, by the developed sensing platform using a surface plasmon resonance technique. The copolymer composition strongly influenced the performance of the developed sensing platform in terms of signal-to-noise ratio in the case of the biotin-SA system and hybridization efficiency and mismatch discrimination for the PNA-DNA system.