Facile Generation of Heterotelechelic Poly(2-Oxazoline)s Towards Accelerated Exploration of Poly(2-Oxazoline)-Based Nanomedicine.

Controlling the end-groups of biocompatible polymers is crucial for enabling polymer-based therapeutics and nanomedicine. Typically, end-group diversification is a challenging and time-consuming endeavor, especially for polymers prepared via ionic polymerization mechanisms with limited functional group tolerance. In this study, we present a facile end-group diversification approach for poly(2-oxazoline)s (POx), enabling quick and reliable production of heterotelechelic polymers to facilitate POxylation. The approach relies on the careful tuning of reaction parameters to establish differential reactivity of a pentafluorobenzyl initiator fragment and the living oxazolinium chain-end, allowing the selective introduction of N-, S-, O-nucleophiles via the termination of the polymerization, and a consecutive nucleophilic para-fluoro substitution. The value of this approach for the accelerated development of nanomedicine is demonstrated through the synthesis of well-defined lipid-polymer conjugates and POx-polypeptide block-copolymers, which are well-suited for drug and gene delivery. Furthermore, we investigated the application of a lipid-POx conjugate for the formulation and delivery of mRNA-loaded lipid nanoparticles for immunization against the SARS-COV-2 virus, underscoring the value of POx as a biocompatible polymer platform.

Knockdown of Bach1 protects periodontal bone regeneration from inflammatory damage.

Periodontal bone regeneration is a major challenge in the treatment of periodontitis. However, the regenerative vitality of periodontal ligament cells (PDLCs) declines in the environment of periodontitis and accompanying oxidative stress. This study aimed to investigate the functional mechanisms of Bach1, a transcriptional suppressor involved in oxidative stress response, and its regulation of PDLC osteogenesis under inflammatory conditions. We observed a significant elevation in Bach1 expression in periodontal tissues with periodontitis and PDLCs under inflammatory conditions. Knockdown of Bach1 alleviated the inflammation-induced oxidative stress level and partly offset the inhibitory effect of inflammatory conditions on osteogenesis, as well as the expression of osteogenic genes BMP6, OPG and RUNX2. Similarly, knockdown of Bach1 protects PDLCs from inflammatory damage to periodontal bone regeneration in vivo. Furthermore, we found that Bach1 could bind to the histone methyltransferase EZH2, and the binding increased under inflammatory conditions. Bach1 enhanced the ability of EZH2 to catalyse H3K27me3 on the promoter region of RUNX2 and BMP6, thus repressing the expression of osteoblastic genes. In conclusion, our study revealed that knockdown of Bach1 effectively rescued the osteogenesis and oxidative stress of PDLCs with inflammation. Bach1 could be a promising target for enhancing periodontal tissue regeneration under periodontitis conditions.

PEGylated IL-10: Clinical Development in Cancer Immunotherapy, Where to Go?

PURPOSEOF REVIEW: The purpose of this review is to discuss the current understanding of the pegilodecakin (PEGylated interleukin 10) and its role in the inhibition of tumour growth and metastasis. This review also focuses on clinical data published to date that have evaluated the efficacy and safety of pegilodecakin. RECENT FINDINGS: Pegilodecakin has shown significant promise in preclinical models, notable for decreased tumour burden and fewer sites of metastatic disease across various malignancies. It has been most widely assessed in a phase I/Ib clinical trial against several solid tumours, leading to the phase II and III clinical trials containing pegilodecakin and its combination with other current treatments. However, the updated data have not shown higher efficacy in renal cell carcinoma, metastatic non-small cell lung cancer or pancreatic cancer, with respect to the controls, yet the adverse events presented more mixed results. Further investigation into combination therapies including pegilodecakin is ongoing. Pegilodecakin showed promise in preclinical and phase I clinical trials on its efficacy in several solid tumours, with expected regulation of IL-10 signalling pathway observed. However, the phase II and III trials did not justify its application as potential immunotherapy in selected cancers. Further evaluation of pegilodecakin's efficacy in other cancers, either as monotherapy or in combination with the current treatments, is worth investigating clinically, which warrants to better understand its potential clinical utility.

Polysaccharide-Derived Ice Recrystallization Inhibitors with a Modular Design: The Case of Dextran-Based Graft Polymers.

Ice recrystallization inhibitors inspired from antifreeze proteins (AFPs) are receiving increasing interest for cryobiology and other extreme environment applications. Here, we present a modular strategy to develop polysaccharide-derived biomimetics, and detailed studies were performed in the case of dextran. Poly(vinyl alcohol) (PVA) which has been termed as one of the most potent biomimetics of AFPs was grafted onto dextran via thiol-ene click chemistry (Dex-g-PVA). This demonstrated that Dex-g-PVA is effective in IRI and its activity increases with the degree of polymerization (DP) (sizes of ice crystals were 18.846 ± 1.759 and 9.700 ± 1.920 µm with DPs of 30 and 80, respectively) and fraction of PVA. By means of the dynamic ice shaping (DIS) assay, Dex-g-PVA is found to engage on the ice crystal surfaces, thus the ice affinity accounts for their IRI activity. In addition, Dex- g-PVA displayed enhanced IRI activity compared to that of equivalent PVA alone. We speculate that the hydrophilic nature of dextran would derive PVA in a stretch conformation that favors ice binding. The modular design can not only offer polysaccharides IRI activity but also favor the ice-binding behavior of PVA.

Gelatin-Reinforced Zwitterionic Organohydrogel with Tough, Self-Adhesive, Long-Term Moisturizing and Antifreezing Properties for Wearable Electronics.

Strong mechanical performance, appropriate adhesion capacity, and excellent biocompatibility of conductive hydrogel-based sensors are of great significance for their application. However, conventional conductive hydrogels usually exhibit insufficient mechanical strength and adhesion. In addition, they will lose flexibility and conductivity under subzero temperature and a dry environment owing to inevitable freezing and evaporation of water. In this study, a tough, flexible, self-adhesive, long-term moisturizing, and antifreezing organohydrogel was prepared, which was composed of gelatin, zwitterionic poly [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) (PSBMA), MXene nanosheets, and glycerol. Natural gelatin was incorporated to enhance mechanical performance via the entanglement of a physical cross-linked network and a PSBMA network, which was also used as a stabilizer to disperse MXene into the organohydrogel. Zwitterionic PSBMA endowed the organohydrogel with good adhesion and self-healing properties. Long-term moisturizing properties and antifreeze tolerance could be achieved owing to the synergistic water retention capacity of PSBMA and glycerol. The resulting PSBMA-gelatin-MXene-glycerol (PGMG) organohydrogel exhibited high mechanical fracture strength (0.65 MPa) and stretchability (over 1000%), excellent toughness (3.87 MJ/m3), strong and repeated adhesion to diverse substrates (e.g., paper, glass, silicon rubber, iron, and pig skin), good fatigue resistance (under the cyclic stretching-releasing process), and rapid recovery capacity. Moreover, the PGMG organohydrogel showed good stability under -40 °C. The sensor based on PGMG organohydrogel could tightly attach to the human skin and real-time-monitor the motions of joints (e.g., bending of the finger, wrist, elbow, and knee) and the change in mood such as smiling and frowning. Therefore, PGMG organohydrogels have a huge potential for wearable sensors under room temperature or extreme environments.

Bio-Inspired Antibacterial Hydrogel Adhesives with High Adhesion Strength.

Traditional adhesives such as cyanoacrylate glue are mostly solvent-based. They are facing the problem of insufficient adhesion to some substrates, and also from the drawback of volatilization and release of small organic molecules in the process of usage. Therefore, a novel adhesive with non-irritating, high adhesive strength, and antibacterial properties is highly required. In this study, a full physically crosslinked zwitterionic poly(betaine sulfonate methacrylate) (PSBMA) hydrogel is proposed. The physical crosslinking interactions endow the hydrogel with good self-healing properties. Furthermore, the pure physical crosslinking hydrogel can form PSBMA powder adhesive after lyophilization and return to the hydrogel state after hydration. The mechanical properties of PSBMA adhesive can be modulated via adjusting the solid content and initiator dosage. Following the cure process similar to that of snail mucus or insect exoskeletons in nature, the adhesion of the PSBMA adhesive is improved at least 100 times than its wet state. In addition, the PSBMA adhesive is easy to be removed due to the dissociation of cross-linked structures in saltwater environments. Moreover, PSBMA adhesive with antifouling properties can effectively prevent the adhesion of proteins and bacteria, which shows potential applications in the assembly of medical devices.

Effective mRNA Protection by Poly(l-ornithine) Synergizes with Endosomal Escape Functionality of a Charge-Conversion Polymer toward Maximizing mRNA Introduction Efficiency.

For efficient delivery of messenger (m)RNA, delivery carriers need two major functions: protecting mRNA from nucleases and translocating mRNA from endolysosomes to the cytoplasm. Herein, these two complementary functionalities are integrated into a single polyplex by fine-tuning the catiomer chemical structure and incorporating the endosomal escape modality. The effect of the methylene spacer length on the catiomer side chain is evaluated by comparing poly(l-lysine) (PLL) with a tetramethylene spacer and poly(L-ornithine) (PLO) with a trimethylene spacer. Noteworthily, the nuclease stability of the mRNA/catiomer polyplexes is largely affected by the difference in one methylene group, with PLO/mRNA polyplex showing enhanced stability compared to PLL/mRNA polyplex. To introduce the endosomal escape function, the PLO/mRNA polyplex is wrapped with a charge-conversion polymer (CCP), which is negatively charged at extracellular pH but turns positive at endosomal acidic pH to disrupt the endosomal membrane. Compared to the parent PLO/mRNA polyplex, CCP facilitated the endosomal escape of the polyplex in cultured cells to improve the protein expression efficiency from mRNA by approximately 80-fold. Collectively, this system synergizes the protective effect of PLO against nucleases and the endosomal escape capability of CCP in mRNA delivery.

Vibration Separation Methodology Compensated by Time-Varying Transfer Function for Fault Diagnosis of Non-Hunting Tooth Planetary Gearbox.

Due to planetary movement of planet gears, the vibration signal perceived by a stationary sensor is modulated and difficult to diagnose. This paper proposed a vibration separation methodology compensated by a time-varying transfer function (TVTF-VS), which is a further development of the vibration separation (VS) method in the diagnosis of non-hunting tooth planetary gearboxes. On the basis of VS, multi-teeth VS is proposed to extract and synthesize the meshing signal of a planet gear using a single transducer. Considering the movement regularity of a planetary gearbox, the time-varying transfer function (TVTF) is represented by a generalized expression. The TVTF is constructed using a segment of healthy signal and an evaluation indicator is established to optimize the parameters of the TVTF. The constructed TVTF is applied to overcome the amplitude modulation effect and highlight fault characteristics. After that, experiments with baseline, pitting, and compound localized faults planet gears were conducted on a non-hunting tooth planetary gearbox test rig, respectively. The results demonstrate that incipient failure on a planet gear can be detected effectively, and relative location of the local faults can be determined accurately.

Preparation Strategies and Applications of MXene-Polymer Composites: A Review.

As a new member of the 2D material family, MXene integrates high metallic conductivity and hydrophilic property simultaneously. It shows tremendous potential in fields of energy storage, sensing, electromagnetic shielding, and so forth. Due to the abundant surface functional groups, the physical and chemical properties of MXene can be tuned by the formation of MXene-polymer composites. The introduction of polymers can expand the interlayer spacing, reduce the distance of ion/electron transport, improve the surface hydrophilicity, and thus guide the assembly of MXene-polymer structures. Herein, the preparation strategies of MXene-polymer composites including physical mixing, surface modification, such as anchoring through TiN and Ti-O-C bonds, bonding through esterification, grafting functional groups through TiOSi/TiOP bonds, photograft reaction, as well as in situ polymerization are highlighted. In addition, the possible mechanisms for each strategy are explained. Furthermore, the applications of MXene-polymer composites obtained by different preparation strategies are summarized. Finally, perspectives and challenges are presented for the designs of MXene-polymer composites.

Self-Boosting Catalytic Nanoreactors Integrated with Triggerable Crosslinking Membrane Networks for Initiation of Immunogenic Cell Death by Pyroptosis.

Synthetic polymer vesicles spur novel strategies for producing intelligent nanodevices with precise and specific functions. Engineering vesicular nanodevices with tunable permeability by a general platform without involving trade-offs between structural integrity, flexibility, and functionality remains challenging. Herein, we present a general strategy to construct responsive nanoreactors based on polyion complex vesicles by integrating stimuli-responsive linkers into a crosslinking membrane network. The formulated ROS-responsive nanoreactor with self-boosting catalytic glucose oxidation could protect glucose oxidase (GOD) to achieve cytocidal function by oxidative stress induction and glucose starvation, which is ascribed to stimuli-responsive vesicle expansion without fracture and size-selective cargo release behavior. The GOD-loaded therapeutic nanoreactor induced an immunostimulatory form of cell death by pyroptosis, which has the great potential to prime anti-tumor immune responses.

Polymer Prodrug-Based Nanoreactors Activated by Tumor Acidity for Orchestrated Oxidation/Chemotherapy.

Therapeutic nanoreactors have been proposed to treat cancers through in situ transformation of low-toxicity prodrugs into toxic therapeutics in the body. However, the in vivo applications are limited by low tissue-specificity and different tissue distributions between sequentially injected nanoreactors and prodrugs. Herein, we construct a block copolymer prodrug-based polymersome nanoreactor that can achieve novel orchestrated oxidation/chemotherapy of cancer via specific activation at tumor sites. The block copolymers composed of poly(ethylene glycol) (PEG) and copolymerized monomers of camptothecin (CPT) and piperidine-modified methacrylate [P(CPTMA-co-PEMA)] were optimized to self-assemble into polymersomes in aqueous solution for encapsulation of glucose oxidase (GOD) to obtain GOD-loaded polymersome nanoreactors (GOD@PCPT-NR). GOD@PCPT-NR maintained inactive in normal tissues upon systemic administration. After deposition in tumor tissues, tumor acidity-triggered protonation of PPEMA segments resulted in high permeability of the polymersome membranes and oxidation reaction of diffused glucose and O2 under the catalysis of GOD. The activation of the reaction generated H2O2, improving the oxidative stress in tumors. Simultaneously, a high level of H2O2 further activated PCPTMA prodrugs, releasing active CPT drugs. High tumor oxidative stress and released CPT drugs synergistically killed cancer cells and suppressed tumor growth via oxidation/chemotherapy. Our study provides a new strategy for engineering therapeutic nanoreactors in an orchestrated fashion for cancer therapy.

Therapeutic Vesicular Nanoreactors with Tumor-Specific Activation and Self-Destruction for Synergistic Tumor Ablation.

Polymeric nanoreactors (NRs) have distinct advantages to improve chemical reaction efficiency, but the in vivo applications are limited by lack of tissue-specificity. Herein, novel glucose oxidase (GOD)-loaded therapeutic vesicular NRs (theraNR) are constructed based on a diblock copolymer containing poly(ethylene glycol) (PEG) and copolymerized phenylboronic ester or piperidine-functionalized methacrylate (P(PBEM-co-PEM)). Upon systemic injection, theraNR are inactive in normal tissues. At a tumor site, theraNR are specifically activated by the tumor acidity via improved permeability of the membranes. Hydrogen peroxide (H2 O2 ) production by the catalysis of GOD in theraNR increases tumor oxidative stress significantly. Meanwhile, high levels of H2 O2 induce self-destruction of theraNR releasing quinone methide (QM) to deplete glutathione and suppress the antioxidant ability of cancer cells. Finally, theraNR efficiently kill cancer cells and ablate tumors via the synergistic effect.

Hepatocellular Carcinoma: Intra-arterial Delivery of Doxorubicin-loaded Hollow Gold Nanospheres for Photothermal Ablation-Chemoembolization Therapy in Rats.

Purpose To determine if combretastatin A-4 phosphate disodium (CA4P) can enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS) mixed with ethiodized oil for improved photothermal ablation (PTA)-chemoembolization therapy (CET) of hepatocellular carcinoma (HCC) in rats. Materials and Methods Animal experiments were approved by the institutional animal care and use committee and performed from February 2014 to April 2015. Male Sprague-Dawley rats (n = 45; age, 12 weeks) were inoculated with N1S1 HCC cells in the liver, and 8 days later, were randomly divided into two groups of 10 rats. Group 1 rats received intrahepatic arterial injection of PEG-HAuNS and ethiodized oil alone; group 2 received pretreatment with CA4P and injection of PEG-HAuNS and ethiodized oil 5 minutes later. The gold content of tumor and liver tissue at 1 hour or 24 hours after injection was quantified by using neutron activation analysis (n = 5 per time point). Five rats received pretreatment CA4P, PEG-copper 64-HAuNS, and ethiodized oil and underwent micro-positron emission tomography (PET)/computed tomography (CT). In a separate study, three groups of six rats with HCC were injected with saline solution (control group); CA4P, Dox-loaded PEG-coated HAuNS (Dox@PEG-HAuNS), and ethiodized oil (CET group); or CA4P, Dox@PEG-HAuNS, ethiodized oil, and near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified at postmortem histopathologic and/or autoradiographic examination. Wilcoxon rank-sum test and Pearson correlation analyses were performed. Results PEG-HAuNS uptake in CA4P-pretreated HCC tumors was significantly higher than that in non-CA4P-pretreated tumors at both 1 hour (P < .03) and 24 hours (P < .01). Mean ± standard deviation of tumor-to-liver PEG-HAuNS uptake ratios at 1 hour and 24 hours, respectively, were 5.63 ± 3.09 and 1.68 ± 0.77 in the CA4P-treated group and 1.29 ± 2.40 and 0.14 ± 0.11 in the non-CA4P-treated group. Micro-PET/CT allowed clear delineation of tumors, enabling quantitative imaging analysis. Laser irradiation increased temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Mean HCC tumor volumes 10 days after therapy were 1.68 cm3 ± 1.01, 3.96 cm3 ± 1.75, and 6.13 cm3 ± 2.27 in the PTA-CET, CET, and control groups, respectively, with significant differences between the PTA-CET group and other groups (P < .05). Conclusion CA4P pretreatment caused a higher concentration of Dox@PEG-HAuNS to be trapped inside the tumor, thereby enhancing the efficacy of anti-HCC treatment with PTA-CET in rats. © RSNA, 2016 Online supplemental material is available for this article.

Modular Design and Facile Synthesis of Enzyme-Responsive Peptide-Linked Block Copolymers for Efficient Delivery of Doxorubicin.

Construction of efficient doxorubicin (DOX) delivery systems addressing a cascade of physiological barriers remains a great challenge for better therapeutic efficacy of tumors. Herein, we design well-defined enzyme-responsive peptide-linked block copolymer, PEG-GPLGVRGDG-P(BLA-co-Asp) [PEG and P(BLA-co-Asp) are poly(ethylene glycol) and partially hydrolyzed poly(ß-benzyl l-aspartate) (PBLA), respectively] (P3), with modular functionality for efficient delivery of DOX. The block copolymers were successfully obtained via click reaction to introduce peptide (alkynyl-GPLGVRGDG) into the end of PEG for initiating ring-opening polymerization of ß-benzyl l-aspartate N-carboxyanhydride (BLA-NCA) by terminal amino groups followed by partial hydrolysis of PBLA segments. P3 micelle was demonstrated to encapsulate DOX efficiently through synergistic effect of benzyl group-based hydrophobic and carboxyl moiety-based electrostatic interactions. Effective matrix metalloproteinase-2 (MMP-2)-triggered cleavage of peptide for dePEGylation of P3 micelles was confirmed and residual RGD ligands were retained on the surfaces. Against HT1080 cells overexpressing MMP-2, DOX-loaded P3 micelles showed approximately 4-fold increase of the cellular internalization amount as compared with free DOX and half maximal inhibitory concentration (IC50) value of DOX-loaded P3 micelles was determined to be 0.38 µg/mL compared with 0.66 µg/mL of free DOX due to MMP-triggered dePEGylation, RGD-mediated cellular uptake, and rapid drug release inside cells. Binding and penetration evaluation toward HT1080 multicellular tumor spheroids (MCTs) confirmed high affinity and deep penetration of P3 micelles in tumor tissues. This modular design of enzyme-responsive block copolymers represents an effective strategy to construct intelligent drug delivery vehicles for addressing a cascade of delivery barriers.

Label-free fluorescence detection of microRNA based on target induced adenosine2-coralyne-adenosine2 formation.

This study develops a simple and label-free biosensor for sensitive and selective detection of microRNA (miRNA) based on the formation of the adenosine2-coralyne-adenosine2 complex mediated by miRNA-specific polyadenosine extension.

Synthesis of magnetic molecularly imprinted polymers for the selective separation and determination of metronidazole in cosmetic samples.

In this study, novel magnetic molecularly imprinted polymers (MMIPs) were developed as a sorbent for solid-phase extraction (SPE) and used for the selective separation of metronidazole (MNZ) in cosmetics; MNZ was detected by high-performance liquid chromatography (HPLC). First, magnetic Fe3O4 nanoparticles (NPs) were prepared by the co-precipitation of Fe(2+)and Fe(3+) ions in an ammonia solution; then oleic acid (OA) was modified onto the surface of Fe3O4NPs. Finally, the MMIP was prepared by aqueous suspension polymerization, involving the copolymerization of Fe3O4NPs@OA with MNZ as the template molecule, methacrylic acid (MAA) as the functional monomer, ethylene glycol maleic rosinate acrylate (EGMRA) as the cross-linking agent, and 2,2-azobisisobutyronitrile (AIBN) as the initiator. The MMIP materials showed high selective adsorption capacity and fast binding kinetics for MNZ; the maximum adsorption amount of the MMIP to MNZ was 46.7 mg/g. The assay showed a linear range from 0.1 to 20.0 µg/mL for MNZ with the correlation coefficient 0.999. The relative standard deviations (RSD) of intra- and inter-day ranging from 0.71 to 2.45% and from 1.06 to 5.20% were obtained. The MMIP can be applied to the enrichment and determination of MNZ in cosmetic products with the recoveries of spiked toner, powder, and cream cosmetic samples ranging from 90.6 to 104.2, 84.1 to 91.4, and 90.3 to 100.4%, respectively, and the RSD was <3.54%.

A Near-Infrared Photothermal Effect-Responsive Drug Delivery System Based on Indocyanine Green and Doxorubicin-Loaded Polymeric Micelles Mediated by Reversible Diels-Alder Reaction.

Near-infrared light (NIR) possesses great advantages for light-responsive controllable drug release, such as deep tissue penetration and low damage to healthy tissues. Herein, a NIR-responsive drug delivery system is developed based on a NIR dye, indocyanine green (ICG), and anticancer drug, doxorubicin (DOX)-loaded thermoresponsive block copolymer micelles, in which the drug release can be controlled via NIR irradiation. First, block copolymers, poly(oligo(ethylene glycol) methacrylate)-block-poly(furfuryl methacrylate) (POEGMA-b-PFMA), are synthesized by sequential reversible addition-fragmentation chain-transfer (RAFT) polymerization, followed by modification with N-octyl maleimide through Diels-Alder (DA) reaction to produce POEGMA-b-POMFMA. The self-assembly of POEGMA-b-POMFMA by nano-precipitation in aqueous solution affords the polymeric micelles which are used to simultaneously encapsulate ICG and DOX. Upon irradiation by NIR light (805 nm), the loaded DOX is released rapidly from the micelles due to partial retro DA reaction and local temperature increase-induced faster drug diffusion by the photothermal effect. Cytotoxicity evaluation and intracellular distribution observation demonstrate significant synergistic effects of NIR-triggered drug release, photothermal, and chemotherapy toward cancer cells under NIR irradiation.

Morphology modulating the wettability of a diamond film.

Control of the wetting property of diamond surface has been a challenge because of its maximal hardness and good chemical inertness. In this work, the micro/nanoarray structures etched into diamond film surfaces by a maskless plasma method are shown to fix a surface's wettability characteristics, and this means that the change in morphology is able to modulate the wettability of a diamond film from weakly hydrophilic to either superhydrophilic or superhydrophobic. It can be seen that the etched diamond surface with a mushroom-shaped array is superhydrophobic following the Cassie mode, whereas the etched surface with nanocone arrays is superhydrophilic in accordance with the hemiwicking mechnism. In addition, the difference in cone densities of superhydrophilic nanocone surfaces has a significant effect on water spreading, which is mainly derived from different driving forces. This low-cost and convenient means of altering the wetting properties of diamond surfaces can be further applied to underlying wetting phenomena and expand the applications of diamond in various fields.

Polyplex micelles with thermoresponsive heterogeneous coronas for prolonged blood retention and promoted gene transfection.

Adequate retention in blood circulation is a prerequisite for construction of gene delivery carriers for systemic applications. The stability of gene carriers in the bloodstream requires them to effectively resist protein adsorption and maintain small size in the bloodstream avoiding dissociation, aggregation, and nuclease digestion under salty and proteinous medium. Herein, a mixture of two block catiomers consisting of the same cationic block, poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PAsp(DET)), but varying shell-forming blocks, poly[2-(2-methoxyethoxy) ethyl methacrylate] (PMEO2MA), and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA), was used to complex with plasmid DNA (pDNA) to fabricate polyplex micelles with mixed shells (MPMs) at 20 °C. The thermoresponsive property of PMEO2MA allows distinct phase transition from hydrophilic to hydrophobic by increasing incubation temperature from 20 to 37 °C, which results in a distinct heterogeneous corona containing hydrophilic and hydrophobic regions at the surface of the MPMs. Subsequent study verified that this transition promoted further condensation of pDNA, thereby giving rise to improved complex and colloidal stability. The proposed system has shown remarkable stability in salty and proteinous solution and superior tolerance to nuclease degradation. As compared with polyplex micelles formed from single POEGMA-b-PAsp(DET) block copolymer, in vivo circulation experiments in the bloodstream further confirmed that the retention time of MPMs was prolonged significantly. Moreover, the proposed system exhibited remarkably high cell transfection activity especially at low N/P ratios and negligible cytotoxicity and thus portends promising utility for systemic gene therapy applications.

Radioiodinated hypericin: its biodistribution, necrosis avidity and therapeutic efficacy are influenced by formulation.

PURPOSE: To study whether formulation influences biodistribution, necrosis avidity and tumoricidal effects of the radioiodinated hypericin, a necrosis avid agent for a dual-targeting anticancer radiotherapy. METHODS: Iodine-123- and 131-labeled hypericin ((123)I-Hyp and (131)I-Hyp) were prepared with Iodogen as oxidant, and formulated in dimethyl sulfoxide (DMSO)/PEG400 (polyethylene glycol 400)/water (25/60/15, v/v/v) or DMSO/saline (20:80, v/v). The formulations with excessive Hyp were optically characterized. Biodistribution, necrosis avidity and tumoricidal effects were studied in rats (n = 42) without and with reperfused liver infarction and implanted rhabdomyosarcomas (R1). To induce tumor necrosis, R1-rats were pre-treated with a vascular disrupting agent. Magnetic resonance imaging, tissue-gamma counting, autoradiography and histology were used. RESULTS: The two formulations differed significantly in fluorescence and precipitation. (123)I-Hyp/Hyp in DMSO/PEG400/water exhibited high uptake in necrosis but lower concentration in the lung, spleen and liver (p < 0.01). Tumor volumes of 0.9 ± 0.3 cm(3) with high radioactivity (3.1 ± 0.3% ID/g) were detected 6 days post-treatment. By contrast, (131)I-Hyp/Hypin DMSO/saline showed low uptake in necrosis but high retention in the spleen and liver (p < 0.01). Tumor volumes reached 2.6 ± 0.7 cm(3) with low tracer accumulation (0.1 ± 0.04%ID/g). CONCLUSIONS: The formulation of radioiodinated hypericin/hypericin appears crucial for its physical property, biodistribution, necrosis avidity and tumoricidal effects.