A mesoporous polydopamine nanoparticle enables highly efficient manganese encapsulation for enhanced MRI-guided photothermal therapy.

Theranostic agents based on magnetic resonance imaging (MRI) and photothermal therapy (PTT) play an important role in tumor therapy. However, the available theranostic agents are facing great challenges such as biocompatibility, MRI contrast effect and photothermal conversion efficiency (η). In this work, mesoporous polydopamine nanoparticles (MPDAPs/Mn) were prepared on MRI and PTT combined theranostic nanoplatforms, of which the high loading manganese ions and specific surface areas enable good MRI contrast and excellent photothermal conversion efficiency, respectively. The MPDAPs/Mn have uniform morphology, good stability and biocompatibility. Meanwhile, in vitro and in vivo studies have confirmed their superior T1-weighted MRI effect and photothermal conversion efficiency. Furthermore, MPDAPs/Mn have excellent antitumor efficacy in HeLa tumor-bearing mice. Therefore, this developed MPDAPs/Mn theranostic nanoplatform could be a promising candidate for MRI-guided photothermal cancer therapy.

A room-temperature interfacial approach towards iron/nitrogen co-doped fibrous porous carbons as electrocatalysts for the oxygen reduction reaction and Zn-Air batteries.

The development of nonprecious and efficient catalysts to boost the oxygen reduction reaction (ORR) is imperative. However, the majority of previously reported approaches suffered from a complicated fabrication procedure, both time consuming and difficult to scale up. Herein, large-scale iron ion embedded polyaniline fibers were successfully fabricated as precursors for preparing iron/nitrogen co-doped fibrous porous carbons (Fe/NPCFs) through an interfacial engineering strategy at room temperature. As ORR electrocatalysts in an alkaline medium (0.1 M KOH), Fe/NPCFs display a positive half-wave potential of 0.827 V (vs. RHE), and high limited current density (up to 5.76 mA cm-2), which are better than those of commercial Pt/C (E1/2 = 0.815 V, JL = 5.47 mA cm-2). Also, Fe/NPCFs exhibit a high ORR catalysis activity (E1/2 = 0.632 V, JL = 5.07 mA cm-2) in acidic medium (0.5 M H2SO4). When used as an air cathode in a primary Zn-air battery, high power density (158.5 mW cm-2) and specific capacity (717.8 mA h g-1) can be easily achieved, outperforming the commercial Pt/C.

Nucleoside Analogue-Based Supramolecular Nanodrugs Driven by Molecular Recognition for Synergistic Cancer Therapy.

The utilization of nanotechnology for the delivery of a wide range of anticancer drugs has the potential to reduce adverse effects of free drugs and improve the anticancer efficacy. However, carrier materials and/or chemical modifications associated with drug delivery make it difficult for nanodrugs to achieve clinical translation and final Food and Drug Administration (FDA) approvals. We have discovered a molecular recognition strategy to directly assemble two FDA-approved small-molecule hydrophobic and hydrophilic anticancer drugs into well-defined, stable nanostructures with high and quantitative drug loading. Molecular dynamics simulations demonstrate that purine nucleoside analogue clofarabine and folate analogue raltitrexed can self-assemble into stable nanoparticles through molecular recognition. In vitro studies exemplify how the clofarabine:raltitrexed nanoparticles could greatly improve synergistic combination effects by arresting more G1 phase of the cell cycle and reducing intracellular deoxynucleotide pools. More importantly, the nanodrugs increase the blood retention half-life of the free drugs, improve accumulation of drugs in tumor sites, and promote the synergistic tumor suppression property in vivo.

Polysaccharide Nanoparticles for Targeted Cancer Therapies.

BACKGROUND: Despite extensive advances have been made in constructing polysaccharide-based nanomedicines for target cancer therapy due to their biocompatibility, easy-functionalizability and high targeting property, there is no review concentrating the significance of the intrinsic targeting properties of polysaccharides. This review mainly focuses on the recent progress on polysaccharide-based nanoparticles which have been applied in gene delivery, drug delivery and theranostics for targeted cancer therapies. Notably, representative polysaccharides with intrinsic targeting capability used as targeting ligand are well discussed. CONCLUSION: It has been found that polysaccharides have become a class of promising biopolymer carrier materials to deliver anti-cancer therapeutic molecules. Among all of polysaccharides, those who are with intrinsic properties of targeting are most frequently used. Therefore, this review revealed the importance of understanding the natural functions of polysaccharides to tailor nanocarrier platforms and ultimately surmount challenges in targeted cancer therapy.

"Bottom-Up" Fabrication of BODIPY-Functionalized Fluorescent Hyperbranched Glycopolymers for Hepatoma-Targeted Imaging.

A novel type of multivalent and highly specific fluorescent hyperbranched glycopolymers h-P(GalEA-co-VBPT-co-BYMA) (hPGVB) is designed and prepared successfully via a facile "bottom-up" strategy. The acetylated hPGVB is prepared by one-pot reversible addition-fragmentation chain transfer (RAFT) copolymerization of acrylate-type galactose monomers AcGalEA and methacrylate-type fluorescent monomers BYMA in presence of an inimer-type RAFT chain transfer agent. After deacetylation, the resulting amphiphilic hPGVB can self-assemble into stable nanoparticles in aqueous media, showing strong green fluorescence with relative high quantum yields and good photostability. The cell viability study indicates the excellent biocompatibility of the hPGVB fluorescent nanoparticles (FNPs) against HepG2 and NIH3T3 cells. More importantly, comparing with the galactose-free fluorescent hyperbranched polymers h-P(OEGMA-co-VBPT-co-BYMA), hPEVB FNPs can be selectively internalized by asialoglycoprotein (ASGP) receptor-rich HepG2 cells, indicating their potential application in the bioimaging fields.

A Crosslinked Nucleic Acid Nanogel for Effective siRNA Delivery and Antitumor Therapy.

Functional siRNAs are employed as cross-linkers to direct the self-assembly of DNA-grafted polycaprolactone (DNA-g-PCL) brushes to form spherical and nanosized hydrogels via nucleic acid hybridization in which small interfering RNAs (siRNAs) are fully embedded and protected for systemic delivery. Owing to the existence of multivalent mutual crosslinking events inside, the crosslinked nanogels with tunable size exhibit not only good thermostability, but also remarkable physiological stability that can resist the enzymatic degradation. As a novel siRNA delivery system with spherical nucleic acid (SNA) architecture, the crosslinked nanogels can assist the delivery of siRNAs into different cells without any transfection agents and achieve the gene silencing effectively both in vitro and in vivo, through which a significant inhibition of tumor growth is realized in the anticancer treatment.

Mustard-inspired delivery shuttle for enhanced blood-brain barrier penetration and effective drug delivery in glioma therapy.

Effective penetration through the blood-brain barrier (BBB) remains a challenge for the treatment of many brain diseases. In this study, a small molecule, sinapic acid (SA), extracted from mustard, was selected as a novel bioinspired BBB-permeable ligand for efficient drug delivery in glioma treatment. SA was conjugated on the surface of zwitterionic polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-encapsulated bovine serum albumin (BSA)-based nanoparticles, yielding nBSA-SA. The PMPC shell serves as a protective layer to prolong the in vivo blood circulation time with a better chance to cross the BBB. Furthermore, temozolomide (TMZ), which can be loaded onto the nanoparticles via electrostatic interactions with acrylic acid (AA) to generate AA-nBSA-SA-TMZ, was applied as an excellent chemotherapeutic drug for glioma therapy. The obtained nanoparticles with a distinct size show great BBB permeability. Through the mechanism study, it was found that the cell internalization of the SA-conjugated nanoparticles is an energy-dependent process with only transient disruption of the BBB. The biological evaluation results unambiguously suggest that drug-loaded nanoparticles can lead to strong apoptosis on the tumor site and increase the median survival time of glioma-bearing mice. Overall, this novel BBB-permeable ligand SA paves the way for the delivery of cargo into the brain and provides a powerful nanoplatform for glioma therapy via intravenous administration.

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.

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.

Aptamer-Functionalized and Backbone Redox-Responsive Hyperbranched Polymer for Targeted Drug Delivery in Cancer Therapy.

A novel type of backbone redox-responsive hyperbranched poly(2-((2-(acryloyloxy)ethyl)disulfanyl)ethyl 4-cyano-4-(((propylthio)carbonothioyl)-thio)-pentanoate-co-poly(ethylene glycol) methacrylate) (HPAEG) has been designed and prepared successfully via the combination of reversible addition-fragmentation chain-transfer (RAFT) polymerization and self-condensing vinyl polymerization (SCVP). Owing to the existence of surface vinyl groups, HPAEG could be efficiently functionalized by DNA aptamer AS1411 via Michael addition reaction to obtain an active tumor targeting drug delivery carrier (HPAEG-AS1411). The amphiphilic HPAEG-AS1411 could form nanoparticles by macromolecular self-assembly strategy. Cell Counting Kit-8 (CCK-8) assay illustrated that HPAEG-AS1411 nanoparticles had low cytotoxicity to normal cell line. Flow cytometry and confocal laser scanning microscopy (CLSM) results demonstrated that HPAEG-AS1411 nanoparticles could be internalized into tumor cells via aptamer-mediated endocytosis. Compared with pure HPAEG nanoparticles, HPAEG-AS1411 nanoparticles displayed enhanced tumor cell uptake. When the HPAEG-AS1411 nanoparticles loaded with anticancer drug doxorubicin (DOX) were internalized into tumor cells, the disulfide bonds in the backbone of HPAEG-AS1411 were cleaved by glutathione (GSH) in the cytoplasm, so that DOX was released rapidly. Therefore, DOX-loaded HPAEG-AS1411 nanoparticles exhibited a high tumor cellular proliferation inhibition rate and low cytotoxicity to normal cells. This aptamer-functionalized and backbone redox-responsive hyperbranched polymer provides a promising platform for targeted drug delivery in cancer therapy.

Real-time monitoring of anticancer drug release with highly fluorescent star-conjugated copolymer as a drug carrier.

Chemotherapy is one of the major systemic treatments for cancer, in which the drug release kinetics is a key factor for drug delivery. In the present work, a versatile fluorescence-based real-time monitoring system for intracellular drug release has been developed. First, two kinds of star-conjugated copolymers with different connections (e.g., pH-responsive acylhydrazone and stable ether) between a hyperbranched conjugated polymer (HCP) core and many linear poly(ethylene glycol) (PEG) arms were synthesized. Owing to the amphiphilic three-dimensional architecture, the star-conjugated copolymers could self-assemble into multimicelle aggregates from unimolecular micelles with excellent emission performance in the aqueous medium. When doxorubicin (DOX) as a model drug was encapsulated into copolymer micelles, the emission of star-conjugated copolymer and DOX was quenched. In vitro biological studies revealed that fluorescent intensities of both star-conjugated copolymer and DOX were activated when the drug was released from copolymeric micelles, resulting in the enhanced cellular proliferation inhibition against cancer cells. Importantly, pH-responsive feature of the star-conjugated copolymer with acylhydrazone linkage exhibited accelerated DOX release at a mildly acidic environment, because of the fast breakage of acylhydrazone in endosome or lysosome of tumor cells. Such fluorescent star-conjugated copolymers may open up new perspectives to real-time study of drug release kinetics of polymeric drug delivery systems for cancer therapy.

Low temperature and template-free synthesis of hollow hydroxy zinc phosphate nanospheres and their application in drug delivery.

Hollow hydroxy zinc phosphate nanospheres (HZnPNSs) with sizes of 30-50 nm and wall thicknesses of about 7 nm were synthesized using a template-free method through wet precipitation of Zn(NO3)2·6H2O and (NH4)2HPO4 at temperatures of 0, 10, and 20 °C. The crystal structures, morphologies, sizes and pore properties, Zn/P molar ratios, and thermal stability properties of nanoparticles have been carefully examined. The methyl-thiotetrazole assay measurements proved the low cell cytotoxicity of the material. The protein adsorption of negatively charged bovine serum albumin (BSA) and positively charged lysozyme on HZnPNSs was also investigated. The results showed that HZnPNSs had high protein adsorption affinity. Furthermore, anticancer doxorubicin as a model drug was used to evaluate the entrapment efficiency and drug loading capacity of HZnPNSs, which showed high loading capacity (>16 wt %) for doxorubicin. The confocal laser scanning microscope observations showed that the drug could be efficiently delivered into cells.

Preparation of pixantrone/poly(γ-glutamic acid) nanoparticles through complex self-assembly for oral chemotherapy.

A facile and green approach is reported to construct pixantrone/poly(γ-glutamic acid) nanoparticles (PIX/γ-PGA NPs) as an oral drug delivery system through the complex self-assembly of polyelectrolyte γ-PGA and the anticancer drug pixantrone dimaleate (PDM). The complex self-assembly behavior is investigated in detail. The results demonstrate that PDM can interact with γ-PGA to conveniently form NPs and the size of NPs can be controlled by adjusting the solution volume ratio of PDM to γ-PGA. These NPs illustrate their pH-dependent release behavior, efficient cellular uptake and enhanced drug efficacy through an in vitro release study, flow cytometry, CLSM analysis and the MTT assay. In summary, PIX/γ-PGA NPs may serve as a promising oral drug delivery system for cancer therapy.

Oxime linkage: a robust tool for the design of pH-sensitive polymeric drug carriers.

Oxime bonds dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their own niche. In the present work, oxime linkages were confirmed to be a robust tool for the design of pH-sensitive polymeric drug delivery systems. The triblock copolymer (PEG-OPCL-PEG) consisting of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic oxime-tethered polycaprolactone (OPCL) was successfully prepared by aminooxy terminals of OPCL ligating with aldehyde-terminated PEG (PEG-CHO). Owing to its amphiphilic architecture, PEG-OPCL-PEG self-assembled into the micelles in aqueous media, validated by the measurement of critical micelle concentration (CMC). The MTT assay showed that PEG-OPCL-PEG exhibited low cytotoxicity against NIH/3T3 normal cells. Doxorubicin (DOX) as a model drug was encapsulated into the PEG-OPCL-PEG micelles. Drug release study revealed that the DOX release from micelles was significantly accelerated at mildly acid pH of 5.0 compared to physiological pH of 7.4, suggesting the pH-responsive feature of the drug delivery systems with oxime linkages. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements indicated that these DOX-loaded micelles were easily internalized by living cells. MTT assay against HeLa cancer cells showed DOX-loaded PEG-OPCL-PEG micelles had a high anticancer efficacy. All of these results demonstrate that these polymeric micelles self-assembled from oxime-tethered block copolymers are promising carriers for the pH-triggered intracellular delivery of hydrophobic anticancer drugs.