Bingran Yu

Multifunctional polycationic photosensitizer conjugates with rich hydroxyl groups for versatile water-soluble photodynamic therapy nanoplatforms

Photodynamic therapy (PDT) has already shown immense potential in antitumor fields due to its low systemic toxicity and negligible drug resistance. However, the clinical application of current photosensitizers is still restricted by the low singlet oxygen yield or insolubility. Herein, series of star-like hydroxyl-rich polycations (Pc-PGEA/Pc) with flanking phthalocyanine (Pc) were proposed for effective water-soluble photosensitizers. The designed Pc-PGEA/Pc polymers consist of one Pc core and four ethanolamine and Pc-difunctionalized poly(glycidyl methacrylate) arms. The strong π-π stacking and hydrophobicity of introduced Pc units drive the amphipathic Pc-PGEA/Pc polymers to self-assemble into well-defined cationic nanoparticles. Such Pc-PGEA/Pc nanoparticles present impressive photodynamic therapy effects under moderate irradiation and remarkable photoacoustic imaging (PAI) ability. These kinds of nanoparticles also exhibit good performance as gene vectors. The PAI ability given by the proper wavelength absorbance of Pc units provides one promising method for PAI-guided combined antitumor therapy. The present work would contribute valuable information for the development of new strategies of visible antitumor therapy.

PGMA-based supramolecular hyperbranched polycations for gene delivery

Supramolecular chemistry has been widely applied in biomedical fields. It was reported that the topological structure has effects on the performance of gene delivery systems. Supramolecular polymer-like gene carriers with hyperbranched topological structures have still not been reported. In this work, a series of ethanolamine-functionalized polyglycidyl methacrylate (PGMA)-armed AB2 type macromonomers were synthesized based on atom transfer radical polymerization. The AB2 type macromonomers can self-assemble into supramolecular hyperbranched polymers by the host–guest interaction between adamantane and β-cyclodextrin. The biophysical properties of self-assembled and dissembled supramolecular hyperbranched polycations were evaluated in detail. The self-assembled supramolecular polycations with hyperbranched structures possessed higher pDNA condensation ability and much better gene transfection performances than the dissembled AB2 type counterparts. The present work would provide a new venue for designing advanced high-performance supramolecular hyperbranched nucleic acid-delivery systems.

Bioreducible Comb-Shaped Conjugates Composed of Secondary Amine and Hydroxyl Group-Containing Backbones and Disulfide-Linked Side Chains with Tertiary Amine Groups for Facilitating Gene Delivery

Comb-shaped polymeric vectors (SS-PGEADMs) consisting of ethanolamine/cystamine-functionalized poly(glycidyl methacrylate) (SS-PGEA-NH2) backbones and bioreducible poly((2-dimethyl amino)ethyl methacrylate) (PDMEAMA) side chains were prepared by a combination of the ring-opening reaction and atom transfer radical polymerization (ATRP). The SS-PGEA-NH2 backbones, which were prepared via the ring-opening reaction of the pendant epoxide groups of poly(glycidyl methacrylate) with the amine moieties of ethanolamine/cystamine, possess plentiful flanking secondary amine and hydroxyl groups and some flanking disulfide bond-containing cystamine derivatives. The primary amine groups of the cystamine derivatives were activated to produce bromoisobutylryl-terminated SS-PGEA (SS-PGEA-Br) as multifunctional initiators for subsequent ATRP of DMAEMA. The resultant disulfide-linked short PDMEAMA side chains possess pendant tertiary amine groups and are biocleavable. Such SS-PGEADMs can effectively condense pDNA. The cytotoxicity of SS-PGEADMs could be controlled by adjusting the grafting amount of PDMEAMA side chains. In comparison with the pristine SS-PGEA-NH2, the moderate introduction of PDMEAMA side chains can further enhance the gene transfection efficiency in different cell lines. The present approach to well-defined comb-shaped vectors with multifunctional groups could provide a versatile means for tailoring the functional structures of advanced gene/drug vectors.

Multiple types of hydroxyl-rich cationic derivatives of PGMA for broad-spectrum antibacterial and antifouling coatings

The development of new antibacterial materials is a constant demand in the manufacturing of personal hygiene products and medical implements. The inhibition of bacterial adhesion onto surfaces is very challenging, and adhesion may cause secondary infection. In this study, we synthesize multiple types of hydroxyl-rich cationic derivatives via a ring-opening reaction of a star-like poly(glycidyl methacrylate) (s-PGMA) for broad-spectrum antibacterial and antifouling coatings. The derivatives containing tertiary amine groups are subsequently quaternized to produce poly(quaternary ammonium). The quaternary and silver-loaded derivatives exhibit potent and broad-spectrum antibacterial activities towards both Gram-negative and Gram-positive bacteria. Particularly, some of the silver-loaded derivatives show a 64-fold improvement in antibacterial activity toward P. aeruginosa compared to their non-silver counterparts, due to the synergistic actions of quaternary ammonium components and silver ions. Moreover, the antibacterial derivatives can be readily coated on substrates such as glass slides via an adhesive layer of polydopamine. The resultant antibacterial coatings with rich hydroxyl groups also endow antifouling capability against killed bacteria, while the release and diffusion of silver ions from the silver-loaded polymer coatings enable the long-range antibacterial abilities. This study offers a new approach for synthesizing effective antibacterial and antifouling coatings that possess promising applications on biomedical devices.

Functionalized PGMA nanoparticles with aggregation-induced emission characteristics for gene delivery systems

Cationic polymers are considered as potential gene carriers due to their intrinsic ability to compact pDNA. Generally, cationic vectors lack the abilities of long-term tracking and real-time imaging. Ethanolamine (EA)-functionalized poly(glycidyl methacrylate) (PGMA), namely BUCT-PGEA, has recently been reported as an effective gene carrier because of its low cytotoxicity and good transfection efficiency. In this work, a series of well-defined star-like PGMA-based cationic vectors (TPE-PGEA/TPE) with plenty of flanking hydrophobic fluorophore tetraphenylethene (TPE) groups was proposed for the development of efficient multifunctional gene delivery systems. TPE-PGEA/TPE polymers could self-assemble into cationic nanoparticles, show bright cyan fluorescence in aqueous media and display aggregation-induced emission phenomena. Compared with TPE-PGEA, TPE-PGEA/TPE nanoparticles had a largely improved transfection performance. In addition, such nanoparticles also possessed the property of real-time imaging, which can help to understand the mechanism of intracellular behavior.

Luminescent detection of the lipopolysaccharide endotoxin and rapid discrimination of bacterial pathogens using cationic platinum(II) complexes

A luminescence probe based on chloroplatinum(II) complexes of 2,6-bis(benzimidazol-2′-yl)pyridine with hexaethylene glycol methyl ether groups ([Pt(N^N^N)Cl]+) was reported for sensing of the lipopolysaccharide (LPS) endotoxin and rapid discrimination of Gram-negative and Gram-positive bacterial pathogens. [Pt(N^N^N)Cl]+ can be dissolved in aqueous solution with minimal luminescence emission. In the presence of LPS, [Pt(N^N^N)Cl]+ binds to negatively charged LPS to form LPS–Pt(II) aggregates. The formation of LPS–Pt(II) aggregates enhances the intermolecular Pt⋯Pt and π–π stacking interactions, and consequently leads to luminescence emission centered at 650 nm due to triplet metal-to-metal-to-ligand charge-transfer (3MMLCT). The limit of detection (LOD) of LPS is 5.7 nM. We also demonstrate a proof-of-concept application of [Pt(N^N^N)Cl]+ for rapid and washing-free discrimination of Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus within 5 min. The above features of [Pt(N^N^N)Cl]+ make it a promising sensor for clinical applications in the detection of endotoxins and discrimination of bacterial pathogens.

Antimicrobial and Antifouling Polymeric Agents for Surface Functionalization of Medical Implants

Combating implant-associated infections is an urgent demand due to the increasing numbers in surgical operations such as joint replacements and dental implantations. Surface functionalization of implantable medical devices with polymeric antimicrobial and antifouling agents is an efficient strategy to prevent bacterial fouling and associated infections. In this work, antimicrobial and antifouling branched polymeric agents (GPEG and GEG) were synthesized via ring-opening reaction involving gentamicin and ethylene glycol species. Due to their rich primary amine groups, they can be readily coated on the polydopamine-modified implant (such as titanium) surfaces. The resultant surface coatings of Ti-GPEG and Ti-GEG produce excellent in vitro antibacterial efficacy toward both Staphylococcus aureus and Escherichia coli, while Ti-GPEG exhibit better antifouling ability. Moreover, the infection model with S. aureus shows that implanted Ti-GPEG possessed excellent antibacterial and antifouling ability in vivo. This study would provide a promising strategy for the surface functionalization of implantable medical devices to prevent implant-associated infections.

Flexible Cationic Nanoparticles with Photosensitizer Cores for Multifunctional Biomedical Applications

One challenge for multimodal therapy is to develop appropriate multifunctional agents to meet the requirements of potential applications. Photodynamic therapy (PDT) is proven to be an effective way to treat cancers. Diverse polycations, such as ethylenediamine-functionalized poly(glycidyl methacrylate) (PGED) with plentiful primary amines, secondary amines, and hydroxyl groups, demonstrate good gene transfection performances. Herein, a series of multifunctional cationic nanoparticles (PRP) consisting of photosensitizer cores and PGED shells are readily developed through simple dopamine-involving processes for versatile bioapplications. A series of experiments demonstrates that PRP nanoparticles are able to effectively mediate gene delivery in different cell lines. PRP nanoparticles are further validated to possess remarkable capability of combined PDT and gene therapy for complementary tumor treatment. In addition, because of their high dispersities in biological matrix, the PRP nanoparticles can also be used for in vitro and in vivo imaging with minimal aggregation-caused quenching. Therefore, such flexible nanoplatforms with photosensitizer cores and polycationic shells are very promising for multimodal tumor therapy with high efficacy.

Fluorinated Acid-Labile Branched Hydroxyl-Rich Nanosystems for Flexible and Robust Delivery of Plasmids

Nucleic acid-based therapy specially needs a safe and robust delivery vector. Herein, a novel fluorinated acid-labile branched hydroxyl-rich polycation (ARP-F) is proposed for the flexible and effective delivery nanovector of different plasmids including reporter genes and the Cas9 plasmid. Acid-responsive polycation (ARP) with plentiful ortho ester linkages and hydroxyl groups is first synthesized via a facile one-pot ring-opening polymerization, followed by decoration of fluorinated alkyl chains onto ARP to achieve ARP-F. ARP-F possesses good pH-responsive degradability, biocompatibility, and its preliminary transfection ability evaluated by reporter plasmids pRL-CMV (encoding Renilla luciferase) and pEGFP-N1 (encoding enhanced green fluorescent protein) is also excellent. CRISPR-Cas9 (clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9) technology is a potent genome-editing tool. The subsequent delivery of pCas9-surv (one typical all-in-one Cas9 plasmid) mediated by ARP-F exhibits impressive in vitro and in vivo tumor inhibition performances. In addition, the combination of ARP-F/pCas9-surv with temozolomide could further enhance tumor inhibition activities by increasing the sensitivity of cancer cells to anticancer drugs. Such high-performance polycation would provide a very promising means to produce efficient delivery nanovectors of versatile plasmids.

Unlockable Nanocomplexes with Self-Accelerating Nucleic Acid Release for Effective Staged Gene Therapy of Cardiovascular Diseases

Nucleic acid (NA)-based therapy is proposed to address serious diseases such as cardiovascular diseases (CVDs). Powerful NA delivery vehicles are essential for effective gene therapy. Herein, a novel type of delivery vehicle, an unlockable core-shell nanocomplex (Hep@PGEA) with self-accelerating NA release, is structurally designed. Hep@PGEA is composed of disulfide-bridged heparin nanoparticle (HepNP) core and low-toxicity PGEA cationic shell. In comparison with NA, heparin, a negatively charged polysaccharide macromolecule, exhibits stronger interactions with cationic species. Upon the breakdown of redox-responsive HepNP cores, unlocked heparin would interact with the outer cationic shells and replace the condensed NA to facilitate NA release. Such unique Hep@PGEA is successfully explored for effective miRNA-pDNA staged gene therapy of myocardial infarction (MI), one of the most serious CVDs. With the progression of MI, glutathione amounts in heart tissues increase. MiR-499 (for the inhibition of cardiomyocyte apoptosis) and plasmid encoding vascular endothelial growth factor (for the promotion of angiogenesis) are sequentially delivered for systemic treatment of MI. Such treatment produces impressive results in restoring heart function and suppressing cardiac hypertrophy. Due to the wide existence of redox agents in cells, the proposed unlockable delivery nanovehicle and staged therapy strategy can provide new methods to effectively treat different serious diseases.