Hybride nanoparticles composed of SN38-modified [12]aneN and biotinylated lipids for targeted and synergistic lung Cancer therapy.

The combination of chemo- and gene-therapy for lung cancer therapy has attracted continuous attention due to its high synergistic therapeutic efficiency. Here, three novel esterase-responsive prodrug-based amphiphiles, SCN1 ∼ SCN3, composed of 7-ethyl-10-hydroxycamptothecin (SN38, S) and di-(triazole-[12]aneN, N) moiety through different length of carbon chain (C, 5, 7, 11‑carbon alkyl chains, respectively) were designed and synthesized. The amphiphiles displayed excellent self-assembly capabilities and the ability to effectively condense and release siRNA, and SCN2 showed the most effective in inhibiting proliferation of A549 cells.

Multifunctional System with Camptothecin and [12]aneN Units for Effective Anti Pancreatic Cancer through Synergistic Chemotherapy, Gene Therapy, and Photodynamic Therapy.

Maximizing drug cargo carrying capacity in blood circulation, controlling the fate of nanoparticles, and precisely drug release to tumor targets are the main aims of multifunctional nanomedicine-based antitumor therapy. Here we combined macrocyclic polyamine di(triazole-[12]aneN) () and chemical drug camptothecin (CPT, ) through photosensitizer 1,1-dicyano-2-phenyl-2-(4-diphenylamino) phenyl-ethylene () containing the cleavable disulfide () linkage as an all-in-one theranostic nanoprodrug, . The corresponding compound with carbon chain () linkage, , was also prepared for a comparison study.

Codelivery of CPT and siPHB1 with GSH/ROS Dual-Responsive Hybrid Nanoparticles Based on a [12]aneN-Derived Lipid for Synergistic Lung Cancer Therapy.

The combination of small-interfering RNA (siRNA)-mediated gene silencing and chemotherapeutic agents for lung cancer treatment has attracted widespread attention in terms of a greater therapeutic effect, minimization of systemic toxicity, and inhibition of multiple drug resistance (MDR). In this work, three amphiphiles, -, were first designed and synthesized as a camptothecin (CPT) conjugate and gene condensation agents by the combination of CPT prodrugs and di(triazole-[12]aneN) through the ROS-responsive phenylborate ester and different lengths of alkyl chains (with 6, 9, 12 carbon chains for -, respectively). - were able to be self-assembled into liposomes with an average diameter in the range of 320-240 nm, showing the ability to effectively condense siRNA.

[12]aneN-modified camptothecin and PEGylated AIEgens co-assembly into core-shell nanoparticles with ROS/NTR dual-response for enhanced cancer therapy.

A novel dual-responsive nanoparticle (NP) system was aimed to be developed for the co-delivery of camptothecin (CPT) and plasmid encoding TNF-related apoptosis-inducing ligand (pTRAIL) DNA in cancer therapy. The combination of the prodrug CPT and the nucleic acid condensing di-(triazole-[12]aneN3) unit with 4-nitrobenzyl ester through alkyl chains resulted in three nitroreductase (NTR) responsive amphiphiles, CNN1-CNN3 (with 5, 8, and 11 carbon chains, respectively). Among them, CNN2 was the most effective in inhibiting the proliferation of HeLa cells in the presence of fusogenic lipid DOPE.

Esterase-Responsive Polymeric Micelles Containing Tetraphenylethene and Poly(ethylene glycol) Moieties for Efficient Doxorubicin Delivery and Tumor Therapy.

Enzyme-responsive drug delivery systems have drawn much attention in the field of cancer theranostics due to their high sensitivity and substrate specificity under mild conditions. In this study, an amphiphilic polymer is reported, which contains a tetraphenylethene unit and a poly(ethylene glycol) chain linked by an esterase-responsive phenolic ester bond. In aqueous solution, formed stable micelles via self-assembly, which showed an aggregation-induced emission enhancement of 32-fold at 532 nm and a critical micelle concentration of 0.

Red fluorescent AIEgens based multifunctional nonviral gene vectors for the efficient combination of gene therapy and photodynamic therapy in anti-cancer.

Precise molecular engineering of AIEgens-based cationic delivery systems for high transfection efficiency (TE) and effective photodynamic therapy (PDT) holds a huge potential for cancer treatment. Herein, three amphiphiles (DT-C-M) consisting of di(triazole-[12]aneN) (M) and 1,1-dicyano-2-phenyl-2-(4-diphenylamino)phenyl-ethylene (DT) units have been developed to achieve luminescent tracking, efficient TE, and effective PDT in vitro and in vivo. These compounds exhibited strong aggregated induced emission (AIE) at 630 nm and mega Stokes shifts of up to 160 nm.

[12]aneN-Conjugated AIEgens with two-photon imaging properties for synergistic gene/photodynamic therapy and .

Six amphiphiles (TTC-L-M-1/2/3/4/5/6), each consisting of hydrophilic macrocyclic polyamine triazole-[12]aneN (M) and a hydrophobic photosensitizer tetraphenylethenethiophene modified cyanoacrylate (TTC) moiety linked with alkyl chains (L), have been designed and synthesized for synergetic anticancer gene therapy and photodynamic therapy (PDT). These amphiphiles showed strong AIE fluorescence emissions around 600 nm with large Stokes shifts up to 168 nm in an aqueous solution. They were able to condense DNA into nanoparticles with appropriate sizes, positive charges, reversible release, and good biocompatibility.

HO-Responsive amphiphilic polymer with aggregation-induced emission (AIE) for DOX delivery and tumor therapy.

Stimuli-responsive drug delivery systems (DDSs) based on amphiphilic polymers have attracted much attention. In this study, we reported an innovative HO-responsive amphiphilic polymer (TBP), bearing a HO-sensitive phenylboronic ester, AIE fluorophore tetraphenylethene (TPE) hydrophobic, and polyethylene glycol hydrophilic (PEG) moieties. TBP could self-assemble into micelles with an encapsulation efficiency as high as 74.

Degradable cationic polyesters via ring-opening copolymerization of valerolactones as nanocarriers for the gene delivery.

The development of cationic polymers as non-viral gene vectors has been hurdled by their high toxicity, thus degradable and biocompatible polymers are urgently demanded. Herein, five polyesters (B3a-B3e) were synthesized based on the ring-opening copolymerization between α-allyl-δ-valerolactone and δ-valerolactone derivatives decorated with alkyl or alkoxyl chains of different lengths, followed by the modification with 1,5,9-triazacyclododecyl ([12]aneN) through thiol-ene click reactions. The five polyesters effectively condensed DNA into nanoparticles.

Integration of [12]aneN3 and Acenaphtho[1,2-b]quinoxaline as non-viral gene vectors with two-photon property for enhanced DNA/siRNA delivery and bioimaging.

Two-photon fluorescent Acenaphtho[1,2-b]quinoxaline (ANQ) and the hydrophilic di-(triazole-[12]aneN) moieties were combined through an alkyl chain (ANQ-A-M) or a β-hairpin motif with two aromatic γ-amino acid residues (ANQ-H-M) to explore their capabilities for in vitro and in vivo gene delivery and tracing. ANQ-A-M and ANQ-H-M showed the same maximum absorption at 420 nm, and their fluorescent intensities around 650 nm were varied in different solvents and became poor in the protic solvents. Gel electrophoresis assays indicated that both compounds completely retarded the migration of pDNA at 20 μM in the presence of DOPE.

Two-Photon Near-Infrared AIE Luminogens as Multifunctional Gene Carriers for Cancer Theranostics.

Construction of multifunctional nonviral gene vectors to execute defined tasks holds great potential for the precise and effective treatment of gene-associated diseases. Herein, we have developed four large π-conjugation triphenylamine derivatives bearing two polar [12]aneN heads and a lipophilic tail for applications in gene delivery, one/two-photon-triggered near-infrared (NIR) fluorescence bioimaging, and combined photodynamic therapy (PDT) and gene therapy of cancer. These compounds possess typical NIR aggregation-induced emission characteristics, mega Stokes shifts, strong two-photon excitation fluorescence, and excellent DNA condensation abilities.

Macrocyclic polyamine [12]aneN modified triphenylamine-pyrazine derivatives as efficient non-viral gene vectors with AIE and two-photon imaging properties.

With the aim to develop a novel multifunctional gene delivery system that may overcome the common barriers of gene transfection, near-infrared fluorescent triphenylamine-pyrazine was modified with a DNA condensing triazole-[12]aneN3 moiety through different length alkyl ester linkages to afford three new non-viral gene vectors, TDM-A/B/C. All compounds showed prominent solvatochromic fluorescence (Stokes shift of up to 383 nm) and two-photon absorption properties (σ2P to 101 GM), and exhibited strong aggregation-induced emission (AIE). Gel electrophoresis demonstrated that plasmid DNA was completely condensed at a concentration of 10 μM (TDM-A), 14 μM (TDM-B) and 16 μM (TDM-C), and released in esterase and acidic environment.

Synthesis of Glutathione (GSH)-Responsive Amphiphilic Duplexes and their Application in Gene Delivery.

Oligoamide molecular strands with hydrogen-bonding sequences DADDAD and guanidine (O-1) or 1,5,9-triazacyclododecane ([12]aneN ; O-2) side chains and oligoamides with hydrogen-bonding sequences ADAADA and octyl moieties (O-3), were synthesized. Two duplexes (D-1 and D-2) were prepared by conjugating the hydrophilic O-1 or O-2 and hydrophobic O-3 through sequence-specific hydrogen-bond association and cross-linked disulfide bonds. Electrophoresis measurements indicated that O-1, O-2, D-1, and D-2 were able to completely retard the DNA mobiliy at concentrations of 30, 30, 10, and 20 μM, respectively.

Combination of [12]aneN and Triphenylamine-Benzylideneimidazolone as Nonviral Gene Vectors with Two-Photon and AIE Properties.

Three nonviral gene vectors, //, have been designed and synthesized by the combination of one or two hydrophilic [12]aneN moieties and two-photon fluorescent triphenylamine-benzylideneimidazolone (TPA-BI) units through different ester linkage. Spectroscopic characterization demonstrated that // had strong aggregation-induced emissions (AIE), large Stokes shifts (230, 284, and 263 nm), and large two-photon absorption cross sections (δ) (67, 592, and 80 GM). Gel electrophoresis indicated that the three compounds completely condensed DNA at 15 μM in the presence of DOPE, and showed the lipase- and pH-triggered reversible release of DNA and the fluorescent recognition of the different lengths of ssDNA and dsDNA.

HO-responsive polymeric micelles with a benzil moiety for efficient DOX delivery and AIE imaging.

Nano drug delivery is a promising domain in biomedical theranostics and has aroused more and more attention in recent years. We report here an amphiphilic polymer TPG1, bearing a H2O2-sensitive benzil and an AIE fluorophore tetraphenylethene (TPE) unit, which is able to self-assemble into spherical nanosized micelles in aqueous solution. Doxorubicin (DOX) can be encapsulated into TPG1 micelles efficiently with the loading capability of up to 59% by weight.

Dihydropyridine-derived BODIPY probe for detecting exogenous and endogenous nitric oxide in mitochondria.

A mitochondria-targetable probe Mito-DHP for nitric oxide (NO) was designed and synthesized by introducing dihydropyridine and triphenylphosphonium (TPP) moieties into boron dipyrromethene (BODIPY) dye. Mito-DHP was able to effectively detect nitric oxide through the aromatization of dihydropyridine to fluorescent pyridine product under oxygen-free conditions. The probe Mito-DHP showed high selectivity to NO over a number of reactive oxygen/nitrogen species (ROS/RNS) as well as high sensitivity (detection limit at 25nM), pH stability and bio-compatibility.

Helical Folding of Meta-Connected Aromatic Oligoureas.

Aromatic oligoureas composed of meta-linked residues bearing phenolic ether side chains are synthesized. The basic N,N'-diarylurea units adopt a trans,trans intramolecularly H-bonded conformation that is further strengthened by additional intermolecular H-bonding. Such basic units, in combination with meta-linked benzene residues, result in stably folded helical oligoureas in the highly polar DMF with up to four turns and with a small cylindrical inner pore that would be difficult to acquire.

NO-Responsive vesicles as a drug delivery system.

A rationally designed amphiphile containing a hydrophobic Hantzsch ester and a hydrophilic phosphate ester was able to form vesicles in aqueous solution, and resulted in the first example of a NO-responsive drug delivery system.