Hongmei Li

Synthesis, characterization and in vitro anticancer activity of the biomolecule-based coordination complex nanotubes

Biomolecule-based coordination complex nanoassemblies are a new type of functional materials that are attracting increasing attention. They could possess functionalities that are not readily attainable with other materials, and represent a promising research area that can be exploited in coordination chemistry and materials science. Using bioactive folic acid molecule as a linker, Ni-folate-hydrazine coordination complex nanotubes (CCNTs) have been effectively constructed using the solvothermal method. This is not only the first example of the CCNTs being formed using a nonpyridyl-based molecule as a linker, but also the first report on biomolecule-based CCNTs (BMB-CCNTs) with anticancer activity. It does not require any post treatment to achieve targeted delivery and biocompatible performance. The BMB-CCNTs are sufficiently stable at normal pH of 7.4 until it enters a tumor cell, subsequently it breaks open to release drug in the tumor cell. Furthermore, it overcomes the major limitations of antibody-drug and folate-drug conjugates and is a potential smart multi-functional nanomedicine system. The results of in vitro cytotoxicity assay reveal that the antitumor ability of BMB-CCNTs is similar to cisplatin (CDDP), while their cytotoxicity for normal cells is lower than the latter. Furthermore, BMB-CCNTs exhibit excellent performance as drug carriers and target agents for delivering drugs into tumor cells. Bio-TEM and confocal laser scanning microscope images trace the uptake process of CDDP-CCNTs by a tumor cell. CDDP-CCNTs exhibit dual anti-cancer effect.

A pH-sensitive nanocarrier for co-delivery of doxorubicin and camptothecin to enhance chemotherapeutic efficacy and overcome multidrug resistance in vitro

To deliver chemotherapeutic drugs simultaneously, using drug carriers is a feasible strategy for a better synergetic effect. We have constructed hollow silica nanoparticles (HSNPs) sealed with ZnO quantum dots (QDs) as a pH-sensitive nanocarrier, where the HSNPs have large hollow interiors for delivering hydrophobic camptothecin (CPT) and a mesoporous structure for delivering hydrophilic doxorubicin (DOX·HCl). This cooperative drug loading has largely increased the drug encapsulation efficiency of both CPT and DOX up to 89.28% and 44.98%, respectively. Meanwhile, the ZnO QD lids in this drug delivery system are found to be rapidly dissolved in the acidic intracellular compartments to trigger pH-sensitive drug release. The co-delivery of multi-drugs with different anticancer mechanisms in the same nanocarrier enables the intracellular release of the drug combinations to greatly enhance chemotherapeutic efficacy and overcome multidrug resistance (MDR).

Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors.

The bromodomain protein module and histone deacetylase (HDAC), which recognize and remove acetylated lysine, respectively, have emerged as important epigenetic therapeutic targets in cancer treatments. Herein we presented a novel design approach for cancer drug development by combination of bromodomain and HDAC inhibitory activity in one molecule. The designed compounds were synthesized which showed inhibitory activity against bromodomain 4 and HDAC1. The representative dual bromodomain/HDAC inhibitors, compound 11 and 12, showed potent antiproliferative activities against human leukaemia cell line K562 and MV4-11 in cellular assays. This work may lay the foundation for developing dual bromodomain/HDAC inhibitors as potential anticancer therapeutics.

An efficient gold nanocarrier for combined chemo-photodynamic therapy on tumour cells

A multimodal nanocarrier based on mesoporous silica coated gold nanoparticles (Au@mSiO2) is developed for effective cancer treatment in vitro. Through introducing octadecyltrimethoxysilane (C18TMS) as a porogen, the porosity of silica shells can be well controlled. The mesoporous silica offers high loading capacity for photosensitizer chlorin e6 (Ce6), thus improving the efficacy of singlet oxygen generation after the cellular uptake to achieve photodynamic therapy. Besides, Au@mSiO2 with high surface area can also be used as a chemotherapy drug carrier to load doxorubicin (DOX). Hence, the Au@mSiO2 nanocarrier combines photodynamic- and chemo-therapy together through simultaneously loading different types of therapeutic agents, Ce6 and DOX, which show obvious synergistic cancer cell killing effects. Therefore, this Au@mSiO2 nanocarrier would exhibit inspiring potential for cancer combination therapy.

An Integrative Folate-Based Metal Complex Nanotube as a Potent Antitumor Nanomedicine as Well as an Efficient Tumor-Targeted Drug Carrier

Metal-organic complexes (MOCs) are emerging developing functional materials, the different categories of metal ions and organic biomolecules provide great possibilities for the morphologies, sizes, and properties of the products. Enlightened by the previous works of folate-nickel nanotubes (FA-Ni NTs), herein, a series of metal ions are tested to coordinate with folate (FA) by the solvothermal method, among which the folate-cobalt(II) complex is formed to be a scaffold for the nanotube with the length of 150-500 nm and inner diameter of 6-11 nm, while the other metal ions fail. In vitro experiments reveal that folate-cobalt nanotubes (FA-Co NTs) have excellent antitumor activity toward tumor cells with high expression levels of folate receptor (FR), whereas they show extremely low toxicity to normal cells. Furthermore, these kinds of NTs show better antitumor ability when the anticancer drug doxorubicin is encapsulated through cell surface receptor-mediated endocytosis. Moreover, we study the fundamental pharmacokinetic profiles and biodistribution of FA-Co NTs on mice and also prove its targeting capability to tumor tissues on tumor-bearing mice using the radioactive iodine-131 (131I) tracing method. FA-Co NTs can also markedly inhibit the growth of tumor with minimal side effects when administered individually in vivo. These findings will expand the research on FA based metal complex nanomaterials as a kind of potential antitumor nanomedicine as well as a targeted drug carrier.

Discovery of the selective and efficacious inhibitors of FLT3 mutations

Fms-like tyrosine kinase 3 (FLT3) is among the most frequently mutated protein in acute myeloid leukemia (AML), which has been confirmed as an important drug target for AML chemotherapy. Starting from the lead compound LT-106-175, a series of 1-H-pyrazole-3-carboxamide derivatives were synthesized to improve the FLT3 inhibitory potency and selectivity. Among them, compound 50 was identified as a highly potent and selective FLT3 inhibitor (IC50u202f=u202f0.213u202fnM), which showed equal activities against various mutants of FLT3 including FLT3 (ITD)-D835V and FLT3 (ITD)-F691L that is resistant to quizartinib. Compound 50 also exhibited efficacy against the human AML cell line MV4-11 (IC50u202f=u202f16.1u202fnM) harboring FLT3-ITD mutants. Inversely, compound 50 displayed no cytotoxicity to FLT3-independent cells, and the biochemical analyses showed that its effects were related to the inhibition of FLT3 signal pathways. Additionally, compound 50 induced apoptosis in MV4-11u202fcell as demonstrated by flow cytometry. Moreover, compound 50 showed enhanced metabolic stability. Altogether, it was concluded that compound 50 could be a promising FLT3 inhibitor for further developing therapeutic remedy of AML.

Physiologically stable F127-GO supramolecular hydrogel with sustained drug release characteristic for chemotherapy and photothermal therapy

A synthetic method for preparing a Pluronic F127 (F127)-stabilized graphene (GO) supramolecular hydrogel as a safe nanovehicle for combination treatment has been studied. Doxorubicin (DOX) as a model drug is non-covalently bound on the great surface area of GO due to strong π–π interaction, hydrophobic interaction, and the strongest hydrogen bonding. In vitro drug release experiments revealed that this F127-stabilized GO supramolecular hydrogel has a sustained drug release characteristic. Furthermore, the supramolecular hydrogel showed better in vitro antitumor ability under NIR (near infrared) laser irradiation because of the excellent photothermal effect of GO. Moreover, we evaluated its antitumor ability in vivo and the results show that the hydrogel system can also markedly inhibit the growth of a tumor when administered individually, especially under laser irradiation. All these findings make the supramolecular hydrogel system promising for combination therapy with good bioavailability and minimal side effects.