Daiqin Chen

Theranostic applications of carbon nanomaterials in cancer: Focus on imaging and cargo delivery.

Carbon based nanomaterials have attracted significant attention over the past decades due to their unique physical properties, versatile functionalization chemistry, and biological compatibility. In this review, we will summarize the current state-of-the-art applications of carbon nanomaterials in cancer imaging and drug delivery/therapy. The carbon nanomaterials will be categorized into fullerenes, nanotubes, nanohorns, nanodiamonds, nanodots and graphene derivatives based on their morphologies. The chemical conjugation/functionalization strategies of each category will be introduced before focusing on their applications in cancer imaging (fluorescence/bioluminescence, magnetic resonance (MR), positron emission tomography (PET), single-photon emission computed tomography (SPECT), photoacoustic, Raman imaging, etc.) and cargo (chemo/gene/therapy) delivery. The advantages and limitations of each category and the potential clinical utilization of these carbon nanomaterials will be discussed. Multifunctional carbon nanoplatforms have the potential to serve as optimal candidates for image-guided delivery vectors for cancer.

Improving ultrasound gene transfection efficiency by controlling ultrasound excitation of microbubbles

Ultrasound application in the presence of microbubbles has shown great potential for non-viral gene transfection via transient disruption of cell membrane (sonoporation). However, improvement of its efficiency has largely relied on empirical approaches without consistent and translatable results. The goal of this study is to develop a rational strategy based on new results obtained using novel experimental techniques and analysis to improve sonoporation gene transfection. In this study, we conducted experiments using targeted microbubbles that were attached to cell membrane to facilitate sonoporation. We quantified the dynamic activities of microbubbles exposed to pulsed ultrasound and the resulting sonoporation outcome, and identified distinct regimes of characteristic microbubble behaviors: stable cavitation, coalescence and translation, and inertial cavitation. We found that inertial cavitation generated the highest rate of membrane poration. By establishing direct correlation of ultrasound-induced bubble activities with intracellular uptake and pore size, we designed a ramped pulse exposure scheme for optimizing microbubble excitation to improve sonoporation gene transfection. We implemented a novel sonoporation gene transfection system using an aqueous two phase system (ATPS) for efficient use of reagents and high throughput operation. Using plasmids coding for the green fluorescence protein (GFP), we achieved a sonoporation transfection efficiency in rate aortic smooth muscle cells (RASMCs) of 6.9%±2.2% (n=9), comparable with lipofection (7.5%±0.8%, n=9). Our results reveal characteristic microbubble behaviors responsible for sonoporation and demonstrated a rational strategy to improve sonoporation gene transfection.

pH-Responsive Mechanism of a Deoxycholic Acid and Folate Comodified Chitosan Micelle under Cancerous Environment

Smart pH-responsive polymeric micelles have attracted much attention as one of the most promising drug delivery candidates. In this paper, a different substitution of deoxycholic acid (DCA) and folic acid (FA) comodified hydroxypropyl chitosans (HPCHS) were synthesized for doxorubicin (DOX) targeted delivery and controllable release. The results indicate that the DOX-release behavior is pH-responsive and closely related with the grafting proportions of the two hydrophobic ingredients. The pH-responsive mechanism for the optimized (6%DCA)-HPCHS-(0.1%FA) was suggested, resulting from a synergistic effect of gradual hydrolysis of the amido bond and electrostatic repulsion between the subsequently protonated DOX and the amino residue of the chitosan backbone under a cancerous microenvironment. Moreover, the DOX/(6%DCA)-HPCHS-(0.1%FA) micelle as a promising targeted drug delivery system in cancer therapy was evaluated by cell growth inhibition assays and confocal laser microscopy in vitro. The results clearly demonstrate a controlled release of its cargo and promoted curative efficacy of DOX.

Ultrasmall Pd/Au bimetallic nanocrystals embedded in hydrogen-bonded supramolecular structures: facile synthesis and catalytic activities in the reduction of 4-nitrophenol

Melamine cyanurate (MCA) – a kind of hydrogen-bonded self-assembly supramolecular structure material – is readily synthesized by a hydrothermal method. Noble metal nanoparticles (NPs) (Pd, Au bimetallic and monometallic NPs) with an ultrasmall size below 5 nm are homogeneously distributed in the as-prepared MCA via a simple procedure at room temperature without any additional reductant and stabilizer. The as-prepared bimetallic noble metal NPs exhibit good catalytic activities toward the reduction of 4-nitrophenol to 4-aminophenol, and the resulting catalytic activities are even much better than those of monometallic counterparts. This unusual catalytic property should be relevant to the small size of noble nanoparticles and the electronic interaction between the support, Pd and Au nanoparticles.

In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal–Organic Frameworks Nanomaterials

Nanoscale metal-organic frameworks (nMOF) materials represent an attractive tool for various biomedical applications. Due to the chemical versatility, enormous porosity, and tunable degradability of nMOFs, they have been adopted as carriers for delivery of imaging and/or therapeutic cargos. However, the relatively low stability of most nMOFs has limited practical in vivo applications. Here we report the production and characterization of an intrinsically radioactive UiO-66 nMOF (89Zr-UiO-66) with incorporation of positron-emitting isotope zirconium-89 (89Zr). 89Zr-UiO-66 was further functionalized with pyrene-derived polyethylene glycol (Py-PGA-PEG) and conjugated with a peptide ligand (F3) to nucleolin for targeting of triple-negative breast tumors. Doxorubicin (DOX) was loaded onto UiO-66 with a relatively high loading capacity (1 mg DOX/mg UiO-66) and served as both a therapeutic cargo and a fluorescence visualizer in this study. Functionalized 89Zr-UiO-66 demonstrated strong radiochemical and material stability in different biological media. Based on the findings from cellular targeting and in vivo positron emission tomography (PET) imaging, we can conclude that 89Zr-UiO-66/Py-PGA-PEG-F3 can serve as an image-guidable, tumor-selective cargo delivery nanoplatform. In addition, toxicity evaluation confirmed that properly PEGylated UiO-66 did not impose acute or chronic toxicity to the test subjects. With selective targeting of nucleolin on both tumor vasculature and tumor cells, this intrinsically radioactive nMOF can find broad application in cancer theranostics.

Formation of nitrogen-doped mesoporous graphitic carbon with the help of melamine.

An efficient and facile synthesis method of nitrogen-doped mesoporous graphitic carbon (NMGC) was reported with melamine as a nitrogen source and citric acid as a carbon source. By taking advantage of the functional groups on melamine and citric acid, a uniform mixture of these two components was obtained via a self-assembly process. Accordingly, the nitrogen-doped mesoporous graphitic carbon (NMGC) can be obtained by means of the high temperature treatment. This as-prepared NMGC showed a promising potential as an anode material in lithium-ion batteries.

Amphiphilic trismethylpyridylporphyrin-fullerene (C70) dyad: an efficient photosensitizer under hypoxia conditions

Amphiphilic trismethylpyridylporphyrin-C70 (PC70) dyad with improved photosensitization has been successfully prepared. The PC70 dyad forms a liposomal nanostructure through molecular self-assembling. An increased absorption coefficient in the visible region, good biocompatibility, and high photostability were observed on the self-assembling structure. Surprisingly, in comparison with previously reported photosensitizer porphyrins, PC70 exhibited an enhanced photodynamic therapy (PDT) effect under hypoxia conditions. Further investigations illustrated that PC70 went through an extremely long-life triplet state (211.3 μs) under hypoxia, which enabled the exiguous oxygen to approach and interact with the activated (3P-C70)* more efficiently and produce more singlet oxygen. This would overcome the problem of existing photosensitizers of low PDT efficiency in cancerous tissues under hypoxia. The excellent properties of PC70 dyad make it a promising phototherapeutic agent, especially for the treatment of early- and late-stage cancers under shallow and hypoxia tissues.

In vitro and in vivo photothermally enhanced chemotherapy by single-walled carbon nanohorns as a drug delivery system

Single-walled carbon nanohorns (SWNHs) have exhibited many special advantages in biomedical applications. Herein, doxorubicin-loaded SWNHs (DOX-SWNHs) are prepared and further modified by amphiphilic deoxycholic acid modified-hydropropyl chitosan (DCA-HPCHS) to improve their biocompatibility. The obtained DOX-SWNH/DCA-HPCHS drug delivery system (DDS) possesses high stability in physiological media and excellent photothermal properties when exposed to laser irradiation in the near-infrared (NIR) region, which dramatically enhances the chemotherapy of DOX. Cell viability assays show that the growth of 4T1 cells are remarkably inhibitory under the conditions of incubation with DOX-SWNH/DCA-HPCHS and subsequent exposure to 808 nm laser irradiation to produce mild photothermal heating to 43 °C. Further investigation reveals that the photothermally enhanced chemotherapy derived from a promotion of DOX-SWNH/DCA-HPCHS uptake by the cancer cells rather than a light-triggered release of DOX. DOX-SWNH/DCA-HPCHS in combination with the use of laser irradiation exhibits a much better anticancer effect than the controls. Hence, the DOX-SWNH/DCA-HPCHS as a multifunctional DDS has been proposed and is hopeful for medicinal use in the future.

Synergistic Effect of Human Serum Albumin and Fullerene on Gd-DO3A for Tumor-Targeting Imaging

A macromolecular magnetic resonance imaging (MRI) contrast agent was successfully synthesized by conjugating the gadolinium/1,4,7,10-tetraazacyclododecane-1,4,7-tetracetic acid complex (Gd-DO3A) with 6,6-phenyl-C61 butyric acid (PC61BA) and upon further modification with human serum albumin (HSA). The final product, PC61BA-(Gd-DO3A)/HSA, has a high stability and exhibits a much higher relaxivity (r1 = 89.1 mM(-1) s(-1) at 0.5 T, 300 K) than Gd-DO3A (r1 = 4.7 mM(-1) s(-1)) does under the same condition, producing the synergistic positive effect of HSA and C60 on the relaxivity of Gd-DO3A. The in vivo MR images of PC61BA-(Gd-DO3A)/HSA-treated tumor-bearing mice show strong signal enhancement for the tumor area due to the enhanced permeability and retention effect. The maximum accumulation of PC61BA-(Gd-DO3A)/HSA at the tumor site was achieved at 4 h postinjection, which may guide surgery. The results from the hematology and histological observations indicate that PC61BA-(Gd-DO3A)/HSA has no obvious toxicity in vivo. These unique properties of PC61BA-(Gd-DO3A)/HSA enable them to be highly efficient for tumor-targeting MRI in vivo, possibly providing a good solution for tumor diagnosis.

A Versatile and Clearable Nanocarbon Theranostic Based on Carbon Dots and Gadolinium Metallofullerene Nanocrystals

Nanocarbons such as carbon nanotubes, graphene derivatives, and carbon nanohorns have illustrated their potential uses as cancer theranostics owing to their intrinsic fluorescence or NIR absorbance as well as superior cargo loading capacity. However, some problems still need to be addressed, such as the fates and long-term toxicology of different nanocarbons in vivo and the improvement of their performance in various biomedical imaging-guided cancer therapy systems. Herein, a versatile and clearable nanocarbon theranostic based on carbon dots (CDs) and gadolinium metallofullerene nanocrystals (GFNCs) is first developed, in which GFNCs enhance the tumor accumulation of CDs, and CDs enhance the relaxivity of GFNCs, leading to an efficient multimodal imaging-guided photodynamic therapy in vivo without obvious long-term toxicity. Furthermore, biochemical analysis reveals that the novel nanotheranostic can harmlessly eliminate from the body in a reasonable period of time after exerting diagnostic and therapeutic function.