Bin Kang

Photoacoustic “nanobombs” fight against undesirable vesicular compartmentalization of anticancer drugs

Undesirable intracellular vesicular compartmentalization of anticancer drugs in cancer cells is a common cause of chemoresistance. Strategies aimed at circumventing this problem may improve chemotherapeutic efficacy. We report a novel photophysical strategy for controlled-disruption of vesicular sequestration of the anticancer drug doxorubicin (DOX). Single-walled carbon nanotubes (SWCNTs), modified with folate, were trapped in acidic vesicles after entering lung cancer cells. Upon irradiation by near-infrared pulsed laser, these vesicles were massively broken by the resulting photoacoustic shockwave, and the vesicle-sequestered contents were released, leading to redistribution of DOX from cytoplasm to the target-containing nucleus. Redistribution resulted in 12-fold decrease of the EC50 of DOX in lung cancer cells, and enhanced antitumor efficacy of low-dose DOX in tumor-bearing mice. Side effects were not observed. These findings provide insights of using nanotechnology to improve cancer chemotherapy, i.e. not only for drug delivery, but also for overcoming intracellular drug-transport hurdles.

Subcellular-Scale Drug Transport via Ultrasound-Degradable Mesoporous Nanosilicon to Bypass Cancer Drug Resistance

Delivering and releasing anticancer agents directly to their subcellular targets of action in a controlled manner are almost the ultimate goal of pharmacology, but it is challenging. In recent decades, plenty of efforts have been made to send drugs to tumor tissue or even specifically to cancer cells; however, at the subcellular scale, cancer cells have multiple cunning ways to hinder drugs from reaching their final action targets. Here, we demonstrate a strategy to bypass the last defense of cancer drug resistance by contolling the drug transportation and release at subcellular scale. We developed a platform based on ultrasound-degradable mesoporous nanosilicon, which allows drug delivery towards, ultrasound controlled drug release into the cell nucleus. This strategy altered the drug distribution within cells and remarkably enhanced the drug accumulation ratio at the action target, i.e. nucleus. In vitro and in vivo studies proved that this strategy reduced the drug dosage by an order of magnitude, prolonged drug retention and amplified therapeutic efficacy in tumor-bearing mice. These results offer new insights into bypassing cancer drug resistance through transport and release drugs directly to their action targets in a controlled manner.

Revealing chemical processes and kinetics of drug action within single living cells via plasmonic Raman probes

Better understanding the drug action within cells may extend our knowledge on drug action mechanisms and promote new drugs discovery. Herein, we studied the processes of drug induced chemical changes on proteins and nucleic acids in human breast adenocarcinoma (MCF-7) cells via time-resolved plasmonic-enhanced Raman spectroscopy (PERS) in combination with principal component analysis (PCA). Using three popular chemotherapy drugs (fluorouracil, cisplatin and camptothecin) as models, chemical changes during drug action process were clearly discriminated. Reaction kinetics related to protein denaturation, conformational modification, DNA damage and their associated biomolecular events were calculated. Through rate constants and reaction delay times, the different action modes of these drugs could be distinguished. These results may provide vital insights into understanding the chemical reactions associated with drug-cell interactions.

Endogenous MicroRNA-Triggered and Real-Time Monitored Drug Release via Cascaded Energy Transfer Payloads

It is a great challenge to design a drug delivery system with a controlled manner, especially one triggered by an exclusive endogenous disease marker and with an easily tracked release process. Herein, we developed a drug delivery platform of carbon dots which were connected to a stem-loop molecular beacon loaded with doxorubicin and polyethylene glycol modified folic acid. Such a platform enables one to release drugs on demand under the stimuli of endogenous microRNA-21, and turn on the fluorescence of carbon dots and doxorubicin, which allows one to monitor the drug release process. The intracellular experiment indicated that folic acid could mediate endocytosis of the nanocarrier, and the overexpressed endogenous microRNA-21 served as a unique key to unlock the drug nanocarrier by competitive hybridization with the molecular beacon, which finally resulted in fluorescence recovery and realized a chemotherapeutic effect within human breast cancer cells. The nanocarrier may have potential application in personalized treatment of different cancer subtypes in which the corresponding miRNAs are overexpressed.

A paper-based SERS test strip for quantitative detection of Mucin-1 in whole blood

A paper-based SERS test strip combining strengths of paper chip and Raman active substrate was demonstrated to overcome challenges in spectroscopic sensing of complicated samples and realize quantitative detection of disease markers in whole blood. The precisely controlled Au NPs were not only capable of generating condensed hot spots on the fibers, but also enhanced the size exclusion effect of paper, resulting in the novel performance on both SERS detection and sample pretreatment. A biosensor for Mucin-1 is developed by equipping the Au NPs with aptamer. Combining all these merits, this small, cheap and portable test strip might find wide application in clinical diagnosis and health evaluation.

Three-level spaser for next-generation luminescent nanoprobe

Delayed spasing dots with ~3-nm spectral width, ~1 mJ cm−2 threshold, and ~102-μs lifetime were developed for a bionanoprobe. The development of modern biological and medical science highly depends on advanced luminescent probes. Current probes typically have wide emission spectra of 30 to 100 nm, which limits the number of resolvable colors that are simultaneously labeled on samples. Spasers, the abbreviation for surface plasmon lasers, have ultranarrow lasing spectra by stimulated light amplification in the plasmon nanocavity. However, high threshold (>102 mJ cm−2) and short lasing lifetime (approximately picoseconds to nanoseconds) still remain obstacles for current two-level spaser systems. We demonstrated a new type of a three-level spaser using triplet-state electrons. By prolonging the upper state lifetime and controlling the energy transfer, high gain compensation was generated. This probe, named delayed spasing dots (dsDs), about 50 to 60 nm in size, exhibited a spectral linewidth of ~3 nm, an ultralow threshold of ~1 mJ cm−2, and a delayed lasing lifetime of ~102 μs. As the first experimental realization of the three-level spaser system, our results suggested a general strategy to tune the spasing threshold and dynamics by engineering the energy level of the gain medium and the energy transfer process. These dsDs have the potential to become new-generation luminescent probes for super-multiplex biological analysis without disturbance from short lifetime background emission.

Plasmon-Resonance-Energy-Transfer-Based Spectroscopy on Single Nanoparticles: Biomolecular Recognition and Enzyme Kinetics

The small absorption cross sections of most molecules led to the low sensitivity of traditional optical absorption spectroscopy. This obstacle might be overcome by applying the near-field plasmon resonance energy transfer (PRET) between plasmonic nanoparticle and surrounding molecules. In this work, we utilized PRET-based spectroscopy on single gold nanostars to study the specific biomolecule recognition and enzyme kinetics choosing biotin-SA pair and DNase I as models. By analyzing the changes of absorption spectra for black hole quencher 3 (BHQ3), derived from spectra difference, we explored the kinetics of specific biomolecule recognition and enzyme digestion in different physiological environment, and we found that the viscosities of media and the sizes of molecules play vital role in biomolecular recognition and enzyme digestion. Compared with the traditional optical absorption spectroscopy techniques, PRET-based spectroscopy offers a nanoscopic resolution owing to the small size of the probe, is more sensitive and achieves detection on the order of hundreds or even dozens of molecules, and can achieve high selectivity due to the specific biomolecular recognition. This method might be used in the fields of molecular diagnostics, drug discovery, cell systems, and clinical diagnostics.