Research Directions


 

The major drawback of conventional photodynamic therapy (PDT) is the adverse reactions in-vitro/in-vivo, caused by variation in physiological conditions and notched distribution of singlet oxygen (1O2), which is well known to be the major cytotoxic agent responsible for photobiological activity. One of the prime challenges in PDT is how to monitor 1O2 generation and the delivery of the PDT drug in-vitro/in-vivo on a single molecule. A solution is to develop PDT agents that can serve dual-function independently: first visualize (confirm) where the agent is through excitation in one wavelength and then trigger 1O2 generation through excitation at another wavelength. Now, we would like to develop a new generation of “smart” organometallic/lanthanide bioprobes that have the above dual functions.

 

a) Subcellular organelle targeting in live cells and PDT agents

 

Several novel organelle specific markers (for lysosome, mitochondria, Golgi apparatus) have been synthesized which can simultaneously trigger the generation of 1O2 and give optical images in-vitro upon visible/NIR irradiation. Such behaviors quench the highly sought-after thirst of gaining spatial control using dual laser excitations to damage selected cell compartments/components with complexes possessing desired subcellular localization profile loaded.

 

 

 

 

Our organelle specific organometallic and lanthanide materials recently reported as PDT agents. (Left or Above) Their subcellular localization has been induced by the linkers between porphyrin and Ru moieties. (Bioconjugate Chem., 2012, 23, 1623)and (Right or Below) an amphiphilic water-soluble ytterbium complex which is photo-selective, functional and Golgi apparatus specific to be a responsive dual probe capable of sensitizing emission within the biological window. (Chem. Commun., 2012, 48, 9646)

 

b) Tumor specific imaging and PDT agents

 

-In vitro studies

Exposure of anionic phosphatidylserine on the cell membrane surface occurs when it comes to, for instance, apoptosis, necrosis, cell injury, and malignant transformation. In our present study, an ytterbium complex (Yb-N) has been developed which can in-vitro recognize such anionic phospholipids with visible to NIR emission, good tumor selectivity and strong binding affinity as confirmed in five cancer (HeLa, A549, HK-1, HONE-1 and SK-N-SH) and three normal (QSG-7701, MRC-5 and WPMY-1) cell lines via confocal microscope, flow cytometry, and isothermal titration calorimetry respectively. Anionic phospholipids on tumor vessels could therefore provide potential markers for tumor cell targeting and imaging, serving as the drug delivery radar.

 

 

 

 

 

 

 

 

A porphyrin ytterbium complex (Yb-N) showed strong binding to phosphatidylserine and capability to differentiate cancer cells via targeting of such anionic membrane phospholipid. (Chem. Comm., 2013, 49, 7252 and Chem. Eur. J., 2014, 971)

 

 

 

The development of organelle specific lanthanide and organometallic materials recently reported by as PDT agents. (Left: Chem. Commun., 2012, 48, 9646; Right: RSC Advances, 2013, 3, 382)

We demonstrate a new modality of photodynamic therapy (PDT) through the design of our truly dual-functional — PDT and imaging — gadolinium complex (Gd-N) which can target cancer cells specifically. In the light of our design, the PDT drug can specifically localize on the anionic cell membrane of cancer cells in which its laser-excited photoemission signal can be monitored without triggering the phototoxic generation of reactive oxygen species — singlet oxygen — prior to due excitation

 

 

(a)

 


(b)
(c)
(d)

 

 

 

In vivo studies of Gd-N as the cancer cell-specific PDT agent. (a) The representative gross images of tumors after PDT using 860 nm laser for excitation, and (b) candidates were divided into four groups (Group 1: Yb-N; Group 2: Gd-N; Group 3: Yb-RhB; Group 4: Gd-RhB); the measurement of tumor volume in (b); (c) In vivo biodistribution of Gd-N via ICP-MS studies; (d) In vivo tumor inhibition assays of Gd-N. (PNAS, 2015, In Press, DOI:10.1073/pnas/414499111)