MOF stable nano for bacterial porphyrin type I and type II photodynamic therapy synchronized

Photodynamic therapy (photodynamic therapy, referred to as PDT) as a minimally invasive and localized cancer treatment, the disease has been made in the clinical treatment of esophageal cancer, head and neck cancer, eye cancer, skin cancer, breast cancer and lung cancer, etc. good effect. PDT photosensitizers by toxic (typically a porphyrin derivative) and the light (generally near infrared light) and the role of oxygen, the generation of reactive oxygen species (reactive oxygen species, referred ROS) induced cytotoxicity and promote cancer withered death or necrosis, and further eliciting an immune response in and around the tumor, the tumor regression. Although very powerful as a PDT treatment, but there are the following disadvantages:

1. photosensitizer remains in the patient and cause photosensitivity side effects (see no light);
2. light penetration poor
3. a cancer cell result in localized high metabolic hypoxic tumors, thereby so that the oxygen-dependent effect of therapy; shallow depth, from the surface can not effectively anti-tumor and metastasis deeper tissues (bottomless) (Mo was oxygen).

As a representative one of the second generation photosensitizer compound, porphin bacteria (bacteriochlorin) has become a candidate for solving all of the above problems. Porphine reducing bacteria as a porphyrin derivative, which has the following advantages:

1. weak absorption in the visible region, can alleviate the side effects of the photosensitive patient;
2. in a wavelength band used in the treatment of human transparent tissue (700 nm-850 nm), have a stronger penetration window;
3. can be carried out simultaneously with the type I type II PDT mechanism can tolerate a certain degree of hypoxia local environment.

mainstream and photosensitizers such as porphyrins chlorin, are based on the mechanism of Type II PDT, singlet oxygen is generated by the excited state of the photosensitizer coupled to a ground state oxygen to kill cancer cells, the disadvantage is totally dependent on oxygen. And the bacteria can be porphine type I PDT, i.e., molecular oxygen or other photosensitizer excited state to thereby generate the active oxygen species in the redox reaction, typically including superoxide anion (of O2-), hydrogen peroxide (H2O2) and hydroxyl free group (OH). Due to the nature of the type I PDT lightOxidation leads to the electron transfer reaction initiated reduction can damage redox balance, induce cell death in the tumor microenvironment, and thus can tolerate relatively hypoxic environment. Redaporfin As a second generation photosensitizer, currently based on bacterial products include porphine have been clinically approved in Europe TOOKAD for the treatment of prostate cancer, and ongoing clinical trials for the treatment of biliary tract cancer, both achieved good clinical treatment outcome. At the same time, due to bacterial porphine very sensitive to light and oxygen, as reducing porphyrin derivative, having a lower redox potential, the Type I mechanism while PDT effect, but also makes routine clinical photodynamic bacterial porphine photobleaching under treatment conditions (photobleaching) prone to loss of efficacy. It can be said that contrary to the original purpose of PDT, this would greatly weaken its proper treatment. Is there a way to maintain the stability of live bacteria PORPHINE both, let it not so easy to photolysis, but able to retain all the advantages already has it? To solve this problem, researchers began fine and full of creative exploration. As a new light-sensitive material of nano – nano metal – organic frameworks compound (nanoscale metal-organic framework, referred nMOF), because it has a porous structure is conducive to the diffusion of active oxygen to prevent self-quenching of the regular frame structure, the higher the photosensitizer loads and good biocompatibility, ideal for PDT of nano-drug. Recently, professor at University of Chicago Lin Wenbin laboratory reported Nano MOF stable as a carrier of bacteria porphine, successful synchronization type I and type II photodynamic therapy, and breast cancer in mice with colon cancer model an excellent effect. Researchers first Tetrakis acid bacteria as nMOF porphine ligands having a high symmetry (abbreviation TBB), and synthesized having a diameter of approximately 100 nm by reaction with PCN solvothermal of ZrCl4 MOF -224 nano structure (abbreviated Zr-TBB). Zr-TBB ultraviolet absorption spectrum which shows a strong absorption near 740 nm, while the PXRD diffraction pattern and TEM demonstrate good Zr-TBB crystallized, having a potential for a nano photosensitizer.

porphine bacterial oxidation process is a light ring [2 + 2] peroxidation of the double bond from the reaction of starting porphyrin, then will reverse [2 + 2] ring opening diketone structure, a last continuously no decomposition reaction becomes photoactive debris. Throughout the course of the reaction, the bacteria will porphin large conformational changes, in order to meet the geometry transformation sp2 and sp3 carbon center. We hypothesized that the fixed structural framework Zr-TBB nMOF, since four clusters benzoic TBB is coupled zirconyl, TBB difficult to produce conformational changes and structure, and therefore free from bacteria porphine in Zr- TBB photooxidation bacterial porphine ligand is suppressed. Experimental results have confirmed the conjecture researchers, under light illumination LED 740 nm 100 mW / cm2 a, Zr-TBB exhibits excellent light stability. Thus, Zr-TBB photosensitizer as bacteria-based nano porphine, and significantly enhance the stability of the bacteria porphine.

In vitro experiment, the researchers verified Zr-TBB active oxygen generating mechanisms and efficiency. By different active oxygen detection reagent, can be demonstrated in vitro environment TBB both Type I and Type II PDT mechanism, i.e. corresponding to produce superoxide anion (of O2-), hydrogen peroxide (by H2O2), hydroxyl radical (OH ) with singlet oxygen (1O2). And compared to the ligand itself (H4TBB), Zr-TBB information to create enhanced ROS, to stabilize the generation of ROS described nMOF porphine bacteria greatly facilitated PDTs efficiency. The researchers also studied under normoxic conditions cytotoxic under hypoxic conditions, proved that even under the hypoxic conditions PDT, Zr-TBB still can efficiently kill cells, proving once again that the bacteria PORPHINE type I PDT adaptation mechanism for hypoxic conditions. Lower dark toxicity described nano MOF good biocompatibility.

After the generation and cytotoxicity of ROS on cellular level proof, researchers followed on both mouse tumor models (4T1 & MC38) Verify cancer photodynamic therapeutic effect of Zr-TBB. On both models, Zr-TBB lighting group exhibited excellent tumor inhibiting effect, and there is a significant difference with a ligand group H4TBB light. Through sections of tumor samples calreticulin (CRT) detecting terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) detection, Zr-TBB lighting group also exhibited the strongest immune and apoptotic signals immunogenicity signal.

In conclusion, the researchers reported that photodynamic therapy using Zr-TBB nMOF framework for stabilizing bacterial porphine. Zr-TBB produce superoxide anion (of O2-) by type I and type II mechanisms of PDT, hydrogen peroxide (by H2O2), hydroxyl radical (OH) and singlet oxygen (1O2) mediated efficient PDT procedure. Zr-TBB in mouse tumor models of breast and colon cancer exhibit excellent anti-tumor effect, the cure rateThey were 40% and 60%. Therefore, based on nano-MOF it provides a stable bacterial PORPHINE new nano photosensitizer platform, but also provides a feasible ideas and methods to other unstable molecules of biological applications. This achievement recently published in the \”American Chemical Society\” (JACS), the first co-author of the University of Chicago graduate student Dr. Luo Tao Kun Ni and Kaiyuan.