Metal-organic frameworks for cancer therapy
Radiotherapy–radiodynamic therapy by nanoscale metal-organic frameworks eradicates local tumours and synergizes with immune checkpoint blockade to control distal tumours
The paper in Nature Biomedical Engineering is here: https://go.nature.com/2Iat5U0
Metal-organic frameworks (MOFs), also known as porous coordination polymers, have attracted significant interest from chemists and materials scientists in the past two decades. My group first contemplated the possibility of shrinking MOFs to the nanoscale 15 years ago, as we recognized that MOF functions could be precisely tuned for biomedical applications via a building block approach. Together with a number of talented graduate students, particularly William J. Rieter, we developed several strategies to precisely control the morphologies and sizes of nanoscale MOFs (nMOFs) and explored their applications as contrast agents for magnetic resonance imaging, optical imaging, and X-ray computed tomography.1 Though successful, we recognized a greater need in advancing cancer therapy and have focused our effort on developing nMOFs to deliver chemotherapeutics, small interfering RNAs, and other therapeutic cargoes over the past decade.2
In our paper just published in Nature Biomedical Engineering, we were able to bridge these two areas to develop novel radioenhancers for X-ray radiotherapy. We first became interested in the possibility of using nMOFs to enhance X-ray radiotherapy almost ten years ago through our involvement in University of North Carolina’s Center for Cancer Nanotechnology Excellence. In a paper published in 2014,3 we observed X-ray scintillation in a hafnium (Hf)-based nMOF through X-ray absorption by Hf secondary building units (SBUs) and energy transfer to anthracene ligands to emit visible light, the first hint that our ideas could be realized.
After relocating to the University of Chicago, my group gained ready access to several X-ray irradiators in the Department of Radiation and Cellular Oncology and started testing a number of nMOFs and other materials as radioenhancers. We discovered Hf-porphyrin nMOFs’ superior performance in enhancing X-ray irradiation over other nanomaterials, including HfO2, and through a series of careful studies uncovered the nMOF-enabled radiotherapy-radiodynamic therapy (RT-RDT) process, which we patented in 2014.
After absorbing X-ray photons, the Hf clusters can enhance RT via the production of ˑOH radicals and enable RDT by exciting the porphyrins to generate 1O2 (Fig. 1). This nMOF-enabled process eradicates several different types of cancer cells with the use of extremely low doses of X-rays both in vitro and in vivo. Interestingly, we found that RT-RDT can trigger an immune response, allowing for strong synergy with immune checkpoint inhibitors (Fig. 2). By loading a small-molecule IDO inhibitor (IDOi) into the pores/channels of the nMOFs, an unprecedented 100% abscopal response (rejecting/regressing both treated, irradiated tumours and untreated, non-irradiated tumours) was observed in syngeneic mouse models of breast and colorectal cancers.
Realizing the potential of RT-RDT technology, I founded RiMO Therapeutics in 2015 in order to translate nMOFs into the clinic for cancer treatment. With the help of friends and family, RiMO Therapeutics closed the SEED round of fundraising in September 2015. After screening a number of potential candidates, RiMO-301 was chosen to enter animal toxicology testing and large-scale production under cGMP and is now being investigated in a phase 1 clinical trial (NCT03444714).
While radiotherapy has been used for cancer treatment for approximately 122 years beginning only a few months after Roentgen’s discovery of X-rays, RT has only been moderately effective for many patients due to the serious side effects from radiation damage to normal tissues and development of resistance. If the anticancer efficacy of nMOF-enabled RT-RDT can be realized on human tumours, RiMO Therapeutics’ radioenhancer technology will revolutionize radiotherapy. By maximizing the therapeutic benefits (such as in situ vaccination) and minimizing the toxicities of RT, nMOF-enabled RT-RDT can not only eradicate local tumours but also increase durable response rates of checkpoint blockade immunotherapy in the clinic.
Our paper: Lu, K. et al. Low-dose X-ray radiotherapy–radiodynamic therapy via nanoscale metal–organic frameworks enhances checkpoint blockade immunotherapy. Nat. Biomed. Eng. doi:10.1038/s41551-018-0203-4.
1. Rieter, B. J., Taylor, K. M. L., An, H., Lin, W. & Lin, W. Nanoscale metal-organic frameworks as potential multimodal contrast enhancing agents. J. Am. Chem. Soc. 128, 9024-9025 (2006).
2. Della Rocca, J., Liu, D. & Lin, W. Nanoscale metal-organic frameworks for biomedical imaging and drug delivery. Acc. Chem. Res. 44, 957-968 (2011).
3. Wang, C. et al. Synergistic assembly of heavy metal clusters and luminescent organic bridging ligands in metal-organic frameworks for highly efficient X-ray scintillation. J. Am. Chem. Soc. 136, 6171-6174 (2014).