@article{Metal-Organic:2259,
      recid = {2259},
      author = {Ni, Kaiyuan},
      title = {Nanoscale Metal-Organic Frameworks for Cancer  Immunotherapy},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2020-06},
      pages = {258},
      abstract = {Immunotherapy has revolutionized cancer treatment by  reactivating host anti-tumor immunity with durable efficacy  and limited toxicity. However, only a small portion of  patients with immunostimulatory tumor microenvironments  respond to cancer immunotherapy. Various methods have been  explored to turn “cold” tumors “hot”. Chapter 1 broadly  discusses current immunoadjuvant therapies to synergize  with cancer immunotherapy, particularly checkpoint blockade  immunotherapy, and a brief overview of nanoscale  metal-organic frameworks (nMOFs), a new class of porous  molecular nanomaterials with potential for biomedical  applications. The introduction to the fundamental principle  of design and application of nMOFs to generate reactive  oxygen species (ROS) for cancer treatment, including  radiotherapy (RT), photodynamic therapy (PDT), and  chemodynamic therapy (CDT), serve as a foundation for  Chapters 2-6. 

Chapter 2 discusses the rational design of  two Hf-oxo based nMOFs, Hf6-DBA and Hf12-DBA, as highly  effective radiosensitizers that significantly outperform  HfO2, a clinically investigated radiosensitizer. The  radiosensitization of Hf-based nMOFs are attributed to  large specific surface areas, facile ROS diffusion and  enhanced energy deposition. Intratumorally injected nMOFs  induce immunogenic cell death upon low-dose X-ray  irradiation for local inflammation. Importantly, the  combination of nMOF-mediated low-dose RT with an  anti-programmed death-ligand 1 antibody effectively extends  the local therapeutic effects of RT to distant tumors via  abscopal effects.

Chapter 3 describes the design of  Hf-DBB-Ru as a mitochondria-targeted nMOF for RT-RDT to  further enhance local radiosensitization. Constructed from  Ru-based photosensitizers, the cationic framework exhibits  strong mitochondria-targeting property. Upon X-ray  irradiation, Hf-DBB-Ru efficiently generates hydroxyl  radicals from the Hf6 SBUs and singlet oxygen from the  DBB-Ru photosensitizers in a unique RT-RDT mode of action.  Mitochondria-targeted RT-RDT depolarizes the mitochondrial  membrane to initiate apoptosis of cancer cells, leading to  significant tumor regression in mouse models and  outperforming Hf6-DBA reported in Chapter 2.

Chapter 4  reports the design of an ultrathin version of nMOFs,  Hf-MOL, with reduced dimensionality to facilitate the  diffusion of ROS generated by RT-RDT to promote anti-tumor  efficacy. Hf-MOL not only outperforms Hf12-DBA reported in  Chapter 2 for local RT-RDT, while eradicates local tumors  and rejects distant tumors on several syngeneic bilateral  tumor models in conjunction with various checkpoint  blockade inhibitors, and eliminates lung metastases by  reactivating anti-tumor immunity and inhibiting  myeloid-derived suppressor cells. 

Chapter 5 describes the  design of cationic nMOF, Hf-DBBF-Ir, to release danger  associated molecular patterns (DAMPs) and tumor antigens  (TAs) via RT-RDT and deliver pathogen-associated molecular  patterns (PAMPs), anionic CpG oligodeoxynucleotides, to  facilitate the maturation of antigen presentation cells  (APC). Together, DAMPs, TAs, and PAMPs promote APC  maturation and activate cytotoxic T cells to reinvigorate  adaptive immune system. 

Chapter 6 illustrates the use of  a Cu-porphyrin nMOF, Cu-TBP, to mediate synergistic  hormone-triggered chemodynamic therapy (CDT) and  light-triggered photodynamic therapy (PDT) as radical  therapy to boost local inflammation. By hijacking  dysregulated hormone production, Cu2+ catalytically  consumes estradiol for ROS generation. The combination of  CDT- and PDT-based radical therapies shows effective  anti-tumor efficacies in hormonally dysregulated tumor  phenotypes. Combination of nMOF-mediated radical therapy  with CBI elicits extends the local therapeutic effects of  CDT and PDT to distant tumors with systemic antitumor  immunity.},
      url = {http://knowledge.uchicago.edu/record/2259},
      doi = {https://doi.org/10.6082/uchicago.2259},
}