Nanoscale Metal-Organic Frameworks for Cancer Therapies

Abstract

Metal–organic frameworks (MOFs) are crystalline molecular materials constructed by metal ions or metal-oxo secondary building units (SBUs) and multidentate organic ligands. Nanoscale metal–organic frameworks (nMOFs) have demonstrated significant potential for biomedical applications by leveraging their high porosity, structural regularity and tunability for multifunctionality and biodegradability. In particular, nMOFs with heavy metal-based SBUs have exhibited extraordinary radiosensitizing abilities owing to the large X-ray attenuation coefficient of the electron-dense SBUs. Furthermore, rational design of the organic ligands enables photosensitizing functionality or X-ray triggerable drug release. In this dissertation, we have further demonstrated the design and development of nMOFs for cancer therapies including radiotherapy (RT), radiodynamic therapy (RDT), chemotherapy, and immunotherapy. Chapter 1 introduces nMOFs and their potential applications with emphasis on heavy metal-based nMOFs in radiotherapy and radiodynamic therapy, and nMOFs as drug delivery systems for chemotherapy. Chapter 2 reports Monte Carlo simulations comparing the radiosensitization effects of nonporous nanoparticles (NPs) and nMOFs when exposed to X-rays or γ-rays. The simulations demonstrate that lattices, constructed with nanoscale SBUs, outperform solid NPs via enhanced scatterings of electrons. The optimization of SBU size and ligand length allows for maximum dose enhancement in nMOFs. Chapter 3 details the rational design of a bismuth-based nMOF, Bi-DBP, for synergistic checkpoint-blockade and radiotherapy–radiodynamic therapy (RT–RDT). Bi-DBP incorporates Bi10O8 clusters and photosensitizing 5,15-di(p-benzoato)-porphyrin (DBP) linkers. Following low-dose X-ray irradiation, Bi-DBP mediates strong RT–RDT effects to reverse immunosuppressive tumor microenvironments by decreasing intratumoral transforming growth factor-beta (TGF-β), thus enhancing the therapeutic effects of checkpoint blockade immunotherapy. Chapter 4 describes the design of a thorium-based nMOF, Th-DBP, composed of Th6O(OH)4 SBUs and DBP linkers, to further enhance RT–RDT guided by MC simulation. Th-lattice outperform Hf-lattice in radiation dose enhancement owing to higher mass attenuation coefficient. Upon irradiation, Th-DBP exhibited enhanced cytotoxicity against cancer cells and significantly suppressed tumor growth in two mouse models. Chapter 5 reports the design of a Hf-based nMOF, Hf-TP-SN (SN = 7-ethyl-10-hydroxycamptothecin, SN38), for synergistic radiotherapy and chemotherapy. Hf-TP-SN contains an X-ray triggerable SN38 prodrug. Upon X-ray irradiation, electron-dense Hf12 SBUs enhances hydroxyl radical generation for the triggered release of SN38, leading to 5-fold higher release of SN38 from Hf-TP-SN than its homogeneous counterpart. As a result, Hf-TP-SN plus X-ray irradiation induced significant cytotoxicity to cancer cells in vitro and efficiently inhibited tumor growth in vivo in a murine colon carcinoma model. Chapter 6 discloses the development of Hf-DBP-QP-SN mixed-ligand nMOF for synergistic RT–RDT and chemotherapy. We developed a quaterphenyl ligand conjugated with SN38 (QP-SN) via a hydroxyl-radical-responsive linkage, which was introduced to Hf-DBP nMOF to form a novel Hf-DBP-QP-SN nMOF with high biocompatibility. Upon 10 Gy X-ray irradiation, Hf-DBP-QP-SN nMOF released 13-fold higher SN38 than a homogeneous prodrug.With low-dose X-ray irradiation, Hf-DBP-QP-SN suppressed tumor growth by 93.5% in a colon cancer mouse model with no dark toxicity.