Nanoscale Metal-Organic Frameworks for Cancer Therapy

用於癌症治療的納米有機金屬骨架的研究

Student thesis: Doctoral Thesis

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Award date15 Sep 2017

Abstract

Nanomedicine is a promising technology for cancer therapy, where nanomaterials are employed to enhance therapeutic efficacy and mitigate undesired side effects. In the past decade, engineering nanoparticles (NPs) by integrating diagnostics with cancer therapeutics has been shown to be highly desirable for precision medicine. In the past decades, various porous nanomaterials (e.g., silica, polymer, and self-assembly NPs) carrying both drugs and imaging agents provide cost-effective solutions for enhancing delivery efficacy by taking advantage of the enhanced permeability and retention (EPR) effect.

Recently, nanoscale metal-organic frameworks (NMOFs) constructed by coordination bonds of metal ions or clusters and organic linkers in the nanoscale regime, have received considerable attention for gas storage, separation, catalyst, sensing and biomedical applications. The high porosity and periodic structures of NMOFs not only enable efficient loading of drugs via encapsulation and adsorption, but also be possible to deliver some photosensitizers to tumour sites for biomedical purpose such as imaging and photo-therapy. However, NMOFs have been extensively reported as drug carriers. Aiming at clinical use, it is requested to exploit novel properties and more advantages of NMOFs for multi-functional imaging and therapy.

Firstly, there has been an emerging interest in combing therapeutic modalities to synergistically handle diseases with multiple approach. When it comes to NMOFs, we successfully integrated photosensitized graphitic carbon nitride nanosheets with zeolitic-imidazolate framework-8 to construct novel core-shell nanoparticles. The core nanosheets are effective visible-light photosensitizer PDT, whereas the shell NMOFs can host doxorubicin for chemotherapy. Thereafter, the core-shell nanoparticles realized combinational photo-chemo therapy upon malignant cells.

Next, we incorporated Ruthenium (II) tris(bipyridyl) cationic complex to UiO-67 (Universitetet i Oslo) nanoscale metal-organic frameworks (NMOFs). Interestingly, after incorporation into porous UiO-67 nanoparticles, the quantum yield, luminescence lifetime and two-photon absorption of guest photosensitizers were much improved owing to the steric confinement effect of MOF pores. The luminescent NMOFs exhibit good performance for in-vitro two-photon fluorescence imaging and photodynamic therapy (PDT).

In order to ensure an efficient PDT, photosensitizers are preferred to obtain not only non-invasive and deep-penetrating light absorption, but also large-amount accumulation at tumour sites. To fulfil this request, we synthesized NMOFs consisting of porphyrin-derivate molecules as organic linkers, which manages to be internalized by two types of cancer cells and generate singlet oxygen efficiently. Moreover, the as-prepared porphyrin NMOFs shows excellent PDT performance on tumour inhibition both in vitro and in vivo.

In summary, the blossoming modern nanomedicine are much beneficial to the development of non-invasive and less-painful clinical cancer treatment. With the aims of build novel nanomedicine from NMOFs, we proposed and worked on three pathways including incorporation of photosensitizers to NMOFs, construction of NMOFs with porphyrin linkers, and integrating other functional nanomaterials with NMOFs. From these routes and results, NMOFs shows great promise to be manufactured into novel nanoplatform to fulfil urgent requirement of precision medicine.