Photo-Responsive Nanoparticles for Hypoxia-Overcoming Photodynamic Cancer Therapy

光響應納米顆粒在乏氧光動力癌症治療中的應用

Student thesis: Doctoral Thesis

View graph of relations

Author(s)

Related Research Unit(s)

Detail(s)

Awarding Institution
Supervisors/Advisors
Award date24 Jul 2020

Abstract

Photodynamic therapy (PDT) employs photosensitizers (PSs) to produce reactive oxygen species (ROS) under optical illumination to kill cancer cells. While much initial success has been demonstrated, the efficiency of PDT often depends on the availability of oxygen for singlet oxygen (1O2) generation referred as type-II PDT. However, typical tumor microenvironments (TME) are infamously known to be hypoxic that would seriously impede PDT efficacy of many conventional PSs. To address the issue of insufficient oxygen supply, novel PS systems have been designed to carry or to generate their own supplies of oxygen into the tumor. On the other hand, a small portion of PS can generate superoxide radicals (O2−•) or hydroxyl radicals (•OH) even under hypoxia photoexcitation referred as type-I PDT. These PSs are obviously high desirable for overcoming the hypoxia issue for PDT. Hence, this thesis mainly concentrates on synthesizing photo-responsive nanoparticles to overcome hypoxia in PDT.

Firstly, a multifunctional nanoreactor C3N4/MnO2 was designed for achieving integrative cancer treatments. Upon 635 nm laser irradiation, activated photosensitizer C3N4 would transfer energy to molecular oxygen (type-II PDT, oxygen-dependent), resulting in generation of excited-stated 1O2. As mentioned, efficacy of type-II PDT would slash upon uncontinuous oxygen supply. To address this, MnO2 was decorated onto C3N4 as an oxygen source. MnO2 was found to show catalase-like activity toward overexpressed H2O2 in mild acidic tumor microenvironment (TME) via Fenton reaction to generate O2. On the other hand, it was found that type-I PDT can also be achieved if the C3N4/MnO2 is activated with irradiation of higher energy. Upon excitation of 635 nm of laser, C3N4/MnO2 can generate hydroxyl radicals (•OH) via a Fenton reaction. This is the first reported realizing type I+II photodynamic therapy and dual Fenton reactions in a simple nanoreactor for enhanced PDT.

Secondly, a π-radical was used for the first time as a versatile photosensitizer for hypoxia-overcoming photodynamic therapy. After self-assembling the radical molecules into nanoparticles (NPs), the NPs show good water dispersibility, good biocompatibility, broad near-infrared (NIR) absorption and emission at ~ 800 nm. Significantly, the radical remains stable in various biological solutions, exposure to the ambient environment, and even long-term laser irradiation, which is superior to many reported radical-based materials. Efficient 1O2 and O2−• generation and cytotoxicity were observed upon 635 nm laser irradiation. More importantly, even under hypoxic conditions, sufficient O2−• generation and cytotoxicity were observed addressing the most important hurdle for successful PDT in the oxygen-deficient tumor microenvironment.

Thirdly, we developed a 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO)-based radical nanoparticles (NDIT NPs) as a novel PS for hypoxia-overcoming photodynamic therapy. The NDIT NPs were prepared by simple nanoprecipitation using a TEMPO-naphthalenediimide (NDI) radical molecule. Upon 635 nm irradiation, the stable NDIT NPs were demonstrated to effectively produce efficient 1O2 as well as •OH, O2−• in hypoxia, which becomes a smart oxygen-responsive system for PDT. The NDIT NPs enable sufficient photoactive cytotoxicity both in vitro and in vivo.