Phototheranostic Agents for Cancer Imaging and Combined Therapy

光學診療劑在癌症成像及聯合治療中的應用

Student thesis: Doctoral Thesis

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Award date3 Sep 2021

Abstract

Photodynamic therapy (PDT) has attracted widespread attention due to its precise controllability, minimal invasiveness, and high spatiotemporal accuracy. To achieve tumor destruction upon light irradiation, PDT employs photosensitizers (PSs) that react with surrounding oxygen (O2) to generate cytotoxic reactive oxygen species (ROS). However, the fast proliferation of cancer cells and contorted vasculature at tumor sites cause a hypoxic atmosphere, which is the main obstacle to restrict the O2-reliant PDT. In addition, both clinical practice and exploratory studies have demonstrated that a single treatment modality is incapable of eliminating the whole tumor, and further it is ineffective in preventing cancer metastasis. Thus, the current research trend has gradually shifted from a focus on monotherapy to combination therapy for enhanced therapeutic efficacy. On the other hand, the rapid development of medical imaging techniques has made early cancer diagnosis possible by the sensitive and accurate detection of previously undetectable tumors. Aiming at these issues, the development of novel PDT-based nanomedicine is of great significance for cancer imaging and therapy.

Firstly, a multifunctional nanotheranostic system (Ce6-CuS/MSN@PDA@MnO2-FA, Ce6 for chlorin e6, CuS for copper sulfide, MSN for mesoporous silica nanoparticle, PDA for polydopamine, MnO2 for manganese dioxide, FA for folic acid) combining PDT, photothermal therapy (PTT), magnetic resonance (MR) imaging with hypoxia-relieving and tumor-targeting functionalities was fabricated. The nanosystem could effectively accumulate at the tumor site, where the outer MnO2 decomposed endogenous H2O2 to O2 for enhanced PDT via hypoxia relief, and the released Mn2+ was able to serve as an ideal MR imaging contrast agent. Owing to the good photothermal performance of CuS and PDA, the nanosystem also showed great potential for PTT.

Secondly, an intelligent ROS nanogenerator (Ce6/GOx@ZIF-8/PDA@MnO2, denoted as CGZPM, GOx for glucose oxidase, ZIF-8 for zeolitic imidazolate frameworks-8) with O2-generating and glutathione (GSH)-/glucose-depleting abilities was constructed for combined PDT, chemodynamic therapy (CDT) and starvation therapy (ST). After intake by tumor cells, the outer MnO2 was rapidly degraded by the acidic pH, overexpressed H2O2 and GSH with abundant Mn2+ and O2 produced. The Mn2+ acted as an ideal Fenton-like agent as well as MR imaging contrast agent, while the O2 promoted the PDT via hypoxia relief and facilitated the intratumoral glucose oxidation by GOx for ST. Benefiting from the GOx-based glycolysis process, sufficient H2O2 was generated to improve the CDT efficacy through Mn2+-mediated Fenton-like reaction. Notably, MnO2 together with PDA could decrease the tumor antioxidant activity by consuming GSH, resulting in remarkably enhanced PDT/CDT effects.

Thirdly, a smart hydroxyl radicals (•OH) and alkyl radicals (•R) nanogenerator (AIPH/PDA@CuS/ZIF-8, denoted as APCZ, AIPH for 2,2’-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride) with promising GSH-depleting ability and photothermal property in the near infrared (NIR)-II biowindow was designed for photoacoustic (PA) imaging and hypoxia-irrelevant PTT/PDT/CDT. Owing to the special features of tumor microenvironment (TME), the outer ZIF-8 was rapidly degraded to allow release of CuS, which served as a self-reinforcing Fenton-like nanoagent to initiate CDT by sequentially reacting with intratumoral GSH and H2O2. More importantly, upon a 1064 nm laser irradiation, the APCZ held satisfied photothermal performance that not only permitted NIR-II PTT but also synergized with CDT as well as decomposed the AIPH to toxic •R for O2-independent PDT. Besides, PDA together with CuS greatly decreased the GSH level and resulted in significantly enhanced PDT/CDT under both normoxic and hypoxic conditions. Lastly, the feasibility of APCZ as an ideal PA imaging contrast agent was also evidenced.

In summary, three kinds of new theranostics were synthesized via integrating PDT with PTT, CDT/ST, and PTT/CDT, respectively. In vitro and in vivo experiments evidenced that all functionalities worked collaboratively as expected, remarkable anti-tumor effects could be achieved via synergistic manners. These nanoagents hold tremendous potential for highly effective cancer diagnosis and treatment with clinical significance.