Engineering Iron-Based Stimuli-Responsive Nanomedicine for Multimodal Synergistic Cancer Therapy

Abstract

Iron-based nanomaterials have attracted broad interests in cancer management due to their favorable biocompatibility, abundant raw materials, and especially, their unique physicochemical properties and biological effects. Magnetic iron-based nanomaterials can respond to static or dynamic magnetic fields, which gives rise to diverse functionalities such as magnetic field-guided targeting and magnetic hyperthermia therapy (MHT). In addition, some iron-based nanomaterials with excellent optical-to-thermal conversion efficiency can be applied to photothermal therapy (PTT). Benefiting from the chemical activities of iron ions, smart nanomaterials in response to intratumoral stimuli (e.g., pH, H₂O₂) can be designed for tumor-specific chemodynamic therapy (CDT). Moreover, recent studies have revealed the biological significance of iron-based nanomaterials, such as programming cell death and triggering immunological responses, which provide novel opportunities in cancer management.

Despite the prosperous development of iron-based nanomaterials and their great potential in cancer management, most of them are far from clinical translation. This is in part due to the insufficient in vivo therapeutic efficacy and specificity of most available iron-based nanomedicines. In addition, the complex biological system poses barriers to the delivery, targeting, and acting of cancer nanomedicines. Besides, the inadequate controllability of iron-based nanomaterials’ synthetic processes poses difficulties in mass production and quality control.

In view of the great potential and challenges of iron-based nanomaterials in clinical cancer therapy, in this thesis project, we focus on improving the therapeutic specificity and efficacy of cancer nanomedicines by employing the stimuli-responsiveness of iron-based nanomaterials and synergistic effects of multimodal therapies. On this basis, a series of cancer therapeutic nanoplatforms have been designed and developed, of which the action mechanisms and therapeutic efficacy are investigated both in vitro and in vivo. The main points in each chapter are listed below:

Chapter 1: Introduction to cancer and cancer nanomedicine, especially iron-based cancer nanomedicines in terms of their properties, engineering approaches, and therapeutic applications. Then, the objectives of this thesis project are highlighted.

Chapter 2: Iron oxide nanocubes (IONCs)-based injectable hydrogel was developed for alternating magnetic field (AMF)/acidity/H₂O₂/glucose-triggered in situ magnetothermal/chemodynamic/starvation synergistic tumor therapy. Specifically, IONCs synthesized by thermal decomposition method were mixed with glucose oxidase (GOx) in a solution containing poly (ethylene glycol) double acrylate (PEGDA) and 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH). Upon intratumoral injection and exposure to the AMF, IONCs in PAFG precursor solution mediated rapid temperature increase, which not only induced hyperthermia damage to tumor tissues, but also promoted chemodynamic effect and GOx-based catalysis, and triggered AIPH to produce radicals for PEGDA polymerization. As an oxido-reductase, GOx could catalyze the oxidation of intratumoral glucose into gluconic acid and H₂O₂, which not only promoted iron-based chemodynamic effect but also depleted glucose and oxygen for tumor starvation. This synergistic antitumor platform leads to complete cancer cell death in vitro and tumor eradication in vivo under mild hyperthermia.

Chapter 3: Magnetic iron oxide nanorods (IONRs)-based delivery system with surface charge conversion capability was developed for second near infrared light (NIR-II)/AMF/tumor acidity-triggered systemic photothermal/magnetothermal/ chemo- cancer treatment. Specifically, magnetic IONRs were decorated with polyethyleneimine (PEI, denoted as P) and 2,3-dimethylmaleic anhydride (DMMA, denoted as D) successively. The pH-labile amide bonds linking PEI and DMMA could be hydrolyzed in a mild acidic tumor microenvironment (TME) thus DMMA was exfoliated from nanoparticles, accompanied with the surface charge reverse to positive. This could subsequently lead to the proton-sponge effect for nanoparticles escaping from the lysosome. Taking advantage of the magnetothermal and photothermal effects of IONRs, both AMF and 1060 nm NIR-II light were utilized to induce hyperthermia from IONRs, wherein the two triggers complemented each other and amplified the in vivo heating efficiency significantly. Moreover, the therapeutic efficacy could be further enhanced by loading chemotherapeutic drug doxorubicin (DOX) onto the nanorods via electrostatic interaction with DMMA. This magnetothermal/photothermal/chemo- triple-mode treatment resulted in nearly complete cancer cell death in vitro and xenograft/metastatic tumor inhibition in vivo at a relatively low dosage, tolerable AMF, and acceptable laser power.

Chapter 4: A core-shell structured multifunctional nanoplatform was prepared by stepwise supramolecular self-assembly for fluorescence imaging-guided, acidity/H₂O₂/NIR-triggered chemo-/chemodynamic/photothermal/photodynamic cancer therapy. Specifically, the nanoparticle core composed of ferroptosis inducer sorafenib (SRF, denoted as S) and photosensitizer indocyanine green (ICG, denoted as I) was synthesized by a brief vortex. Then the ferric iron (Fe³⁺, denoted as F) and naturally derived polyphenol compound tannic acid (TA, denoted as T) were self-assembled by vortex to form a network-like shell onto the SI core. The synthesized nanoparticle could respond to an acidic environment with the destruction of FT shell, releasing SRF for ferroptosis induction. Meanwhile, TA molecules could reduce the endogenous and liberated Fe³⁺ ions into ferrous iron Fe²⁺, thus promoting the chemodynamic process continuously. With 808 nm laser irradiation, SIFT nanoparticles showed excellent photothermal effect and photodynamic performance. This novel SIFT nanoassemblies-based theranostic nanoplatform will open new perspectives for conquering malignancies via ferroptosis induction.

Chapter 5: Conclusions and future perspectives.

Date of Award	4 Jan 2022
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	M YANG (Supervisor)