Development of a mesoporous silica based nanosystem for safe and efficient therapeutic delivery

Abstract

The emergence of nanotechnology have revolutionized the landscape of cancer therapy, offering an effective and universal platform for delivery of various anti-cancer therapeutics with improved potency and safety. As a classic family of drug delivery vehicle, mesoporous silica based nanomaterials have attracted tremendous attention due to their tuneable size, morphology, structure and surface/framework chemistry. Moreover, mesoporous silica based nanomaterials have recently been reported as potent immuno-adjuvant to stimulate robust immune response, and exhibited promising performance in cancer immunotherapy. However, given the complicated in vivo environment and the potential risks of accumulation in major organs as well as unwanted toxicity, the design of mesoporous silica based nanomaterials with improved biosafety and delivery efficiency is of great importance. This thesis aims to develop new generation of mesoporous silica based nanoparticles mediated nanosystem for cancer therapy via rationally engineered architecture and molecular structure.The first section of this thesis reports an innovative anion assisted approach to prepare large pore dendritic mesoporous silica nanoparticles. More importantly, this synthetic approach can not only be used for prepare inorganic silica materials, but also for hybrid dendritic mesoporous organosilica nanoparticles (DMONs). The key innovation of our approach is that we selected a water soluble anion, salicylate, as the structure directing agent to match the hydrolysis and condensation kinetics of organic and inorganic silica precursors, leading to self-assembly of a unique dendritic structure, while conventional methods using nonpolar oil molecules would significantly interfere the co-condensation behaviour of two types of precursors and results in aggregated and irregular nanoparticles. Furthermore, we found that the hybrid DMONs possess a composition gradient with an organosilica rich shell and inorganic silica rich core. Selective etching of the inorganic silica part results in the formation of dendritic hollow mesoporous organosilica nanoparticles. With negligible cytotoxicity and hemolytic activity, these nanoparticles are promising candidates for drug delivery applications. This work has been published on Chemistry of Materials.Building on the successful development of the anion assisted synthetic approach, in the second section of this thesis, we incorporated disulphide bond in the hybrid dendritic silica framework and reported the first example of cancer cell-specific degradable dendritic mesoporous organosilica nanoparticles (DDMONs). These smart nanoparticles were able to recognize and respond to the minor difference of glutathione (GSH) concentration between normal cells and cancer cells, causing preferential nanoparticle degradation and concomitant drug release in the latter. As a proof of concept, we delivered a cytotoxic protein using DDMONs and observed a dramatically higher inhibition rate in cancer cells (B16F0) than normal cells (HEK293). The cancer cell specific degradable nanoparticles significantly reduced the side effects of therapeutics, providing new opportunities in designing safe and effective drug delivery nanosystems. This work has been published on Chemistry of Materials.In the third section of the thesis, we extended the findings the previous work to design a novel cascade delivery system with tandem functions by integrating a hypoxia-activated prodrug (AQ4N) and glucose oxidase (GOx). Yolknshell organosilica nanoparticles with a tetrasulfide bridged composition, a small-pore yolk, and a large-pore shell featuring a shell-to-yolk stepwise degradability are constructed as a carrier for AQ4N and GOx, one enzyme that catalyzes the oxidation of glucose to produce hydrogen peroxide. The glutathione (GSH) is depleted by tetrasulfide bond in the framework and induces shell degradation for fast release of GOx, which in turn induces starvation (glucose removal), oxidative cytotoxicity (H2O2 production and GSH depletion), and hypoxia (oxygen consumption). Finally, the hypoxia activates the liberated prodrug AQ4N for chemotherapy. The cascading and synergistic functions including GSH depletion, starvation, oxidative cytotoxicity, and chemotherapy lead to improved performance in tumour inhibition and antimetastasis. This work has been published on Advanced Functional Materials.In the fourth section of this thesis, we developed silica based immune-adjuvants for the stimulation of robust immune response for cancer immunotherapy. We constructed double-shelled dendritic mesoporous organosilica hollow spheres with ethyl incorporated framework, and demonstrated their excellent adjuvant performance and provide superior immunity in cancer immunotherapy, and better than their counterparts either with a pure silica composition or a single-walled architecture. This study provides new insights in the rational design of effective nanostructured adjuvants for vaccine developments. This work has been published on Angewandte Chemie.In the last section of this thesis, we report rationally designed hybrid nanoreactors with integrated functions as Fenton catalysts and glutathione depletion agents for amplifying the immunogenic cell death and activating immune cells. A simple physical mixture of nanoreactors and chemodrugs in combination with immune checkpoint blockades show synergistically and concurrently enhanced chemo-immunotherapy efficacy, inhibiting the growth of both treated primary immuno-suppressive tumours and untreated distant tumours. The loff-the-shelfr strategy uses in situ generated tumour antigens and avoids cargo loading, representing a substantial advance in personalized nanomedicine for clinical translation. This work has been published on Angewandte Chemie.