Constructing Clinically Translatable Silica Nanohybrids to Eradicate Hypoxic Tumor Cells

Nanomedicine is promising and capable of integrating therapeutics with nanocarriers to improve treatment for cancers. However, a review paper published recently in Nature Reviews Materials highlighted that only 0.7% (median) of a systemically administrated dose of nanoparticle-based drugs ends up in the tumor, and the targeting efficiency is not improving in the past ten years. In addition, hypoxia is crucially involved in tumor progression, resulting in resistance to cancer therapy. Consequently, efforts only focus on solving one issue at a time is not enough to meet the emerging field of nanomedicine. In this proposal, we propose three progressive strategies to bridge the gap between academic research and clinical practice, focusing on targeting hypoxia in cancer therapy. The first part regarding the enhanced permeability and retention (EPR) effect based tumor targeting would be approached by (1) high density PEGylation; (2) spatial control of functional groups on the surface and (3) making of small mesoporous silica nanoparticles (MSN). Here, MSN with various size and surface modification, which are the particularly important two parameters for interface interaction, will be highlighted. On the one hand, blood circulation time and tumor-targeted accumulation of MSN will be investigated by using the intravital two-photon laser scanning fluorescence microscopy and in vivo imaging system (IVIS), respectively. On the other hand, the time-dependent evolution of the in vivo formed protein corona, including the type and amount of proteins, will be investigated by high-resolution quantitative LC-MS/MS based proteomics. Particularly important would be the understanding of how protein corona affects the tumor-targeting efficiency and biodistribution of nanoparticles. Such a database would allow us to uncover the fundamental mechanisms of nano-bio interactions, and enable the prediction of biological function based on nanoparticle design. The second part regards the synthesis of compartmentalized hollow silica nanoparticles (cHSN) with exterior modification of polyethylene glycol (PEG) and interior encapsulation of theranostic agents, including but not limiting to (1) anticancer drug doxorubicin (Dox); (2) MR contrast agent magnetite (Fe3O4); (3) radiosensitizer tantalum oxide (TaOx) and (4) enzyme catalase (CAT). Modification of PEG can take advantage of the EPR effect in tumor by slowing clearance and prolonging blood circulation of nanoparticles. The presence of CAT, serving as an oxygen-generating center, can rapidly decompose endogenous H2O2 into O2, thereby enhancing the cytotoxicity of DOX against hypoxia in tumor cells. At the same time, synergistic effects would occur while combining the above approaches with radiotherapy of applying the high-Z material TaOx, which can concentrate radiation energy within the tumor and enhance radiation-induced DNA damage. In addition, Fe3O4 and TaOx can serve respectively as MR and CT contrast agent for diagnostic purposes. The third part regards the feasibility of scaled-up production of MSN and HSN. To manufacture nanoparticles for pre/clinical trials and drive successful transitions from lab to market, a scalable protocol (proof-of-process) will be developed by careful selection of process parameters. In summary, this proposal is aimed towards clarifying the relationship between synthetic identity and physiological responses, with a focus on developing clinically translatable nanomedicine to eradicate hypoxic tumor cells.