LMP And Mth1-Targeted Multifunctional Nanocomposites For Liver Cancer Theranostics

Malignant tumors, also known as cancer, are one of the major diseases that seriously affect human health. As a common cancer type with a high mortality, liver cancer is an important part in cancer prevention and control. With the discovery of new drugs and the improvement of therapeutic modalities, the clinical arsenal in treating liver cancer has been greatly extended in recent years. Traditional approaches, such as surgery, radiotherapy and chemotherapy still occupy the leading position. However, these traditional methods face serious limitations such as the potential side effects, the drug resistance and the lack of targeting ability, which made it difficult to achieve the desired therapeutic effect. The development of nanotechnology has the potential to solve these problems. Based on the superior properties of nanomaterials, nano probes and drug carriers have become a powerful tool for diagnosis and treatment of liver cancer. However, the hidden initial symptoms and rapid deterioration make it difficult for early detection and therapy of liver cancer. Therefore, the development of theranostic nanoplatform with highly targeting and precision controlled-release drug has become a foucs in the research of liver cancer.Heterogeneous nanostructured materials have attracted more and more attention because of their unique shape and excellent performance. These multicomponent nanomaterials with adjustable composition and morphology, can serve as a multifunctional platform for simultaneous detection, imaging and therapy. Therefore, they have become the best choice for the construction of theranostic probes. Gold nanoparticles(Au NPs), due to its superior ability of fluorescence quenching and surface modification, are commonly used for constructing of theranostic nanoprobes. Mesoporous silica nanoparticles(MSNs) are considered to be ideal candidates for drug delivery because of their high surface area, large pore volume, easy functionalization and good biocompatibility in vivo. Worth of noting, lysosomal membrane permeabilization(LMP) and the MutT Homolog1 protein(MTH1), “Achilles heel” for cancer cells, provides new targets for cancer treatment. However, LMP and MTH1-based theranostic nanoprobes have not yet been exploited at all.In this study, the recent research progress on the application of nanomaterials in liver cancer diagnosis and treatment are reviewed. Based on the new type of heterogeneous nanostructured materials and nanocomposites assembled by Au NPs with MSN, and the LMP and MTH1 anti-cancer targets, we carried out the following work:1. Through targeting LMP, we have developed multifunctional Au-ZnO hybrid nanoparticles(NPs) for targeted induction LMP-dependent apoptosis in cancer cells and real-time imaging. The as-prepared Au-ZnO NPs combine the merits of both Au and ZnO NPs, maintaining excellent fluorescence quenching properties and catalytic activity. Conjugated with the fluorescein isothiocyanate(FITC)-labeled lysosomal protease Cathepsin B substrate sequence(Arg-Arg, RR) and the αvβ3 integrin-targeting peptide(RGD) on the Au and ZnO surface, respectively, the resulting FITC-RR-Au-ZnO-RGD NPs bind preferentially to integrin ανβ3-rich human liver cancer cells(HepG2), sequentially accumulate in their lysosomes to catalyze lysosomal ROS production and enable the real-time monitoring of ROS-induced LMP-dependent apoptosis in these cancer cells. The Au-ZnO hybrid NPs can serve as a multifunctional platform for simultaneous targeting, therapy and imaging, thus the result implicated the potential application of killing cancer cells and cancer treatment by activating lysosomal death pathway.2. Through targeting MTH1, we have designed and constructed a gold nanoparticle(AuNP) flares-capped mesoporous silica nanoplatform for MTH1 detection and inhibition, simultaneously targeting therapy and imaging analysis for liver cancer. The AuNP flares are made from AuNPs that are functionalized with a dense shell of MTH1 recognition sequences hybridized to short cyanine(Cy5)-labeled reporter sequences and employed to seal the pores of MSN to prevent the premature MTH1 inhibitors(S-crizotinib) release. Just like the pyrotechnic flares that produce brilliant light when activated, the resulting AuNP flares@MSN(S-crizotinib) undergo a significant burst of red fluorescence enhancement upon MTH1 mRNA binding. This hybridization event subsequently induces the opening of the pores and the release of S-crizotinib in an mRNA-dependent manner, leading to significant cytotoxicity in cancer cells and improved therapeutic response in mouse xenograft models. We anticipate that this nanoplatform may be an important step toward the development of MTH1-targeting theranostics and also be a useful tool for cancer phenotypic lethal anticancer therapy.