Abstract
Cancer phenotypic lethality targets a nonessential enzyme in normal cells that is required for cancer survival, which can overcome the problem of the high degree of intra-tumor heterogeneity and be more widely applicable, irrespective of the cancer genotype. Altered redox regulation is a cancer phenotype and damages both the DNA and free deoxynucleoside triphosphates (dNTPs) pool. MutT Homolog1 (MTH1) plays a critical role in removing oxidized dNTPs, avoiding incorporation of these damaged bases. This study aimed to construct a self-assembly reproducible nanoplatform (SRNA) to actualize cancer phenotypic lethality in solid tumors by efficiently delivering of MTH1 siRNA (siMTH1). Compared with conventional polymer vectors, the synthesized cholesteryl-peptides had precise molecular weights, good biocompatibility and low variability. Thus, the cholesteryl-peptides were used to form a compact SRNA with siMTH1 and protect siMTH1 against degradation. The SRNA silenced MTH1 expression and accumulated oxidized dNTPs in cancer cells, leading to a therapeutic response in ovarian cancer. In summary, the SRNA for the efficient delivery of siMTH1 may provide a practical paradigm to induce cancer phenotypic lethality in solid tumors.
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