Abstract
Knocking down the oncogene ROC1 with siRNA inhibits the proliferation of cancer cells by suppressing the Neddylation pathway. However, methods for delivering siRNA in vivo to induce this high anticancer activity with low potential side effects are urgently needed. Herein, a folic acid (FA)-modified polydopamine (PDA) nanomedicine used in photothermal therapy was designed for siRNA delivery. The designed nanovector can undergo photothermal conversion with good biocompatibility. Importantly, this genetic nanomedicine was selectively delivered to liver cancer cells by FA through receptor-mediated endocytosis. Subsequently, the siRNA cargo was released from the PDA nanomedicine into the tumor microenvironment by controlled release triggered by pH. More importantly, the genetic nanomedicine not only inhibited liver cancer cell proliferation but also promoted liver cell apoptosis by slowing ROC1 activity, suppressing the Neddylation pathway, enabling the accumulation of apototic factor ATF4 and DNA damage factor P-H2AX. Combined with photothermal therapy, this genetic nanomedicine showed superior inhibition of the growth of liver cancer in vitro and in vivo. Taken together, the results indicate that this biodegradable nanomedicine exhibits good target recognition, an effective pH response, application potential for genetic therapy, photothermal imaging and treatment of liver cancer. Therefore, this work contributes to the design of a multifunctional nanoplatform that combines genetic therapy and photothermal therapy for the treatment of liver cancer.
Highlights
Liver cancer is one of the most common human malignant tumors with high morbidity and extremely high mortality rates [1]
The folic acid (FA) molecule used for targeting cancer tissues was added the surface of the PDA nanomedicine through an ethylcarbodiimide hydrochloride (EDC)/NHS-mediated covalent coupling reaction involving the amino groups of PDA and the carboxyl groups of FA
The genetic nanomedicine knock down the oncogene ROC1 (E3) and suppressed the Neddylation pathway, and its effect was combined with that of photothermal therapy to efficiently inhibit the growth of liver cancer
Summary
Liver cancer is one of the most common human malignant tumors with high morbidity and extremely high mortality rates [1]. Liver cancer seriously endangers human health and life safety, traditional anticancer drugs are characterized by low efficiency and highly toxic side effects, which severely restrict the therapeutic efficiency of liver cancer [2]. Neddylation is a newly discovered posttranslational protein modification pathway that regulates the biological activity of target proteins by binding and degrading them [3]. Neddylation modification is an energy-consuming cascade of reaction processes [4]. The ubiquitin-like small molecule NEDD8 (neural precursor cell-expressed developmentally downregulated 8) is activated by an E1 NEDD8-activating enzyme (NAE, a heterodimer consisting of NAE1 and UBA3) in the presence of ATP [5]. Activated NEDD8 is transferred to an E2 NEDD8-conjugating enzyme
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