Abstract
BackgroundAutophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). Therefore, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors.ResultsIn this work, we developed a biomimetic nanoformulation (TH-NP) co-encapsulating Oxaliplatin (OXA)/hydroxychloroquine (HCQ, an autophagy inhibitor) to execute targeted autophagy inhibition, reduce tumor cell migration and invasion in vitro and attenuate metastasis in vivo. The tumor cell-specific ligand TRAIL was bioengineered to be stably expressed on HUVECs and the resultant membrane vesicles were wrapped on OXA/HCQ-loaded PLGA nanocores. Especially, TH-NPs could significantly improve OXA and HCQ effective concentration by approximately 21 and 13 times in tumor tissues compared to the free mixture of HCQ/OXA. Moreover, the tumor-targeting TH-NPs released HCQ alkalized the acidic lysosomes and inhibited the fusion of autophagosomes and lysosomes, leading to effective blockade of autophagic flux. In short, the system largely improved chemotherapeutic performance of OXA on subcutaneous and orthotopic HCC mice models. Importantly, TH-NPs also exhibited the most effective inhibition of tumor metastasis in orthotopic HCCLM3 models, and in the HepG2, Huh-7 or HCCLM3 metastatic mice models. Finally, we illustrated the enhanced metastasis inhibition was attributed to the blockade or reverse of the autophagy-mediated degradation of focal adhesions (FAs) including E-cadherin and paxillin.ConclusionsTH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics.Graphical
Highlights
Despite the enormous therapeutic potential of chemotherapy, it benefits only a small subset of patients and the response rate of OXA-based chemotherapy in overall patients is unsatisfactory, which limits the application in clinical practice [1,2,3]
To further evaluate whether the synergistic effect was associated with autophagy, the HCCLM3 GFP-LC3 overexpressing cells were co-cultured with the indicated drugs
The results showed that GFP-LC3 puncta aggregated more in the cells treated with the HCQ/OXA than other treatments, indicating HCQ blocked OXA-triggered protective autophagy and enhanced OXA chemosensitivity, confirming by the increased expression of cleaved PARP (Additional file 1: Figure S1B–D)
Summary
Despite the enormous therapeutic potential of chemotherapy, it benefits only a small subset of patients and the response rate of OXA-based chemotherapy in overall patients is unsatisfactory, which limits the application in clinical practice [1,2,3]. Chemotherapy-triggered protective autophagy plays a crucial role in producing negative chemotherapeutic response rates on cancer patients [4, 5]. The triggered protective autophagy is the process, in which autophagosomes fused with lysosomes to form autolysosomes [12, 13], subsequently degrades protein aggregates or damaged organelles, and is activated during chemotherapy to generate metabolites and energy to meet the metabolic demands of cancer cells [14,15,16]. Autophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). A vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors
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