Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly.

Abstract

BACKGROUND:

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). Therefore, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors.

RESULTS:

In 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.

CONCLUSIONS:

TH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics.

• Authors: Yesi Shi, Gan Lin, Huili Zheng, Dan Mu, Hu Chen, Zhixiang Lu, Pan He, Yang Zhang, Chao Liu, Zhongning Lin, Gang Liu
• Journal: Journal of nanobiotechnology (J Nanobiotechnology) Vol. 19 Issue 1 Pg. 447 (Dec 24 2021) ISSN: 1477-3155 [Electronic] England
• PMID: 34952594 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Antineoplastic Agents
• Cadherins
• Drug Carriers
• Paxillin
• Oxaliplatin
• Polylactic Acid-Polyglycolic Acid Copolymer
• Hydroxychloroquine

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology, therapeutic use)
• Autophagy (drug effects)
• Biomimetic Materials (chemistry)
• Cadherins (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Drug Carriers (chemistry)
• Drug Liberation
• Focal Adhesions (chemistry, drug effects, metabolism)
• Humans
• Hydroxychloroquine (chemistry, metabolism, pharmacology, therapeutic use)
• Lung Neoplasms (drug therapy, secondary)
• Mice
• Nanoparticles (chemistry)
• Neoplasms (pathology)
• Oxaliplatin (chemistry, metabolism, pharmacology, therapeutic use)
• Paxillin (metabolism)
• Polylactic Acid-Polyglycolic Acid Copolymer (chemistry)