PMID- 35577150 OWN - NLM STAT- MEDLINE DCOM- 20220628 LR - 20220801 IS - 1873-4995 (Electronic) IS - 0168-3659 (Linking) VI - 347 DP - 2022 Jul TI - Prolonged blood circulation outperforms active targeting for nanocarriers-mediated enhanced hepatocellular carcinoma therapy in vivo. PG - 400-413 LID - S0168-3659(22)00287-5 [pii] LID - 10.1016/j.jconrel.2022.05.024 [doi] AB - Successful hepatocellular carcinoma (HCC) therapy in vivo remains a significant challenge due to the down-regulated expression of the receptors on the surface of tumor cells for compromised active targeting efficiency and cellular uptake of nanoparticles (NPs)-based drug delivery systems (DDSs) and "accelerated blood clearance" and premature unpackaging of NPs in vivo induced by the poly(ethylene glycol)ylation (PEGylation). Inspired by the repeatedly highlighted prolonged blood circulation property of RBCm-camouflaged NPs, we hypothesis that the prolonged blood circulation property resulting from RBCm coating outperforms the active targeting mechanisms of various targeting ligands for enhanced HCC therapy in vivo. Clarification of this hypothesis is therefore of great significance and urgency to break the afore mentioned bottlenecks that hamper the efficient HCC treatment in vivo. For this purpose, we reported in this study the first identification of a determining factor of nanocarriers for enhanced HCC therapy in vivo by the use of the previously fabricated pectin-doxorubicin nanoparticles (PDC-NPs) as a typical example, i.e., the natural RBCm was used as a stealth coating of PDC-NPs for the fabrication of biomimetic DDSs, PDC@RBC-NPs via hypotonic dialysis and mechanical co-extrusion methods. Comprehensive in vitro and in vivo evaluation and comparison of the properties and performance of PDC@RBC-NPs and PDC-NPs were performed in terms of colloidal stability, biosafety, drug release profiles, macrophage escape, anti-HCC effect. The resulting PDC@RBC-NPs outperformed PDC-NPs for HCC therapy in vitro and in vivo. Notably, PDC@RBC-NPs-treated BALB/c nude mice showed a significantly smaller final average tumor volume of 613 mm(3) after 16 days than the PDC-NPs-treated group with an average value of 957 mm(3). Therefore, the PDC@RBC-NPs developed herein showed great potential for clinical transformations due to the facile preparation and superior therapeutic efficiency against HCC. Most importantly, prolonged blood circulation was identified as a determining factor of nanocarriers instead of active targeting for enhanced HCC therapy in vivo, which could be used to direct the future design and development of advanced DDSs with greater therapeutic efficiency for HCC. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Wang, Yue-Qing AU - Wang YQ AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. FAU - Huang, Cong AU - Huang C AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. FAU - Ye, Peng-Ju AU - Ye PJ AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. FAU - Long, Jin-Rong AU - Long JR AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. FAU - Xu, Cheng-Hu AU - Xu CH AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. FAU - Liu, Ying AU - Liu Y AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. FAU - Ling, Xiao-Li AU - Ling XL AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. FAU - Lv, Shao-Yang AU - Lv SY AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. FAU - He, Dong-Xiu AU - He DX AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. FAU - Wei, Hua AU - Wei H AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. Electronic address: weih@usc.edu.cn. FAU - Yu, Cui-Yun AU - Yu CY AD - Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. Electronic address: yucuiyunusc@hotmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220518 PL - Netherlands TA - J Control Release JT - Journal of controlled release : official journal of the Controlled Release Society JID - 8607908 RN - 80168379AG (Doxorubicin) SB - IM MH - Animals MH - *Carcinoma, Hepatocellular/pathology MH - Doxorubicin MH - *Liver Neoplasms/metabolism MH - Mice MH - Mice, Nude MH - *Nanoparticles MH - Renal Dialysis OTO - NOTNLM OT - Biomimetic nanoparticle OT - Erythrocyte membrane OT - Hepatocellular carcinoma OT - Long circulation OT - Macrophage escape EDAT- 2022/05/17 06:00 MHDA- 2022/06/29 06:00 CRDT- 2022/05/16 19:34 PHST- 2021/09/29 00:00 [received] PHST- 2022/04/17 00:00 [revised] PHST- 2022/05/10 00:00 [accepted] PHST- 2022/05/17 06:00 [pubmed] PHST- 2022/06/29 06:00 [medline] PHST- 2022/05/16 19:34 [entrez] AID - S0168-3659(22)00287-5 [pii] AID - 10.1016/j.jconrel.2022.05.024 [doi] PST - ppublish SO - J Control Release. 2022 Jul;347:400-413. doi: 10.1016/j.jconrel.2022.05.024. Epub 2022 May 18.