PMID- 32081779 OWN - NLM STAT- MEDLINE DCOM- 20210330 LR - 20210330 IS - 1878-7568 (Electronic) IS - 1742-7061 (Linking) VI - 106 DP - 2020 Apr 1 TI - Cell-penetrating corosolic acid liposome as a functional carrier for delivering chemotherapeutic drugs. PG - 301-313 LID - S1742-7061(20)30092-1 [pii] LID - 10.1016/j.actbio.2020.02.013 [doi] AB - Corosolic acid (CA), a natural pentacyclic triterpenoid, exhibits antitumor and synergistic therapy effect with chemotherapeutic drugs mainly through inhibiting STAT3 activation. In this study, it is found that CA possesses cholesterol-like properties in liposome by regulating membrane phase behavior to form stable cholesterol-free CA liposomes (CALP). Compared with traditional cholesterol liposomes (CHOLP), CALP exhibit stronger membrane fusion and higher cellular uptake, and other functions including inhibition of STAT3 activation and suppression of the recruitment of macrophages to tumor microenvironment. Therefore, CALP is used as a functional carrier, and doxorubicin-loaded CALP (DOX/CALP) based on PEGylated liposomal doxorubicin (DOXIL(Ⓡ)) are prepared by replacing its cholesterol with CA. The physicochemical properties and biological activities are compared with those of doxorubicin-loaded cholesterol liposomes (DOX/LP). Both DOX/CALP and DOX/LP possess approximately similar physical properties and exhibit high stability and low drug leakage as shown by the published data of DOXIL(Ⓡ). Nevertheless, it is noteworthy that DOX/CALP displays higher in vitro cellular uptake and tumor spheroid permeation along with stronger cytotoxicity against tumor cells than DOX/LP. Despite DOX/CALP has the same PK parameters, normal tissue biodistribution, and safety profile as DOX/LP, the results of an in vivo study in 4T1-bearing mice indicate that the DOX/CALP treatment group exhibit higher tumor accumulation, more significant tumor growth inhibition, and longer life span than the DOX/LP group. Overall, DOX/CALP is a representative example of CA-doped liposomes, suggesting that CALP as a functional drug carrier for solving low efficacy of present liposomal drugs might have promising application potential. STATEMENT OF SIGNIFICANCE: An original drug delivery nanocarrier, corosolic acid liposome (CALP), was developed in this study. It was found that CA possesses cholesterol-like function to regulate phospholipid membrane phase behavior. By replacing the cholesterol with CA, the liposomes were converted into high cellular uptake carriers, possessing anti-inflammatory activity and synergism with chemotherapeutic drugs. The variability of CALP formulations enabled to deliver therapeutic agents. The use of CALP to deliver doxorubicin not only significantly enhanced the therapeutic efficacy compared with the classic PEGylated liposomal doxorubicin, but also maintained the improved safety. Because CALP can be obtained by conventional liposome preparation methods, its use as functional drug carriers for solving low efficacy of present liposomal drugs would have promising application potential. CI - Copyright (c) 2020. Published by Elsevier Ltd. FAU - Li, Xuqian AU - Li X AD - Key Laboratory of Smart Drug Delivery, Ministry of Education (Fudan University), Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China. FAU - Widjaya, Andy Samuel AU - Widjaya AS AD - Key Laboratory of Smart Drug Delivery, Ministry of Education (Fudan University), Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China. FAU - Liu, Jingxuan AU - Liu J AD - Key Laboratory of Smart Drug Delivery, Ministry of Education (Fudan University), Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China. FAU - Liu, Xiao AU - Liu X AD - Key Laboratory of Smart Drug Delivery, Ministry of Education (Fudan University), Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China. FAU - Long, Zhiguo AU - Long Z AD - Department of Hematology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, PR China. FAU - Jiang, Yanyan AU - Jiang Y AD - Key Laboratory of Smart Drug Delivery, Ministry of Education (Fudan University), Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: yanyanjiang@fudan.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200217 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 0 (Antineoplastic Agents) RN - 0 (Drug Carriers) RN - 0 (Liposomes) RN - 0 (Triterpenes) RN - 80168379AG (Doxorubicin) RN - AMX2I57A98 (corosolic acid) SB - IM MH - Animals MH - Antineoplastic Agents/chemistry/pharmacokinetics/*therapeutic use MH - Breast Neoplasms/*drug therapy MH - Cell Line, Tumor MH - Doxorubicin/chemistry/pharmacokinetics/*therapeutic use MH - Drug Carriers/*chemistry MH - Drug Liberation MH - Female MH - Liposomes/*chemistry MH - Mice MH - RAW 264.7 Cells MH - Rats, Sprague-Dawley MH - Triterpenes/chemistry/pharmacokinetics/*therapeutic use OTO - NOTNLM OT - Cholesterol OT - Coroslic acid OT - Doxorubicin OT - Liposome OT - Synergistic therapy COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/02/23 06:00 MHDA- 2021/03/31 06:00 CRDT- 2020/02/22 06:00 PHST- 2019/08/05 00:00 [received] PHST- 2020/01/17 00:00 [revised] PHST- 2020/02/11 00:00 [accepted] PHST- 2020/02/23 06:00 [pubmed] PHST- 2021/03/31 06:00 [medline] PHST- 2020/02/22 06:00 [entrez] AID - S1742-7061(20)30092-1 [pii] AID - 10.1016/j.actbio.2020.02.013 [doi] PST - ppublish SO - Acta Biomater. 2020 Apr 1;106:301-313. doi: 10.1016/j.actbio.2020.02.013. Epub 2020 Feb 17.