PMID- 33975609 OWN - NLM STAT- MEDLINE DCOM- 20211108 LR - 20211108 IS - 1477-3155 (Electronic) IS - 1477-3155 (Linking) VI - 19 IP - 1 DP - 2021 May 11 TI - ROS-responsive liposomes with NIR light-triggered doxorubicin release for combinatorial therapy of breast cancer. PG - 134 LID - 10.1186/s12951-021-00877-6 [doi] LID - 134 AB - BACKGROUND: Reactive oxygen species (ROS)-responsive drug delivery systems (DDSs) are potential tools to minimize the side effects and substantially enhance the therapeutic efficacy of chemotherapy. However, it is challenging to achieve spatially and temporally controllable and accurate drug release in tumor sites based on ROS-responsive DDSs. To solve this problem, we designed a nanosystem combined photodynamic therapy (PDT) and ROS-responsive chemotherapy. METHODS: Indocyanine green (ICG), an ROS trigger and photosensitizer, and pB-DOX, a ROS-responsive prodrug of doxorubicin (DOX), were coencapsulated in polyethylene glycol modified liposomes (Lipo/pB-DOX/ICG) to construct a combination therapy nanosystem. The safety of nanosystem was assessed on normal HEK-293 cells, and the cellular uptake, intracellular ROS production capacity, target cell toxicity, and combined treatment effect were estimated on human breast cancer cells MDA-MB-231. In vivo biodistribution, biosafety assessment, and combination therapy effects were investigated based on MDA-MB-231 subcutaneous tumor model. RESULTS: Compared with DOX.HCl, Lipo/pB-DOX/ICG showed higher safety on normal cells. The toxicity of target cells of Lipo/pB-DOX/ICG was much higher than that of DOX.HCl, Lipo/pB-DOX, and Lipo/ICG. After endocytosis by MDA-MB-231 cells, Lipo/pB-DOX/ICG produced a large amount of ROS for PDT by laser irradiation, and pB-DOX was converted to DOX by ROS for chemotherapy. The cell inhibition rate of combination therapy reached up to 93.5 %. After the tail vein injection (DOX equivalent of 3.0 mg/kg, ICG of 3.5 mg/kg) in mice bearing MDA-MB-231 tumors, Lipo/pB-DOX/ICG continuously accumulated at the tumor site and reached the peak at 24 h post injection. Under irradiation at this time point, the tumors in Lipo/pB-DOX/ICG group almost disappeared with 94.9 % tumor growth inhibition, while those in the control groups were only partially inhibited. Negligible cardiotoxicity and no treatment-induced side effects were observed. CONCLUSIONS: Lipo/pB-DOX/ICG is a novel tool for on-demand drug release at tumor site and also a promising candidate for controllable and accurate combinatorial tumor therapy. FAU - Yi, Hanxi AU - Yi H AD - Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo road 172, Changsha, 410000, China. FAU - Lu, Wangxing AU - Lu W AD - Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo road 172, Changsha, 410000, China. FAU - Liu, Fan AU - Liu F AD - Neurology department, The First affiliated Xiangya hospital, Central South University, Changsha, China. FAU - Zhang, Guoqing AU - Zhang G AD - Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo road 172, Changsha, 410000, China. FAU - Xie, Feifan AU - Xie F AD - Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo road 172, Changsha, 410000, China. FAU - Liu, Wenjie AU - Liu W AD - Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo road 172, Changsha, 410000, China. FAU - Wang, Lei AU - Wang L AD - Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo road 172, Changsha, 410000, China. FAU - Zhou, Wenhu AU - Zhou W AD - Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China. FAU - Cheng, Zeneng AU - Cheng Z AUID- ORCID: 0000-0001-9352-9744 AD - Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo road 172, Changsha, 410000, China. chengzn@csu.edu.cn. LA - eng GR - 82073932/National Natural Science Foundation of China/ PT - Journal Article DEP - 20210511 PL - England TA - J Nanobiotechnology JT - Journal of nanobiotechnology JID - 101152208 RN - 0 (Liposomes) RN - 0 (Photosensitizing Agents) RN - 0 (Prodrugs) RN - 0 (Reactive Oxygen Species) RN - 17778-80-2 (Singlet Oxygen) RN - 80168379AG (Doxorubicin) RN - IX6J1063HV (Indocyanine Green) SB - IM MH - Animals MH - Breast Neoplasms/*drug therapy MH - Cell Line, Tumor MH - Combined Modality Therapy MH - Doxorubicin/*pharmacology MH - Drug Delivery Systems MH - Drug Liberation MH - Female MH - HEK293 Cells MH - Humans MH - Indocyanine Green MH - *Liposomes MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Photochemotherapy MH - Photosensitizing Agents/pharmacology MH - Phototherapy MH - Prodrugs MH - *Reactive Oxygen Species MH - Singlet Oxygen MH - Tissue Distribution PMC - PMC8111982 OTO - NOTNLM OT - Photodynamic therapy OT - Photothermal therapy OT - Prodrug OT - Reactive oxygen species response OT - Synergistic therapy COIS- The authors declare that they have no competing interests. EDAT- 2021/05/13 06:00 MHDA- 2021/11/09 06:00 PMCR- 2021/05/11 CRDT- 2021/05/12 05:50 PHST- 2021/03/05 00:00 [received] PHST- 2021/04/28 00:00 [accepted] PHST- 2021/05/12 05:50 [entrez] PHST- 2021/05/13 06:00 [pubmed] PHST- 2021/11/09 06:00 [medline] PHST- 2021/05/11 00:00 [pmc-release] AID - 10.1186/s12951-021-00877-6 [pii] AID - 877 [pii] AID - 10.1186/s12951-021-00877-6 [doi] PST - epublish SO - J Nanobiotechnology. 2021 May 11;19(1):134. doi: 10.1186/s12951-021-00877-6.