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triphenylphosphonium-modified mitochondria-targeted paclitaxel nanocrystals for overcoming multidrug resistance

Asian Journal of Pharmaceutical Sciences 2019年第5期14卷 569-580页

作者： Xue Han Ruijuan Su Xiuqing Huang Yingli Wang Xiao Kuang Shuang Zhou Hongzhuo Liu Shenyang Pharmaceutical University

Mitochondria are currently known as novel targets for treating cancer,especially for tumors displaying multidrug resistance(MDR). This present study aimed to develop a mitochondriatargeted delivery system by using triphenylphosphonium cation(TPP+)-conjugated Brij 98 as the functional stabilizer to modify paclitaxel(PTX) nanocrystals(NCs) against drugresistant cancer cells. Evaluations were performed on 2 D monolayer and 3 D multicellular spheroids(MCs) of MCF-7 cells and MCF-7/ADR cells. In comparison with free PTX and the non-targeted PTX NCs,the targeted PTX NCs showed the strongest cytotoxicity against both2 D MCF-7 and MCF-7/ADR cells,which was correlated with decreased mitochondrial membrane potential. The targeted PTX NCs exhibited deeper penetration on MCF-7 MCs and more significant growth inhibition on both MCF-7 and MCF-7/ADR MCs. The proposed strategy indicated that the TPP+-modified NCs represent a potentially viable approach for targeted chemotherapeutic molecules to mitochondria. This strategy might provide promising therapeutic outcomes to overcome MDR.

关键词： Paclitaxel Nanocrystals Brij 98 triphenylphosphonium Multidrug resistance Mitochondria

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Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood-brain barrier

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药学学报:英文版 2023年第9期13卷 3834-3848页

作者： Thuy Giang Nguyen Cao Ji Hee Kang Su Jin Kang Quan Truong Hoang Han Chang Kang Won Jong Rhee Yu Shrike Zhang Young Tag Ko Min Suk Shim Division of Bioengineering Incheon National UniversityIncheon 22012Republic of Korea College of Pharmacy Gachon UniversityIncheon 21936Republic of Korea Department of Pharmacy Integrated Research Institute of Pharmaceutical Sciencesand BK21 PLUS Team for Creative Leader Program for Pharmacomics-based Future PharmacyCollege of Pharmacythe Catholic University of KoreaGyeonggi-do 14662Republic of Korea Research Center for Bio Materials&Process Development Incheon National UniversityIncheon 22012Republic of Korea Division of Engineering in Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolCambridgeMA 02139USA

Glioblastoma(GBM)is the most aggressive malignant brain tumor and has a high mortality *** therapy(PDT)has emerged as a promising approach for the treatment of malignant brain ***,the use of PDT for the treatment of GBM has been limited by its low blood-brain barrier(BBB)permeability and lack of cancer-targeting ***,brain endothelial cell-derived extracellular vesicles(bEVs)were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the *** enhance PDT efficacy,the photosensitizer chlorin e6(Ce6)was linked to mitochondria-targeting triphenylphosphonium(TPP)and entrapped into *** Ce6(TPP-Ce6)selectively accumulated in the mitochondria,which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light ***,the encapsulation of TPP-Ce6 into b EVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6,leading to significantly enhanced PDT efficacy in U87MG GBM *** in vivo biodistribution study using orthotopic GBM-xenografted mice showed that b EVs containing TPP-Ce6[b EV(TPP-Ce6)]substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated *** such,b EV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity,suggesting that mitochondria are an effective target for photodynamic GBM therapy.

关键词： Extracellular vesicle Chlorin e6 triphenylphosphonium Mitochondria-targeting photosensitizer Photodynamic therapy Blood-brain barrier Glioblastoma Transferrin receptor

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