Mitochondria apoptosis pathway synergistically activated by hierarchical targeted nanoparticles co-delivering siRNA and lonidamine |
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| Affiliation: | 1. Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, 30 S. 2000 E., University of Utah, Salt Lake City, UT 84112, USA;2. Department of Pharmaceutics and Biopharmacy, Phillips-Universität, 35037 Marburg, Germany;1. Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA;2. Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA;3. School of Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD, UK;4. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA |
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| Abstract: | The mitochondria-mediated apoptosis pathway is an effective option for cancer therapy due to the presence of cell-suicide weapons in mitochondria. However, anti-apoptotic proteins that are over-expressed in the mitochondria of many malignant tumors, such as Bcl-2 protein, could allow the cancer cells to evade apoptosis, greatly reducing the efficacy of this type of chemotherapy. Here, we constructed a hierarchical targeted delivery system that can deliver siRNA and chemotherapeutic agents sequentially to tumor cells and mitochondria. In detail, the copolymer TPP-CP-LND (TCPL) was synthesized by the mitochondria-targeting ligand triphenylphosphine (TPP) and therapeutic drug lonidamine (LND) conjugated to the polyethyleneimine in chitosan-graft-PEI (CP), and then complexed with siRNA. Followed, the complexes were coated with poly(acrylic acid)-polyethylene glycol-folic acid (PPF) copolymer to form a hierarchical targeted co-delivery system (TCPL/siRNA/PPF NPs). The TCPL/siRNA/PPF NPs had a neutral surface charge, were stable in plasma and exhibited pH-responsive shell separation. Remarkably, the TCPL/siRNA/PPF NPs simultaneously released siBcl-2 into the cytoplasm and delivered LND to mitochondria in the same cancer cell after FA-directed internalization, and even synergistically activated mitochondria apoptosis pathway. This work demonstrated the potential of RNA-interference and mitochondria-targeted chemotherapeutics to collaboratively stimulate the mitochondria apoptosis pathway for cancer therapy. |
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| Keywords: | Hierarchical targeting Mitochondria apoptosis pathway Multifunctional nanoparticle Co-delivery Lonidamine siRNA TPP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0045" }," $$" :[{" #name" :" text" ," _" :" triphenylphosphine LND" },{" #name" :" keyword" ," $" :{" id" :" kwrd0055" }," $$" :[{" #name" :" text" ," _" :" lonidamine CS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0065" }," $$" :[{" #name" :" text" ," _" :" chitosan PEI" },{" #name" :" keyword" ," $" :{" id" :" kwrd0075" }," $$" :[{" #name" :" text" ," _" :" polyethylenimine CP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0085" }," $$" :[{" #name" :" text" ," _" :" CS-PEI TCPL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0095" }," $$" :[{" #name" :" text" ," _" :" TPP-CP-LND CPL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0105" }," $$" :[{" #name" :" text" ," _" :" CP-LND TCP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0115" }," $$" :[{" #name" :" text" ," _" :" TPP-CP FA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0125" }," $$" :[{" #name" :" text" ," _" :" folic acid PEG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0135" }," $$" :[{" #name" :" text" ," _" :" poly(ethylene glycol) PAA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0145" }," $$" :[{" #name" :" text" ," _" :" poly(acrylic acid) PPF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0155" }," $$" :[{" #name" :" text" ," _" :" PAA-PEG-FA PP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0165" }," $$" :[{" #name" :" text" ," _" :" PAA-PEG siBcl-2" },{" #name" :" keyword" ," $" :{" id" :" kwrd0175" }," $$" :[{" #name" :" text" ," _" :" Bcl-2 siRNA siSCR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0185" }," $$" :[{" #name" :" text" ," _" :" scrambled siRNA FITC-TCPL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0195" }," $$" :[{" #name" :" text" ," _" :" FITC-labeled TCPL FITC-CPL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0205" }," $$" :[{" #name" :" text" ," _" :" FITC-labeled CPL Cy3-siRNA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0215" }," $$" :[{" #name" :" text" ," _" :" Cy3-labeled siRNA NPs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0225" }," $$" :[{" #name" :" text" ," _" :" nanoparticles TCPL/siBcl-2/PPF NPs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0235" }," $$" :[{" #name" :" text" ," _" :" NPs contain LND, siBcl-2, TPP and FA TCPL/siBcl-2/PP NPs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0245" }," $$" :[{" #name" :" text" ," _" :" NPs contain LND, siBcl-2 and TPP TCPL/siSCR/PPF NPs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0255" }," $$" :[{" #name" :" text" ," _" :" NPs contain LND, siSCR, TPP and FA CPL/siSCR/PPF NPs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0265" }," $$" :[{" #name" :" text" ," _" :" NPs contain LND, siSCR, and FA TCP/siBcl-2/PPF NPs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0275" }," $$" :[{" #name" :" text" ," _" :" NPs contain siBcl-2, TPP and FA TCP/siSCR/PPF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0285" }," $$" :[{" #name" :" text" ," _" :" NPs contain siSCR, TPP and FA |
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