Combinational delivery of c-myc siRNA and nucleoside analogs in a single, synthetic nanocarrier for targeted cancer therapy.
The treatment of aggressive non-small-cell lung cancer (NSCLC) depends on the creation of new therapeutic regimens in clinical settings. In this study, we developed a Lipid/Calcium/Phosphate (LCP) nanoparticle that combines chemotherapy with gene therapy. By encapsulating a chemodrug, gemcitabine monophosphate (GMP), and siRNA specific to the undruggable cMyc oncogene (cMyc siRNA) into a single nano-sized vesicle and systemically administering them to nude mice, we achieved potent anti-tumor activity in both subcutaneous and orthotopic models of NSCLC. The improvements in therapeutic response over either cMyc siRNA or GMP therapy alone, were demonstrated by the ability to effectively induce the apoptosis of tumor cells and the significant reduction of proliferation of tumor cells. The combination therapy led to dramatic inhibition of tumor growth, with little in vivo toxicity. Additionally, the current studies demonstrated the possibility of incorporating both nucleic acid molecules and phosphorylated small molecule drugs into the inner core of a single nanoparticle formulation. Co-encapsulation of an oncogene-modulating siRNA and a chemotherapeutic agent will allow simultaneous interruption of diverse anti-cancer pathways, leading to increased therapeutic efficacy and reduced toxicities.
Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Yuan
Y
Zhang
Lei
L
Peng
Russell J
RJ
Mumper
Leaf
L
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002130:Calcium Phosphates / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002130:Calcium Phosphates; D020598:Proto-Oncogene Proteins c-myb; D034741:RNA, Small Interfering; C020243:calcium phosphate
Apoptosis; Calcium phosphate nanoparticle; Gemcitabine monophosphate; Proliferation; c-Myc siRNA