Jiayi Pan1, Livia P Mendes2, Momei Yao1, Nina Filipczak3, Sumanta Garai4, Ganesh A Thakur4, Can Sarisozen1, Vladimir P Torchilin5. 1. Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA. 2. Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA; CAPES Foundation, Ministry of Education of Brazil, Brasilia 70040-020, Brazil. 3. Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA; Laboratory of Lipids and Liposomes, Department of Biotechnology, University of Wroclaw, 50-383 Wroclaw, Poland. 4. Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA. 5. Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA. Electronic address: v.torchilin@northeastern.edu.
Abstract
Multidrug resistance (MDR) significantly decreases the therapeutic efficiency of anti-cancer drugs. Its reversal could serve as a potential method to restore the chemotherapeutic efficiency. Downregulation of MDR-related proteins with a small interfering RNA (siRNA) is a promising way to reverse the MDR effect. Additionally, delivery of small molecule therapeutics simultaneously with siRNA can enhance the efficiency of chemotherapy by dual action in MDR cell lines. Here, we conjugated the dendrimer, generation 4 polyamidoamine (G4 PAMAM), with a polyethylene glycol (PEG)-phospholipid copolymer. The amphiphilic conjugates obtained spontaneously self-assembled into a micellar nano-preparation, which can be co-loaded with siRNA onto PAMAM moieties and sparingly water-soluble chemotherapeutics into the lipid hydrophobic core. This system was co-loaded with doxorubicin (DOX) and therapeutic siRNA (siMDR-1) and tested for cytotoxicity against MDR cancer cells: human ovarian carcinoma (A2780 ADR) and breast cancer (MCF7 ADR). The combination nanopreparation effectively downregulated P-gp in MDR cancer cells and reversed the resistance towards DOX.
Multidrug resistance (MDR) significantly decreases the therapeutic efficiency of anti-cancer drugs. Its reversal could serve as a potential method to restore the chemotherapn>eutic efficiency. Downregulation of MDR-related proteins with a small interfering RNA (siRNA) is a promising way to reverse the MDR effect. Additionally, delivery of small molecule therapn>eutics simultaneously with siRNA can enhance the efficiency of chemotherapn>y by dual action in MDR cell lines. Here, we conjugated the dendrimer, generation 4 n>an class="Chemical">polyamidoamine (G4 PAMAM), with a polyethylene glycol (PEG)-phospholipid copolymer. The amphiphilic conjugates obtained spontaneously self-assembled into a micellar nano-preparation, which can be co-loaded with siRNA onto PAMAM moieties and sparingly water-soluble chemotherapeutics into the lipid hydrophobic core. This system was co-loaded with doxorubicin (DOX) and therapeutic siRNA (siMDR-1) and tested for cytotoxicity against MDR cancer cells: humanovarian carcinoma (A2780 ADR) and breast cancer (MCF7 ADR). The combination nanopreparation effectively downregulated P-gp in MDR cancer cells and reversed the resistance towards DOX.
Authors: M Maliepaard; M A van Gastelen; L A de Jong; D Pluim; R C van Waardenburg; M C Ruevekamp-Helmers; B G Floot; J H Schellens Journal: Cancer Res Date: 1999-09-15 Impact factor: 12.701
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