Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer.

AIMS To develop a novel nanomedicine approach for the treatment of multidrug-resistant (MDR) cancer by combining an anticancer drug and suppressors of cellular resistance within one multifunctional nanocarrier-based delivery system (NDS). MATERIALS & METHODS The NDS consisted of cationic liposomes (carrier, 100-140 nm), doxorubicin (DOX, anticancer drug), siRNA targeted to MRP1 and BCL2 mRNA (suppressors of pump and nonpump cellular-resistance, respectively). The resulting approximately 500 nm complex has a zeta potential of +4 mV. RESULTS & DISCUSSION The NDS provides an effective co-delivery of DOX and siRNA as well as cell-death induction and suppression of cellular resistance in MDR lung cancer cells. CONCLUSION We demonstrate NDS-enhanced efficiency of chemotherapy to a level that cannot be achieved by applying its components separately.

[1]  J. Kopeček,et al.  Comparison of the Anticancer Effect of Free and HPMA Copolymer-Bound Adriamycin in Human Ovarian Carcinoma Cells , 1999, Pharmaceutical Research.

[2]  D. Richardson,et al.  Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1 , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Joseph Kost,et al.  Controlling liposomal drug release with low frequency ultrasound: mechanism and feasibility. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[4]  S. Parveen,et al.  Polymeric nanoparticles for cancer therapy , 2008, Journal of drug targeting.

[5]  E. Chang,et al.  Targeted delivery of small interfering RNA: approaching effective cancer therapies. , 2008, Cancer research.

[6]  D. Putnam,et al.  RNA-interference effectors and their delivery. , 2006, Critical reviews in therapeutic drug carrier systems.

[7]  S. Kassim,et al.  Increased bcl-2 expression is associated with primary resistance to chemotherapy in human epithelial ovarian cancer. , 1999, Clinical biochemistry.

[8]  D. Ross,et al.  Biochemical and clinical aspects of efflux pump related resistance to anti-cancer drugs. , 1998, Anticancer research.

[9]  G. Scagliotti,et al.  Multidrug resistance in non-small-cell lung cancer. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[10]  J. Kopeček,et al.  Chronic exposure to HPMA copolymer-bound adriamycin does not induce multidrug resistance in a human ovarian carcinoma cell line. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[11]  I. Toth,et al.  Particulate systems as adjuvants and carriers for peptide and protein antigens. , 2006, Current drug delivery.

[12]  M. Ihnat,et al.  Effects of mitomycin C and carboplatin pretreatment on multidrug resistance-associated P-glycoprotein expression and on subsequent suppression of tumor growth by doxorubicin and paclitaxel in human metastatic breast cancer xenografted nude mice. , 1999, Oncology Research.

[13]  S. Ho,et al.  Relationship Between Chemotherapy Response of Small Cell Lung Cancer and P-glycoprotein or Multidrug Resistance-Related Protein Expression , 2002, Lung.

[14]  T. Minko,et al.  New generation of liposomal drugs for cancer. , 2006, Anti-cancer agents in medicinal chemistry.

[15]  S. Dharap,et al.  Molecular Targeting of BCL2 and BCLXL Proteins by Synthetic BCL2 Homology 3 Domain Peptide Enhances the Efficacy of Chemotherapy , 2006, Journal of Pharmacology and Experimental Therapeutics.

[16]  Yang Wang,et al.  In vitro and in vivo intracellular liposomal delivery of antisense oligonucleotides and anticancer drug. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[17]  R. Mahato Biomaterials for Delivery and Targeting of Proteins and Nucleic Acids , 2009 .

[18]  H. Galehdari,et al.  In vivo transfection rat small intestine K-cell with pGIP/Ins plasmid by DOTAP liposome , 2007, Journal of drug targeting.

[19]  A. Mucci,et al.  DOTAP/UDCA vesicles: novel approach in oligonucleotide delivery. , 2007, Nanomedicine : nanotechnology, biology, and medicine.

[20]  S. Dharap,et al.  Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[21]  Alexandre A. Vetcher,et al.  Nonviral Nanoscale-Based Delivery of Antisense Oligonucleotides Targeted to Hypoxia-Inducible Factor 1α Enhances the Efficacy of Chemotherapy in Drug-Resistant Tumor , 2008, Clinical Cancer Research.

[22]  S. Dharap,et al.  Targeted Proapoptotic LHRH-BH3 Peptide , 2003, Pharmaceutical Research.

[23]  Yang Wang,et al.  Enhancement of the Efficacy of Chemotherapy for Lung Cancer by Simultaneous Suppression of Multidrug Resistance and Antiapoptotic Cellular Defense , 2004, Cancer Research.

[24]  S. Korsmeyer,et al.  Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death , 1993, Cell.

[25]  W. Hait,et al.  Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. , 2003, Cancer research.

[26]  R. Lutz,et al.  Role of the BH3 (Bcl-2 homology 3) domain in the regulation of apoptosis and Bcl-2-related proteins. , 2000, Biochemical Society transactions.

[27]  N. Ballatori,et al.  Glutathione Export during Apoptosis Requires Functional Multidrug Resistance-associated Proteins* , 2007, Journal of Biological Chemistry.

[28]  S. Dharap,et al.  Molecular targeting of drug delivery systems to cancer. , 2004, Current drug targets.

[29]  A. T. Fabbricatore,et al.  Enhancing the efficacy of chemotherapeutic drugs by the suppression of antiapoptotic cellular defense. , 2003, Cancer detection and prevention.

[30]  J C Reed,et al.  Dysregulation of apoptosis in cancer. , 1998, The cancer journal from Scientific American.

[31]  C. Cametti,et al.  Role of Cholesterol, DOTAP, and DPPC in Prostasome/Spermatozoa Interaction and Fusion , 2006, The Journal of Membrane Biology.

[32]  A. Sood,et al.  Strategies for in vivo siRNA delivery in cancer. , 2008, Mini reviews in medicinal chemistry.

[33]  B. Sarkadi,et al.  Multidrug resistance‐associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate , 2003, BioFactors.

[34]  A. Baniahmad,et al.  Modulation of thyroid hormone receptor silencing function by co-repressors and a synergizing transcription factor. , 2000, Biochemical Society Transactions.

[35]  H. Harashima,et al.  Nonviral gene delivery. , 2008, Contributions to nephrology.

[36]  V. Soldatenkov,et al.  Multifunctional Nanotherapeutics for Cancer , 2008 .

[37]  P. Clarke,et al.  Regulation of apoptosis by BH3 domains in a cell-free system , 1997, Current Biology.

[38]  R. Lutz,et al.  Bak BH3 Peptides Antagonize Bcl-xL Function and Induce Apoptosis through Cytochrome c-independent Activation of Caspases* , 1999, The Journal of Biological Chemistry.

[39]  Yanping Hu,et al.  Combined treatment of Bcl-2 antisense oligodeoxynucleotides (G3139), p-glycoprotein inhibitor (PSC833), and sterically stabilized liposomal doxorubicin suppresses growth of drug-resistant growth of drug-resistant breast cancer in severely combined immunodeficient mice. , 2003, Journal of experimental therapeutics & oncology.

[40]  K. Braeckmans,et al.  A fast and sensitive method for measuring the integrity of siRNA-carrier complexes in full human serum. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[41]  S. Korsmeyer,et al.  BCL-2 family members and the mitochondria in apoptosis. , 1999, Genes & development.

[42]  R. Chandra,et al.  Reversal of P-glycoprotein-mediated multidrug resistance in cancer cells by the c-Jun NH2-terminal kinase. , 2006, Cancer research.

[43]  R. Reilly,et al.  Functional comparison of single- and double-stranded mdr1 antisense oligodeoxynucleotides in human ovarian cancer cell lines. , 2005, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[44]  S. Cory,et al.  The Bcl-2 protein family: arbiters of cell survival. , 1998, Science.

[45]  C. Malvy,et al.  Delivery of Small Interfering RNA. A Review and an Example of Application to a Junction Oncogene , 2008, Tumori.

[46]  E. Flescher Jasmonates in cancer therapy. , 2007, Cancer letters.

[47]  W. Hait,et al.  Small Interfering RNA-induced Suppression of MDR 1 ( P-Glycoprotein ) Restores Sensitivity to Multidrug-resistant Cancer Cells 1 , 2003 .

[48]  Y. Minagawa,et al.  Gamma-glutamyl cysteine synthetase up-regulates glutathione and multidrug resistance-associated protein in patients with chemoresistant epithelial ovarian cancer. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[49]  S. Betigeri,et al.  Surface-modified and internally cationic polyamidoamine dendrimers for efficient siRNA delivery. , 2008, Bioconjugate chemistry.

[50]  T. Minko,et al.  Novel Polymeric Prodrug with Multivalent Components for Cancer Therapy , 2006, Journal of Pharmacology and Experimental Therapeutics.

[51]  Minagawa,et al.  Glutamyl Cysteine Synthetase UpRegulates Glutathione and Multidrug Resistance-associated Protein in Patients with Chemoresistant Epithelial Ovarian Cancer , 2005 .

[52]  V. Soldatenkov,et al.  Targeted proapoptotic anticancer drug delivery system. , 2007, Molecular pharmaceutics.

[53]  L. Mayer,et al.  Molecular and pharmacokinetic properties associated with the therapeutics of bcl-2 antisense oligonucleotide G3139 combined with free and liposomal doxorubicin. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[54]  T. Minko Mechanisms of cellular drug resistance and strategies to overcome it , 2004 .

[55]  T. Sakaeda,et al.  An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy. , 2006, Current pharmaceutical design.

[56]  T. Minko,et al.  Receptor targeted polymers, dendrimers, liposomes: which nanocarrier is the most efficient for tumor-specific treatment and imaging? , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[57]  T. Minko,et al.  Simultaneous Modulation of Multidrug Resistance and Antiapoptotic Cellular Defense by MDR1 and BCL-2 Targeted Antisense Oligonucleotides Enhances the Anticancer Efficacy of Doxorubicin , 2003, Pharmaceutical Research.

[58]  S. Lowe,et al.  Apoptosis in cancer. , 2000, Carcinogenesis.

[59]  S. Dharap,et al.  Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[60]  F. He,et al.  Cationic lipids enhance siRNA-mediated interferon response in mice. , 2005, Biochemical and biophysical research communications.

[61]  Jayant Khandare,et al.  Polymer-drug conjugates: Progress in polymeric prodrugs , 2006 .