title: RNA Interference Using c-Myc-Conjugated Nanoparticles Suppresses Breast and Colorectal Cancer Models.
abstract: In this article, we report the development and preclinical validation of combinatorial therapy for treatment of cancers using RNA interference (RNAi). RNAi technology is an attractive approach to silence genes responsible for disease onset and progression. Currently, the critical challenge facing the clinical success of RNAi technology is in the difficulty of delivery of RNAi inducers, due to low transfection efficiency, difficulties of integration into host DNA and unstable expression. Using the macromolecule polyglycidal methacrylate (PGMA) as a platform to graft multiple polyethyleneimine (PEI) chains, we demonstrate effective delivery of small oligos (anti-miRs and mimics) and larger DNAs (encoding shRNAs) in a wide variety of cancer cell lines by successful silencing/activation of their respective target genes. Furthermore, the effectiveness of this therapy was validated for in vivo tumor suppression using two transgenic mouse models; first, tumor growth arrest and increased animal survival was seen in mice bearing Brca2/p53-mutant mammary tumors following daily intratumoral treatment with nanoparticles conjugated to c-Myc shRNA. Second, oral delivery of the conjugate to an Apc-deficient crypt progenitor colon cancer model increased animal survival and returned intestinal tissue to a non-wnt-deregulated state. This study demonstrates, through careful design of nonviral nanoparticles and appropriate selection of therapeutic gene targets, that RNAi technology can be made an affordable and amenable therapy for cancer.
authors.affiliation: Cancer Biology, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India.
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Tangudu
authors.affiliation: Cancer Biology, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India.
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Verma
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, Australia.
authors.forename: Tristan D
authors.initials: TD
authors.lastname: Clemons
authors.affiliation: Cancer Biology, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India.
authors.forename: Syed S
authors.initials: SS
authors.lastname: Beevi
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cathays, Cardiff, United Kingdom.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hay
authors.affiliation: Cancer Biology, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Mahidhara
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cathays, Cardiff, United Kingdom.
authors.forename: Meera
authors.initials: M
authors.lastname: Raja
authors.affiliation: Department of Pathology, Regional Cancer Centre, Trivandrum, India.
authors.forename: Rekha A
authors.initials: RA
authors.lastname: Nair
authors.affiliation: Department of Pathology, Regional Cancer Centre, Trivandrum, India.
authors.forename: Liza E
authors.initials: LE
authors.lastname: Alexander
authors.affiliation: Cancer Biology, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India.
authors.forename: Anant B
authors.initials: AB
authors.lastname: Patel
authors.affiliation: Cancer Biology, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India.
authors.forename: Jedy
authors.initials: J
authors.lastname: Jose
authors.affiliation: Univ de Bordeaux, INSERM U869, IECB, ARNA Laboratory, Pessac, France.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Smith
authors.affiliation: School of Materials Science and Engineering, Clemson University, Clemson, South Carolina.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Zdyrko
authors.affiliation: Univ de Bordeaux, INSERM U869, IECB, ARNA Laboratory, Pessac, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bourdoncle
authors.affiliation: School of Materials Science and Engineering, Clemson University, Clemson, South Carolina.
authors.forename: Igor
authors.initials: I
authors.lastname: Luzinov
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, Australia. lekha@ccmb.res.in swaminatha.iyer@uwa.edu.au ClarkeAR@cf.ac.uk.
authors.forename: K Swaminathan
authors.initials: KS
authors.lastname: Iyer
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cathays, Cardiff, United Kingdom. lekha@ccmb.res.in swaminatha.iyer@uwa.edu.au ClarkeAR@cf.ac.uk.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
authors.affiliation: Cancer Biology, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India. lekha@ccmb.res.in swaminatha.iyer@uwa.edu.au ClarkeAR@cf.ac.uk.
authors.forename: Lekha
authors.initials: L
authors.lastname: Dinesh Kumar
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000628:therapy*; D005260:Female; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D061986:MCF-7 Cells; D051379:Mice; D041681:NIH 3T3 Cells; D058726:Nanoconjugates; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D011126:Polypropylenes / Q000737:chemistry; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D000067492:RNAi Therapeutics / Q000379:methods*
chemical_list: D058726:Nanoconjugates; D016376:Oligonucleotides, Antisense; D011126:Polypropylenes; D016271:Proto-Oncogene Proteins c-myc; C443641:poly(propyleneimine)