RNA interference using c-Myc-conjugated nanoparticles suppresses breast and colorectal cancer models

Naveen Kumar Tangudu, Vinod Kumar Verma, Tristan Clemons, Syed Sultan Beevi, Trevor Hay, Ganesh Mahidhara, Meera Raja, Rekha A. Nair, Liza E. Alexander, Anant Bahadur Patel, Jedy Jose, N.M. Smith, Bogdan Zdyrko, Anne Bourdoncle, Igor Luzinov, Killugudi Swaminatha Iyer, Alan Richard Clarke, Lekha Dinesh Kumar

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 polyglycidalmethacrylate (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.
Original languageEnglish
Pages (from-to)1259-1269
JournalMolecular Cancer Therapeutics
Volume14
Issue number5
Early online date18 Feb 2015
DOIs
Publication statusPublished - May 2015

    Fingerprint

Cite this