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

Tangudu, N. K., Verma, V. K., Clemons, T. D., Beevi, S. S., Hay, Trevor, Mahidhara, G., Raja, Meera, Nair, R. A., Alexander, L. E., Patel, A. B., Jose, J., Smith, N. M., Zdyrko, B., Bourdoncle, A., Luzinov, I., Iyer, K. S., Clarke, Alan Richard and Dinesh Kumar, L. 2015. RNA interference using c-Myc-conjugated nanoparticles suppresses breast and colorectal cancer models. Molecular Cancer Therapeutics 14 (5) , pp. 1259-1269. 10.1158/1535-7163.MCT-14-0970

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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. Mol Cancer Ther; 14(5); 1259–69. ©2015 AACR.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: American Association for Cancer Research
ISSN: 1535-7163
Date of Acceptance: 10 February 2015
Last Modified: 12 Jun 2019 02:26
URI: http://orca.cf.ac.uk/id/eprint/77226

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