Nanoscopic Poly-DNA-Cleaver for Breast Cancer Regression with Induced Oxidative Damage

A novel strategy for efficient “nanodelivery” of DNA-cleaving molecules for breast cancer regression is presented here. The synthetic methodology can be tweaked for controlled delivery and better bioavailability of effective doses of these DNA-cleaving agents through a defined self-assembled polymer...

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Bibliographic Details
Published in:Molecular pharmaceutics 2014-11, Vol.11 (11), p.4218-4227
Main Authors: Misra, Santosh K, Kus, Joseph, Kim, Sumin, Pan, Dipanjan
Format: Article
Language:English
Subjects:
Antioxidants - pharmacology
Ascorbic Acid - pharmacology
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Breast Neoplasms - prevention & control
DNA, Neoplasm - metabolism
Drug Delivery Systems
Female
Humans
Hydrogen Peroxide - pharmacology
Nanoparticles - chemistry
Oxidants - pharmacology
Oxidative Stress
Polymers - chemistry
Polymers - pharmacology
Receptors, Estrogen - metabolism
Receptors, Progesterone - metabolism
Regression Analysis
Small Molecule Libraries - pharmacology
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Summary:A novel strategy for efficient “nanodelivery” of DNA-cleaving molecules for breast cancer regression is presented here. The synthetic methodology can be tweaked for controlled delivery and better bioavailability of effective doses of these DNA-cleaving agents through a defined self-assembled polymeric nanoarchitecture. In vitro studies in ER+ and ER- breast cancer human cell lines confirmed an efficient “nano”-delivery of DNA-cleaving molecules and indicated their capability to mediate oxidative damage to nucleobases and/or to the 2-deoxyribose moiety. Prepared E-poly-DNA-cleaver and C-poly-DNA-cleaver were found to be interacting with plasmid DNA pBR322 (pDNA) and active to cause oxidative cleavage of pDNA in the presence of ascorbic acid and H2O2. They were found to be significantly active as DNA cleaving agents in vitro and showed highly improved cancer regression in MCF-7 and MD-MB231 cancer cells compared to small molecule DNA cleaver. Surface conjugated nanoparticles were found to be more effective than noncovalent encapsulation and the small molecule agent, whereas in all the cases RCM was significantly inactive toward DNA cleavage. Blood contact complement activation properties were evaluated to gauge their likelihood to promote acute toxicity following systemic administration. The complement activation analyses together with the blood smear study confirm the feasibility of using these poly-DNA-cleavers without risk of induced immune response.
ISSN:1543-8384
1543-8392
DOI:10.1021/mp500444c