Back to Search
Start Over
Nano-delivery of RAD6/Translesion Synthesis Inhibitor SMI#9 for Triple-negative Breast Cancer Therapy
- Source :
- Molecular Cancer Therapeutics. 17:2586-2597
- Publication Year :
- 2018
- Publisher :
- American Association for Cancer Research (AACR), 2018.
-
Abstract
- The triple-negative breast cancer (TNBC) subtype, regardless of their BRCA1 status, has the poorest outcome compared with other breast cancer subtypes, and currently there are no approved targeted therapies for TNBC. We have previously demonstrated the importance of RAD6-mediated translesion synthesis pathway in TNBC development/progression and chemoresistance, and the potential therapeutic benefit of targeting RAD6 with a RAD6-selective small-molecule inhibitor, SMI#9. To overcome SMI#9 solubility limitations, we recently developed a gold nanoparticle (GNP)-based platform for conjugation and intracellular release of SMI#9, and demonstrated its in vitro cytotoxic activity toward TNBC cells. Here, we characterized the in vivo pharmacokinetic and therapeutic properties of PEGylated GNP-conjugated SMI#9 in BRCA1 wild-type and BRCA1-mutant TNBC xenograft models, and investigated the impact of RAD6 inhibition on TNBC metabolism by 1H-NMR spectroscopy. GNP conjugation allowed the released SMI#9 to achieve higher systemic exposure and longer retention as compared with the unconjugated drug. Systemically administered SMI#9-GNP inhibited the TNBC growth as effectively as intratumorally injected unconjugated SMI#9. Inductively coupled mass spectrometry analysis showed highest GNP concentrations in tumors and liver of SMI#9-GNP and blank-GNP–treated mice; however, tumor growth inhibition occurred only in the SMI#9-GNP–treated group. SMI#9-GNP was tolerated without overt signs of toxicity. SMI#9-induced sensitization was associated with perturbation of a common set of glycolytic pathways in BRCA1 wild-type and BRCA1-mutant TNBC cells. These data reveal novel SMI#9 sensitive markers of metabolic vulnerability for TNBC management and suggest that nanotherapy-mediated RAD6 inhibition offers a promising strategy for TNBC treatment.
- Subjects :
- 0301 basic medicine
Drug
Cancer Research
business.industry
media_common.quotation_subject
education
fungi
Wild type
medicine.disease
03 medical and health sciences
030104 developmental biology
medicine.anatomical_structure
Breast cancer
Oncology
In vivo
mental disorders
Toxicity
Cancer research
medicine
Cytotoxic T cell
business
Sensitization
Triple-negative breast cancer
media_common
Subjects
Details
- ISSN :
- 15388514 and 15357163
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Therapeutics
- Accession number :
- edsair.doi...........9a2a6fe03bbcb8186d0c921442b2a31f