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J Am Chem Soc. 2018 Jan 31;140(4):1438-1446. doi: 10.1021/jacs.7b11462. Epub 2018 Jan 19.

Chemical Design of Both a Glutathione-Sensitive Dimeric Drug Guest and a Glucose-Derived Nanocarrier Host to Achieve Enhanced Osteosarcoma Lung Metastatic Anticancer Selectivity.

Author information

1
Departments of Chemistry, Chemical Engineering, and Materials Science & Engineering, Texas A&M University , College Station, Texas 77842, United States.
2
Departments of Nuclear Engineering and Veterinary Integrative Biosciences and Texas A&M Institute for Preclinical Studies, Texas A&M University , College Station, Texas 77842, United States.
3
College of Medicine, Texas A&M University , Bryan, Texas 77807, United States.
4
Aerogen , IDA Business Park, Dangan, Galway, Ireland .
5
School of Pharmacy, Royal College of Surgeons , Dublin, Ireland .
6
School of Pharmacy and Pharmaceutical Sciences, Trinity College , Dublin, Ireland.

Abstract

Although nanomedicines have been pursued for nearly 20 years, fundamental chemical strategies that seek to optimize both the drug and drug carrier together in a concerted effort remain uncommon yet may be powerful. In this work, two block polymers and one dimeric prodrug molecule were designed to be coassembled into degradable, functional nanocarriers, where the chemistry of each component was defined to accomplish important tasks. The result is a poly(ethylene glycol) (PEG)-protected redox-responsive dimeric paclitaxel (diPTX)-loaded cationic poly(d-glucose carbonate) micelle (diPTX@CPGC). These nanostructures showed tunable sizes and surface charges and displayed controlled PTX drug release profiles in the presence of reducing agents, such as glutathione (GSH) and dithiothreitol (DTT), thereby resulting in significant selectivity for killing cancer cells over healthy cells. Compared to free PTX and diPTX, diPTX@CPGC exhibited improved tumor penetration and significant inhibition of tumor cell growth toward osteosarcoma (OS) lung metastases with minimal side effects both in vitro and in vivo, indicating the promise of diPTX@CPGC as optimized anticancer therapeutic agents for treatment of OS lung metastases.

PMID:
29350522
DOI:
10.1021/jacs.7b11462
[Indexed for MEDLINE]

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