Chemical Design of Both a Glutathione-Sensitive Dimeric Drug Guest and a Glucose-Derived Nanocarrier Host to Achieve Enhanced Osteosarcoma Lung Metastatic Anticancer Selectivity
| Autor: | Fuwu Zhang, Lu Su, Ronan MacLoughlin, Justin A. Smolen, Ryan Clanton, Andrew Sterling Butters, Yue Song, Karen L. Wooley, Yen-Nan Lin, Richen Li, Sarosh Khan, Soleil Hernandez, Gamal Akabani, Jingwei Fan, Hai Wang |
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| Rok vydání: | 2018 |
| Předmět: |
Lung Neoplasms
Paclitaxel Molecular Conformation 02 engineering and technology 010402 general chemistry 01 natural sciences Biochemistry Micelle Catalysis chemistry.chemical_compound Colloid and Surface Chemistry Humans Cell Proliferation Drug Carriers Osteosarcoma General Chemistry Glutathione Prodrug 021001 nanoscience & nanotechnology Antineoplastic Agents Phytogenic 0104 chemical sciences Dithiothreitol Glucose chemistry Drug Design Cancer cell Biophysics Nanoparticles Nanocarriers 0210 nano-technology Drug carrier Dimerization Ethylene glycol |
| Zdroj: | Journal of the American Chemical Society. 140:1438-1446 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.7b11462 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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