Evaluation of an elastin-like polypeptide–doxorubicin conjugate for cancer therapy
| Autor: | Drazen Raucher, Narayanan Balu, Susan M. Ludeman, Matthew R. Dreher, Ashutosh Chilkoti, O. Michael Colvin |
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| Rok vydání: | 2003 |
| Předmět: |
Chemical Phenomena
Cell Survival Population Pharmaceutical Science Neoplasms Tumor Cells Cultured Fluorescence microscope Humans education Cytotoxicity education.field_of_study Antibiotics Antineoplastic Microscopy Confocal Chemistry Physical Chemistry Hydrazones Subcellular localization Elastin Epidermoid carcinoma Biochemistry Doxorubicin Cytoplasm Drug delivery Carcinoma Squamous Cell Thermodynamics Peptides Conjugate |
| Zdroj: | Journal of Controlled Release. 91:31-43 |
| ISSN: | 0168-3659 |
| Popis: | Thermally responsive elastin-like polypeptides (ELPs) were synthesized by recombinant DNA techniques and conjugated to doxorubicin through an acid-labile hydrazone bond to enable release of the drug in the acidic environment of lysosomes. The thermal properties, intracellular localization and cytotoxicity of the conjugate were investigated in this study. The conjugation procedure resulted in a mixed population of free ELP and ELP-doxorubicin (ELP-dox) conjugates that exhibit a broader transition than the parent ELP. A simple centrifugation procedure was developed to purify the ELP-dox conjugate from other reactants and resulted in a sharper thermal transition, similar to the parent ELP. The ELP was endocytosed by squamous cell carcinoma cells (FaDu) and trafficked into lysosomes, as observed by the colocalization of the ELP with a lysosome-specific dye through confocal fluorescence microscopy. Interestingly, both the ELP-dox conjugate and free drug exhibited near equivalent in vitro cytotoxicity, although their subcellular localization was significantly different. The free drug was largely concentrated in the nucleus, while the conjugate was dispersed throughout the cytoplasm with limited nuclear accumulation. These differences are significant because they suggest a different mechanism of cytotoxicity for the conjugate as compared with the free drug. |
| Databáze: | OpenAIRE |
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