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P-glycoprotein antibody functionalized carbon nanotube overcomes the multidrug resistance of human leukemia cells
Ruibin Li1, Ren'an Wu, Liang Zhao
1National Chromatographic R&A Center, CAS Key Laboratory of Separation Sciences for Analytical Chemistry,Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China.
Abstract:
Multidrug resistance (MDR), which is related to cancer chemotherapy, tumor stem cells, and tumor metastasis, is a huge obstacle for the effective cancer therapy. One of the underlying mechanisms of MDR is the increased efflux of anticancer drugs by overexpressed P-glycoprotein (P-gp) of multidrug resistant cells. In this work, the antibody of P-gp (anti-P-gp) functionalized water-soluble single-walled carbon nanotubes (Ap-SWNTs) loaded with doxorubicin (Dox), Dox/Ap-SWNTs, were synthesized for challenging the MDR of K562 human leukemia cells. The resulting Ap-SWNTs could not only specifically recognize the multidrug resistant human leukemia cells (K562R), but also demonstrate the effective loading and controllable release performance for Dox toward the target K562R cells by exposing to near-infrared radiation (NIR). The recognition capability of Ap-SWNTs toward the K562R cells was confirmed by flow cytometry (FCM) and confocal laser scanning microscopy (CLSM). The binding affinity of Ap-SWNTs toward drug-resistant K562R cells was ca. 23-fold higher than that toward drug-sensitive K562S cells. Additionally, CLSM indicated that Ap-SWNTs could specifically localize on the cell membrane of K562R cells and the fluorescence of Dox in K562R cells could be significantly enhanced after the employment of Ap-SWNTs as carrier. Moreover, the composite of Dox and Ap-SWNTs (Dox/Ap-SWNTs) expressed 2.4-fold higher cytotoxicity and showed the significant cell proliferation suppression toward K562R leukemia cells (p < 0.05) as compared with free Dox which is popularly employed in clinic trials. These results suggest that the Ap-SWNTs are the promising drug delivery vehicle for overcoming the MDR induced by the overexpression of P-gp on cell membrane. Ap-SWNTs loaded with drug molecules could be used to suppress the proliferation of multidrug resistant cells, destroy the tumor stem cells, and inhibit the metastasis of tumor.
Insights
Researchers developed anti-P-gp functionalized carbon nanotubes (Ap-SWNTs) to deliver doxorubicin (Dox) to drug-resistant cancer cells. This targeted delivery system effectively overcomes multidrug resistance (MDR) by enhancing drug uptake and cytotoxicity in resistant leukemia cells.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Multidrug resistance (MDR) is a major challenge in cancer therapy, often caused by P-glycoprotein (P-gp) overexpression.
- P-gp facilitates the efflux of anticancer drugs, reducing their efficacy.
- Targeted drug delivery systems are needed to overcome MDR.
Purpose of the Study:
- To synthesize and evaluate anti-P-gp functionalized single-walled carbon nanotubes (Ap-SWNTs) loaded with doxorubicin (Dox) for overcoming MDR in K562 human leukemia cells.
- To investigate the specific targeting and drug delivery capabilities of Dox/Ap-SWNTs to P-gp overexpressing cells.
- To assess the enhanced cytotoxicity of Dox/Ap-SWNTs against multidrug-resistant leukemia cells.
Main Methods:
- Synthesis of doxorubicin-loaded, anti-P-gp functionalized single-walled carbon nanotubes (Dox/Ap-SWNTs).
- Characterization of Ap-SWNTs' recognition of K562R cells using flow cytometry (FCM) and confocal laser scanning microscopy (CLSM).
- Evaluation of Dox/Ap-SWNTs' cytotoxicity and cell proliferation suppression against K562R cells compared to free Dox.
Main Results:
- Ap-SWNTs specifically recognized and bound to multidrug-resistant K562R cells with significantly higher affinity (23-fold) than drug-sensitive K562S cells.
- Dox/Ap-SWNTs demonstrated effective loading and controlled release of Dox, enhanced intracellular drug concentration, and specific localization on K562R cell membranes.
- Dox/Ap-SWNTs exhibited 2.4-fold higher cytotoxicity and significant cell proliferation suppression in K562R cells compared to free Dox.
Conclusions:
- Ap-SWNTs are a promising drug delivery vehicle for overcoming P-gp-mediated MDR.
- This targeted nanocarrier system can enhance anticancer drug efficacy against resistant cancer cells.
- The Dox/Ap-SWNTs hold potential for suppressing resistant tumor cell proliferation, destroying tumor stem cells, and inhibiting metastasis.
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