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Sugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells -
Krzysztof Sztandera1, Paula Działak1, Monika Marcinkowska1
1Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St, 90-236, Lodz, Poland.
Purpose:
In order to overcome the obstacles and side effects of classical chemotherapy, numerous studies have been performed to develop the treatment based on targeted transport of active compounds directly to the site of action. Since tumor cells are featured with intensified glucose metabolism, we set out to develop innovative, glucose-modified PAMAM dendrimer for the delivery of doxorubicin to breast cancer cells.
Methods:
PAMAM-dox-glc conjugate was synthesized and characterized by 1H NMR, FT-IR, size and zeta potential measurements. The drug release rate from conjugate was evaluated by dialysis under different pH conditions. The expression level of GLUT family receptors in cells cultured in full and glucose-deprived medium was evaluated by quantitative real-time RT-PCR and flow cytometry. The cytotoxicity of conjugate in presence or absence of GLUT1 inhibitors was determined by MTT assay.
Results:
We showed that PAMAM-dox-glc conjugate exhibits pH-dependent drug release and increased cytotoxic activity compared to free drug in cells cultured in medium without glucose. Further, we proved that these cells overexpress transporters of GLUT family. The toxic effect of conjugate was eliminated by the application of specific GLUT1 inhibitors.
Conclusion:
Our findings revealed that the glucose moiety plays a crucial role in the recognition of cells with high expression of GLUT receptors. By selectively blocking GLUT1 transporter we showed its importance for the cytotoxic activity of PAMAM-dox-glc conjugate. These results suggest that PAMAM-glucose formulations may constitute an efficient platform for the specific delivery of anticancer drugs to tumor cells overexpressing transporters of GLUT family.
Insights
This study developed a glucose-modified dendrimer for targeted doxorubicin delivery to breast cancer cells. The formulation enhances drug efficacy by targeting glucose transporters (GLUTs) overexpressed on tumor cells, offering a promising platform for cancer therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Classical chemotherapy faces challenges including side effects and lack of targeted delivery.
- Tumor cells exhibit heightened glucose metabolism, presenting a potential target for drug delivery systems.
Purpose of the Study:
- To develop an innovative, glucose-modified polyamidoamine (PAMAM) dendrimer for targeted delivery of doxorubicin to breast cancer cells.
- To leverage the intensified glucose metabolism of cancer cells for selective drug targeting.
Main Methods:
- Synthesis and characterization of the glucose-modified PAMAM-doxorubicin conjugate (PAMAM-dox-glc).
- Evaluation of drug release kinetics under varying pH conditions.
- Assessment of glucose transporter (GLUT) family receptor expression via RT-PCR and flow cytometry.
- Determination of conjugate cytotoxicity using MTT assay, with and without GLUT1 inhibitors.
Main Results:
- The PAMAM-dox-glc conjugate demonstrated pH-dependent doxorubicin release.
- Enhanced cytotoxic activity was observed in glucose-deprived medium, correlating with GLUT family receptor overexpression in cancer cells.
- Specific GLUT1 inhibitors effectively eliminated the toxic effect of the conjugate, confirming targeted uptake.
Conclusions:
- Glucose modification is critical for the recognition and uptake of the dendrimer by cells overexpressing GLUT receptors.
- The GLUT1 transporter plays a significant role in the cytotoxic efficacy of the PAMAM-dox-glc conjugate.
- PAMAM-glucose formulations represent a viable platform for targeted anticancer drug delivery to tumors with high GLUT transporter expression.
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