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Multifunctional Polymeric Micelles for Enhanced Intracellular Delivery of Doxorubicin to Metastatic Cancer Cells

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Abstract

Purposes

To develop multifunctional RGD-decorated poly(ethylene oxide)-b-poly(ester) based micelles and assess their pH-triggered core degradation and targeted drug release in tumor cells that overexpress RGD receptors.

Methods

Novel poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) based copolymers modified with RGD ligands on PEO and pendent functional groups on PCL, i.e., GRGDS-PEO-b-poly(α-benzylcarboxylate-ε-caprolactone) (GRGDS-PEO-b-PBCL) and GRGDS-PEO-b-poly(α-carboxyl-ε-caprolactone) (GRGDS-PEO-b-PCCL), were synthesized. Chemical conjugation of doxorubicin (DOX) to PCCL core produced GRGDS-PEO-b-P(CL-DOX) micellar conjugates, while GRGDS-PEO-b-PBCL were used to physically encapsulate DOX. For both systems, micellar core degradation, drug release, intracellular drug uptake/disposition, and cytotoxicity against B16F10 metastatic cells were investigated.

Results

The PBCL and P(CL-DOX) cores were found resistant to degradation in pH 7.2, but showed 10% and 40% loss in core molecular weight in pH 5.0 within 144 h, respectively. Preferential release of DOX and DOX derivatives from PBCL and P(CL-DOX) cores was noted in pH 5.0, respectively. The GRGDS-modified micelles showed enhanced cellular internalization through endocytosis, increased intracellular DOX release, nuclear localization, and improved cytotoxicity against metastatic B16F10 cells compared to their unmodified counterparts.

Conclusions

The results clearly suggest a promise for the development of multifunctional polymeric micelles with RGD ligand decorated shell and endosomal pH-triggered degradable core for selective DOX delivery to metastatic cancer cells.

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Acknowledgements

This study was supported by the Natural Sciences and Engineering Council of Canada (NSERC) grant Nos. G121210926 and G121220086. AM was supported by Rx and D HRF/CIHR graduate student research scholarship.

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Authors and Affiliations

  1. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8, Canada

    Xiao-Bing Xiong, Abdullah Mahmud & Afsaneh Lavasanifar

  2. Department of Chemical & Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, Canada

    Hasan Uludağ

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  1. Xiao-Bing Xiong
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  2. Abdullah Mahmud
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  3. Hasan Uludağ
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  4. Afsaneh Lavasanifar
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Correspondence to Afsaneh Lavasanifar.

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Xiong, XB., Mahmud, A., Uludağ, H. et al. Multifunctional Polymeric Micelles for Enhanced Intracellular Delivery of Doxorubicin to Metastatic Cancer Cells. Pharm Res 25, 2555–2566 (2008). https://doi.org/10.1007/s11095-008-9673-5

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  • DOI: https://doi.org/10.1007/s11095-008-9673-5

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