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In Vitro and In Vivo Co-delivery of siRNA and Doxorubicin by Folate-PEG-Appended Dendrimer/Glucuronylglucosyl-β-Cyclodextrin Conjugate

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Abstract

We have previously reported the utility of folate-polyethylene glycol-appended dendrimer conjugate with glucuronylglucosyl-β-cyclodextrin (Fol-PEG-GUG-β-CDE) (generation 3) as a tumor-selective carrier for siRNA against polo-like kinase 1 (siPLK1) in vitro. In the present study, we evaluated the potential of Fol-PEG-GUG-β-CDE as a carrier for the low-molecular antitumor drug doxorubicin (DOX). Further, to fabricate advanced antitumor agents, we have prepared a ternary complex of Fol-PEG-GUG-β-CDE/DOX/siPLK1 and evaluated its antitumor activity both in vitro and in vivo. Fol-PEG-GUG-β-CDE released DOX in an acidic pH and enhanced the cellular accumulation and cytotoxic activity of DOX in folate receptor-α (FR-α)-overexpressing KB cells. Importantly, the Fol-PEG-GUG-β-CDE/DOX/siPLK1 ternary complex exhibited higher cytotoxic activity than a binary complex of Fol-PEG-GUG-β-CDE with DOX or siPLK1 in KB cells. In addition, the cytotoxic activity of the ternary complex was reduced by the addition of folic acid, a competitor against FR-α. Furthermore, the ternary complex showed a significant antitumor activity after intravenous administration to the tumor-bearing mice. These results suggest that Fol-PEG-GUG-β-CDE has the potential of a tumor-selective co-delivery carrier for DOX and siPLK1.

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Acknowledgments

The authors thank Ensuiko Sugar Refining for donating GUG-β-CyD.

Author information

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan

    Ahmed Fouad Abdelwahab Mohammed, Taishi Higashi, Keiichi Motoyama, Ayumu Ohyama & Hidetoshi Arima

  2. Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, Egypt

    Ahmed Fouad Abdelwahab Mohammed, Khaled Ali Khaled, Hatem Abdelmonsef Sarhan & Amal Kamal Hussein

  3. Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University, Kumamoto, Japan

    Ahmed Fouad Abdelwahab Mohammed, Ayumu Ohyama & Hidetoshi Arima

  4. Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan

    Taishi Higashi

  5. School of Pharmacy, Building Regional Innovation Ecosystems, Kumamoto University, Kumamoto, Japan

    Risako Onodera

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  1. Ahmed Fouad Abdelwahab Mohammed
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Contributions

AFAM, TH, KM, AO, RO, and HA had participated in the research design. AFAM and AO had conducted the experiments. AFAM, TH, KM, AO, and RO had performed the data analysis. AFAM and TH had drafted or contributed to the writing of the manuscript. TH, KM, KAK, HAS, AKH and HA had supervised the experiments.

Corresponding authors

Correspondence to Taishi Higashi or Hidetoshi Arima.

Ethics declarations

All animal procedures were carried out in accordance with the approved guidelines and with the approval of the Ethics Committee for Animal Care and Use of Kumamoto University (approval no.: C29-162).

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The authors declare that they have no conflict of interest.

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Mohammed, A.F.A., Higashi, T., Motoyama, K. et al. In Vitro and In Vivo Co-delivery of siRNA and Doxorubicin by Folate-PEG-Appended Dendrimer/Glucuronylglucosyl-β-Cyclodextrin Conjugate. AAPS J 21, 54 (2019). https://doi.org/10.1208/s12248-019-0327-9

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