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Targeted siRNA delivery to tumor cells by folate-PEG-appended dendrimer/glucuronylglucosyl-β-cyclodextrin conjugate

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Journal of Inclusion Phenomena and Macrocyclic Chemistry Aims and scope Submit manuscript

Abstract

We previously reported the utility of 6-O-α-(4-O-α-d-glucuronyl)-d-glucosyl-β-cyclodextrin (GUG-β-CyD) conjugates with polyamidoamine dendrimer [GUG-β-CDE (generation 3; G3)] as siRNA carriers. In this study, to prepare GUG-β-CDE (G3) possessing a targeting ability to tumor cells overexpressing folate receptor-α (FR-α), we newly synthesized folate-polyethylene glycol (PEG)-appended GUG-β-CDEs (G3) [Fol-PEG-GUG-β-CDEs (G3)] having degrees of substitution of folate (DSF) of 3.9, 6.7 and 7.3, and evaluated their utility as tumor-selective siRNA carriers. Of various Fol-PEG-GUG-β-CDEs (G3), Fol-PEG-GUG-β-CDE (G3, DSF6.7) showed the highest siRNA transfection activity at a charge ratio of 50 (carrier/siRNA) in both 786-0-luc cells [FR-α (+)] and KB cells [FR-α (+)]. In addition, the cellular uptake of the complex was significantly decreased by an addition of folic acid in a concentration-dependent manner, suggesting its FR-α-mediated endocytosis pathway. Moreover, Fol-PEG-GUG-β-CDE (G3, DSF6.7)/siRNA complex induced a potent RNAi effect, comparable to Lipofectamine™ 2000/siRNA complex. Furthermore, Fol-PEG-GUG-β-CDE (G3, DSF6.7) complex with siRNA against Polo-like kinase 1 (siPLK1) showed a significant cytotoxic activity in KB cells. Thus, Fol-PEG-GUG-β-CDE (G3, DSF6.7) has the potential as the targeted siRNA delivery carrier for FR-α-overexpressing tumor cells.

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Abbreviations

RNAi:

RNA interference

siRNA:

Small interfering RNA

FR:

Folate receptor

FA:

Folic acid

CyD:

Cyclodextrin

GUG-β-CyD:

6-O-α-(4-O-α-d-Glucuronyl)-d-glucosyl-β-cyclodextrin

PAMAM:

Polyamindoamine

G:

Generation

GUG-β-CDE:

GUG-β-CyD/dendrimer conjugate

DS:

Degrees of substitution of GUG-β-CyD

α-CDE:

α-CyD/dendrimer conjugate

PEG:

Polyethylene glycol

Fol-PEG-GUG-β-CDE:

Folate-PEG-appended GUG-β-CDE

FBS:

Fetal bovine serum

DSF:

Degrees of substitution of folate

PLK1:

Polo-like kinase 1

siPLK1:

siRNA against PLK1

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Acknowledgements

The authors thank Ensuiko Sugar Refining for providing GUG-CyD.

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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. 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. 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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  2. Taishi Higashi
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Correspondence to Hidetoshi Arima.

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Mohammed, A.F.A., Higashi, T., Motoyama, K. et al. Targeted siRNA delivery to tumor cells by folate-PEG-appended dendrimer/glucuronylglucosyl-β-cyclodextrin conjugate. J Incl Phenom Macrocycl Chem 93, 41–52 (2019). https://doi.org/10.1007/s10847-018-0834-9

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