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. 2019 Feb 1;11(2):63.
doi: 10.3390/pharmaceutics11020063.

Transferrin-Conjugated Polymeric Nanoparticle for Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells

Zar Chi Soe  1   2 , Jun Bum Kwon  3 , Raj Kumar Thapa  4 , Wenquan Ou  5 , Hanh Thuy Nguyen  6 , Milan Gautam  7 , Kyung Taek Oh  8 , Han-Gon Choi  9 , Sae Kwang Ku  10 , Chul Soon Yong  11 , Jong Oh Kim  12
Affiliations

Transferrin-Conjugated Polymeric Nanoparticle for Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells

Zar Chi Soe et al. Pharmaceutics. .

Abstract

In this study, a transferrin (Tf)-conjugated polymeric nanoparticle was developed for the targeted delivery of the chemotherapeutic agent doxorubicin (Dox) in order to overcome multi-drug resistance in cancer treatment. Our objective was to improve Dox delivery for producing significant antitumor efficacy in Dox-resistant (R) breast cancer cell lines with minimum toxicity to healthy cells. The results of our experiments revealed that Dox was successfully loaded inside a transferrin (Tf)-conjugated polymeric nanoparticle composed of poloxamer 407 (F127) and 123 (P123) (Dox/F127&P123-Tf), which produced nanosized particles (~90 nm) with a low polydispersity index (~0.23). The accelerated and controlled release profiles of Dox from the nanoparticles were characterized in acidic and physiological pH and Dox/F127&P123-Tf enhanced Dox cytotoxicity in OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cell lines through induction of cellular apoptosis. Moreover, Dox/F127&P123-Tf inhibited cell migration and altered the cell cycle patterns of different cancer cells. In vivo study in MDA-MB-231(R) tumor-bearing mice demonstrated enhanced delivery of nanoparticles to the tumor site when coated in a targeting moiety. Therefore, Dox/F127&P123-Tf has been tailored, using the principles of nanotherapeutics, to overcome drug-resistant chemotherapy.

Keywords: doxorubicin; doxorubicin-resistant cancer; polymeric nanoparticles; transferrin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of the preparation of transferrin-conjugated polymeric nanoparticle for receptor-mediated delivery of Dox in Dox-resistant breast cancer cells.
Figure 2
Figure 2
(A) Particle sizes and polydispersity indexes (PDIs), (B) zeta potentials, and (C) TEM images of F127&P123 NPs, Dox/F127&P123, and Dox/F127&P123-Tf; (D) AFM images of Dox/F127&P123-Tf; (E) FTIR spectra, and (F) X-ray diffraction patterns of Dox, Tf, Dox/F127&P123, and Dox/F127&P123-Tf; (G) entrapment efficiency (EE) and loading capacity (LC) of Dox in Dox/F127&P123, and Dox/F127&P123-Tf.
Figure 3
Figure 3
(A) In vitro release profiles of Dox from Dox/F127&P123 and Dox/F127&P123-Tf in ABS (pH 5.0) and PBS (pH 6.5 and 7.4) at 37 °C; data shown represent mean ± SD, (n = 6) (* p < 0.05, ** p < 0.01, *** p < 0.001); (B) cellular uptake of Dox/F127&P123-Tf with and without Tf pretreatment in OVCAR-3, MDA-MB-231, and MDA-MB-231(R); (C) effects of Dox, Dox/F127&P123, and Dox/F127&P123-Tf on wound healing and migration of OVCAR-3, MDA-MB-231, and MDA-MB-231(R); the images were observed under the optical microscope with 4× magnification at 0 h and 24 h; data shown represent mean ± SD (n = 3).
Figure 4
Figure 4
(A) In vitro cytotoxic effects of Dox, Dox/F127&P123, and Dox/F127&P123-Tf on OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cells; data shown represent mean ± SD in three different experiments (n = 6) (* p < 0.05, ** p < 0.01, *** p < 0.001); (B) live/dead assay of OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cells incubated with (ii) Dox, (iii) Dox/F127&P123, and (iv) Dox/F127&P123-Tf for 24 h, visualized with fluorescence microscopy; green and red fluorescence is defined as live and dead cells, (i) untreated group was used as control respectively; scale bars represent 100 µm.
Figure 4
Figure 4
(A) In vitro cytotoxic effects of Dox, Dox/F127&P123, and Dox/F127&P123-Tf on OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cells; data shown represent mean ± SD in three different experiments (n = 6) (* p < 0.05, ** p < 0.01, *** p < 0.001); (B) live/dead assay of OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cells incubated with (ii) Dox, (iii) Dox/F127&P123, and (iv) Dox/F127&P123-Tf for 24 h, visualized with fluorescence microscopy; green and red fluorescence is defined as live and dead cells, (i) untreated group was used as control respectively; scale bars represent 100 µm.
Figure 5
Figure 5
(A) Cell cycle analysis of OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cells treated with Dox, Dox/F127&P123, and Dox/F127&P123-Tf; scale bars represent 100 µm; (B) Western blot analysis of apoptotic and anti-apoptotic proteins induced in OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cells treated with (ii) Dox, (iii) Dox/F127&P123 and (iv) Dox/F127&P123-Tf for 24 h.
Figure 6
Figure 6
(A) In vivo biodistribution pattern of Cy5.5/F127&P123 and Cy5.5/F127&P123-Tf in MDA-MB-231(R) tumor-bearing mice; (B) ex vivo tissue distribution of Cy5.5/F127&P123 and Cy5.5/F127&P123-Tf in (i) heart, (ii) liver, (iii) spleen, (iv) lungs, (v) kidneys, and (vi) tumor excised from MDA-MB-231(R) tumor-bearing mice; (C) quantification of fluorescent signals from part B; data shown represent mean ± SD (n = 3).
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References

    1. Le Q.-V., Choi J., Oh Y.-K. Nano delivery systems and cancer immunotherapy. J. Pharm. Investig. 2018;48:527–539. doi: 10.1007/s40005-018-0399-z. - DOI
    1. Gupta B., Yong C.S., Kim J.O. Solid matrix-based lipid nanoplatforms as carriers for combinational therapeutics in cancer. J. Pharm. Investig. 2017;47:461–473. doi: 10.1007/s40005-017-0337-5. - DOI
    1. Bazak R., Houri M., Achy S.E., Hussein W., Refaat T. Passive targeting of nanoparticles to cancer: A comprehensive review of the literature. Mol. Clin. Oncol. 2014;2:904–908. doi: 10.3892/mco.2014.356. - DOI - PMC - PubMed
    1. Gullotti E., Yeo Y. Extracellularly Activated Nanocarriers: A New Paradigm of Tumor Targeted Drug Delivery. Mol. Pharm. 2009;6:1041–1051. doi: 10.1021/mp900090z. - DOI - PMC - PubMed
    1. Choi Y.H., Han H.-K. Nanomedicines: Current status and future perspectives in aspect of drug delivery and pharmacokinetics. J. Pharm. Investig. 2018;48:43–60. doi: 10.1007/s40005-017-0370-4. - DOI - PMC - PubMed

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