CD44-targeting PLGA nanoparticles incorporating paclitaxel and FAK siRNA overcome chemoresistance in epithelial ovarian cancer

Yeongseon Byeon; Jeong Won Lee; Whan Soo Choi; Ji Eun Won; Ga Hee Kim; Min Gi Kim; Tae In Wi; Jae Myeong Lee; Tae Heung Kang; In Duk Jung; Young Jae Cho; Hyung Jun Ahn; Byung Cheol Shin; Young Joo Lee; Anil K. Sood; Hee Dong Han; Yeong Min Park

doi:10.1158/0008-5472.CAN-17-3871

CD44-targeting PLGA nanoparticles incorporating paclitaxel and FAK siRNA overcome chemoresistance in epithelial ovarian cancer

Yeongseon Byeon, Jeong Won Lee, Whan Soo Choi, Ji Eun Won, Ga Hee Kim, Min Gi Kim, Tae In Wi, Jae Myeong Lee, Tae Heung Kang, In Duk Jung, Young Jae Cho, Hyung Jun Ahn, Byung Cheol Shin, Young Joo Lee, Anil K. Sood, Hee Dong Han, Yeong Min Park

Gynecological Oncology & Reproductive Medicine

Research output: Contribution to journal › Article › peer-review

95 Scopus citations

Abstract

Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTXþFAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR (P < 0.001) and SKOV3-TR (P < 0.001) with HA-PLGA (PTXþFAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTXþFAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone (P < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma. Significance: These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer.

Original language	English (US)
Pages (from-to)	6247-6256
Number of pages	10
Journal	Cancer Research
Volume	78
Issue number	21
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-3871
State	Published - Nov 1 2018

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/0008-5472.CAN-17-3871

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Byeon, Y., Lee, J. W., Choi, W. S., Won, J. E., Kim, G. H., Kim, M. G., Wi, T. I., Lee, J. M., Kang, T. H., Jung, I. D., Cho, Y. J., Ahn, H. J., Shin, B. C., Lee, Y. J., Sood, A. K., Han, H. D., & Park, Y. M. (2018). CD44-targeting PLGA nanoparticles incorporating paclitaxel and FAK siRNA overcome chemoresistance in epithelial ovarian cancer. Cancer Research, 78(21), 6247-6256. https://doi.org/10.1158/0008-5472.CAN-17-3871

Byeon, Y, Lee, JW, Choi, WS, Won, JE, Kim, GH, Kim, MG, Wi, TI, Lee, JM, Kang, TH, Jung, ID, Cho, YJ, Ahn, HJ, Shin, BC, Lee, YJ, Sood, AK, Han, HD & Park, YM 2018, 'CD44-targeting PLGA nanoparticles incorporating paclitaxel and FAK siRNA overcome chemoresistance in epithelial ovarian cancer', Cancer Research, vol. 78, no. 21, pp. 6247-6256. https://doi.org/10.1158/0008-5472.CAN-17-3871

@article{c27ac314e7d94845847c9ea8a339d81c,

title = "CD44-targeting PLGA nanoparticles incorporating paclitaxel and FAK siRNA overcome chemoresistance in epithelial ovarian cancer",

abstract = "Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTX{\th}FAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR (P < 0.001) and SKOV3-TR (P < 0.001) with HA-PLGA (PTX{\th}FAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTX{\th}FAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone (P < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma. Significance: These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer.",

author = "Yeongseon Byeon and Lee, {Jeong Won} and Choi, {Whan Soo} and Won, {Ji Eun} and Kim, {Ga Hee} and Kim, {Min Gi} and Wi, {Tae In} and Lee, {Jae Myeong} and Kang, {Tae Heung} and Jung, {In Duk} and Cho, {Young Jae} and Ahn, {Hyung Jun} and Shin, {Byung Cheol} and Lee, {Young Joo} and Sood, {Anil K.} and Han, {Hee Dong} and Park, {Yeong Min}",

note = "Funding Information: This work was supported by National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2016R1A5A2012284, NRF-2016R1A2B2007327, and NRF-2015R1A2A2A04003620 to Y.-M. Park, H.D. Han, and Y.J. Lee). This work was also supported by Basic Research Laboratory Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (No. 2013R1A4A1069575 to H.D. Han, T.H. Kang, and I.D. Jung) and a grant from the National R&D program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1520100 to H.D. Han, H.J. Ahn, and J.-W. Lee). This work was also supported by American Cancer Society Research Professor Award and R35CA209904 to A.K. Sood). Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

year = "2018",

month = nov,

day = "1",

doi = "10.1158/0008-5472.CAN-17-3871",

language = "English (US)",

volume = "78",

pages = "6247--6256",

journal = "Cancer Research",

issn = "0008-5472",

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TY - JOUR

T1 - CD44-targeting PLGA nanoparticles incorporating paclitaxel and FAK siRNA overcome chemoresistance in epithelial ovarian cancer

AU - Byeon, Yeongseon

AU - Lee, Jeong Won

AU - Choi, Whan Soo

AU - Won, Ji Eun

AU - Kim, Ga Hee

AU - Kim, Min Gi

AU - Wi, Tae In

AU - Lee, Jae Myeong

AU - Kang, Tae Heung

AU - Jung, In Duk

AU - Cho, Young Jae

AU - Ahn, Hyung Jun

AU - Shin, Byung Cheol

AU - Lee, Young Joo

AU - Sood, Anil K.

AU - Han, Hee Dong

AU - Park, Yeong Min

N1 - Funding Information: This work was supported by National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2016R1A5A2012284, NRF-2016R1A2B2007327, and NRF-2015R1A2A2A04003620 to Y.-M. Park, H.D. Han, and Y.J. Lee). This work was also supported by Basic Research Laboratory Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (No. 2013R1A4A1069575 to H.D. Han, T.H. Kang, and I.D. Jung) and a grant from the National R&D program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1520100 to H.D. Han, H.J. Ahn, and J.-W. Lee). This work was also supported by American Cancer Society Research Professor Award and R35CA209904 to A.K. Sood). Publisher Copyright: © 2018 American Association for Cancer Research.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTXþFAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR (P < 0.001) and SKOV3-TR (P < 0.001) with HA-PLGA (PTXþFAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTXþFAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone (P < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma. Significance: These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer.

AB - Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTXþFAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR (P < 0.001) and SKOV3-TR (P < 0.001) with HA-PLGA (PTXþFAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTXþFAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone (P < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma. Significance: These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer.

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U2 - 10.1158/0008-5472.CAN-17-3871

DO - 10.1158/0008-5472.CAN-17-3871

M3 - Article

C2 - 30115698

AN - SCOPUS:85055907384

SN - 0008-5472

VL - 78

SP - 6247

EP - 6256

JO - Cancer Research

JF - Cancer Research

IS - 21

ER -

CD44-targeting PLGA nanoparticles incorporating paclitaxel and FAK siRNA overcome chemoresistance in epithelial ovarian cancer

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