Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Cancer Treatment and Fertility

Maria Poley; Patricia Mora-Raimundo; Yael Shammai; Maya Kaduri; Lilach Koren; Omer  Adir; Jeny Shklover; Janna Shainsky-Roitman; Srinivas Ramishetti; Francis Man; Rafael T. M. de Rosales; Assaf Zinger; Dan Peer; Irit Ben-Aharon; Avi Schroeder

doi:10.1021/acsnano.1c07237

Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Cancer Treatment and Fertility

Maria Poley, Patricia Mora-Raimundo, Yael Shammai, Maya Kaduri, Lilach Koren, Omer Adir, Jeny Shklover, Janna Shainsky-Roitman, Srinivas Ramishetti, Francis Man, Rafael T. M. de Rosales, Assaf Zinger^*, Dan Peer, Irit Ben-Aharon, Avi Schroeder^*

^*Corresponding author for this work

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

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Abstract

Throughout the female menstrual cycle, physiological changes occur that affect the biodistribution of nanoparticles within the reproductive system. We demonstrate a 2-fold increase in nanoparticle accumulation in murine ovaries and uterus during ovulation, compared to the nonovulatory stage, following intravenous administration. This biodistribution pattern had positive or negative effects when drug-loaded nanoparticles, sized 100 nm or smaller, were used to treat different cancers. For example, treating ovarian cancer with nanomedicines during mouse ovulation resulted in higher drug accumulation in the ovaries, improving therapeutic efficacy. Conversely, treating breast cancer during ovulation, led to reduced therapeutic efficacy, due to enhanced nanoparticle accumulation in the reproductive system rather than at the tumor site. Moreover, chemotherapeutic nanoparticles administered during ovulation increased ovarian toxicity and decreased fertility compared to the free drug. The menstrual cycle should be accounted for when designing and implementing nanomedicines for females.

Original language	English
Pages (from-to)	5246-5257
Number of pages	12
Journal	ACS Nano
Volume	16
Issue number	4
Early online date	16 Mar 2022
DOIs	https://doi.org/10.1021/acsnano.1c07237
Publication status	Published - 26 Apr 2022

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Poley, M., Mora-Raimundo, P., Shammai, Y., Kaduri, M., Koren, L., Adir, O., Shklover, J., Shainsky-Roitman, J., Ramishetti, S., Man, F., T. M. de Rosales, R., Zinger, A., Peer, D., Ben-Aharon, I., & Schroeder, A. (2022). Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Cancer Treatment and Fertility. ACS Nano, 16(4), 5246-5257. https://doi.org/10.1021/acsnano.1c07237

@article{d6ae5dddcf814d5b95993859e961b11d,

title = "Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Cancer Treatment and Fertility",

abstract = "Throughout the female menstrual cycle, physiological changes occur that affect the biodistribution of nanoparticles within the reproductive system. We demonstrate a 2-fold increase in nanoparticle accumulation in murine ovaries and uterus during ovulation, compared to the nonovulatory stage, following intravenous administration. This biodistribution pattern had positive or negative effects when drug-loaded nanoparticles, sized 100 nm or smaller, were used to treat different cancers. For example, treating ovarian cancer with nanomedicines during mouse ovulation resulted in higher drug accumulation in the ovaries, improving therapeutic efficacy. Conversely, treating breast cancer during ovulation, led to reduced therapeutic efficacy, due to enhanced nanoparticle accumulation in the reproductive system rather than at the tumor site. Moreover, chemotherapeutic nanoparticles administered during ovulation increased ovarian toxicity and decreased fertility compared to the free drug. The menstrual cycle should be accounted for when designing and implementing nanomedicines for females.",

author = "Maria Poley and Patricia Mora-Raimundo and Yael Shammai and Maya Kaduri and Lilach Koren and Omer Adir and Jeny Shklover and Janna Shainsky-Roitman and Srinivas Ramishetti and Francis Man and {T. M. de Rosales}, Rafael and Assaf Zinger and Dan Peer and Irit Ben-Aharon and Avi Schroeder",

note = "Funding Information: This work was supported by the European Union{\textquoteright}s Horizon 2020 research and innovation program under the grant agreement no. 680242-ERC [Next-Generation Personalized Diagnostic Nanotechnologies for Predicting Response to Cancer Medicine]; a Phospholipid Research Center grant (ASC-2018-062/1-1); the Israel Science Foundation (1881/21, 1778/13, 1421/17); the Israel Ministry of Science & Technology (3-16963, 3-17418); Ministry of Agriculture & Rural Development, Office of the Chief Scientist (323/19); Israel Innovation Authority for a Nofar grant (67967, 880326), the Israel Ministry of Economy for a Kamin grant (69230, 63379); the Israel Cancer Association (2015-0116); the German-Israeli Foundation for Scientific Research and Development for a GIF Young grant (I-2328-1139.10/2012); the European Union FP-7 IRG Program for a Career Integration grant (908049); the Louis Family Cancer Research Fund, Leventhal 2020 COVID19 Research Fund (ATS #11947); a Mallat Family Foundation grant; The Unger Family Fund; and the Carrie Rosenblatt Foundation for Cancer Research. A.S. acknowledges Alon and Taub Fellowships. Images in this paper were created with BioRender.com and Adobe Illustrator. The authors also acknowledge the support of the Technion Integrated Cancer Center (TICC), the Russell Berrie Nanotechnology Institute, and the Lorry I. Lokey Interdisciplinary Center for Life Sciences & Engineering. M.P. wishes to thank the Israeli Ministry of Science and Technology for the Shulamit Aloni Doctoral Fellowship. O.A. wishes to thank the Miriam and Aaron Gutwirth Memorial Fellowship. M.K. wishes to thank TEVA Pharmaceuticals–NFBI–The National Forum for BioInnovators for a doctoral grant and the Technion Integrated Cancer Center (TICC) Rubinstein scholarship. The SPECT-CT imaging studies were funded by a CRUK Multidisciplinary Project Award [C48390/A21153], the EPSRC program for next generation molecular imaging and therapy with radionuclides [EP/S032789/1], the Wellcome EPSRC Centre for Medical Engineering at King{\textquoteright}s College London [WT 203148/Z/16/Z], a Wellcome Trust Multiuser Equipment Grant [212885/Z/18/Z], and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and KCL [IS-BRC-1215-20006]. Publisher Copyright: {\textcopyright} 2022 American Chemical Society.",

year = "2022",

month = apr,

day = "26",

doi = "10.1021/acsnano.1c07237",

language = "English",

volume = "16",

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publisher = "American Chemical Society",

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Poley, M, Mora-Raimundo, P, Shammai, Y, Kaduri, M, Koren, L, Adir, O, Shklover, J, Shainsky-Roitman, J, Ramishetti, S, Man, F , T. M. de Rosales, R, Zinger, A, Peer, D, Ben-Aharon, I & Schroeder, A 2022, 'Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Cancer Treatment and Fertility', ACS Nano, vol. 16, no. 4, pp. 5246-5257. https://doi.org/10.1021/acsnano.1c07237

TY - JOUR

T1 - Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Cancer Treatment and Fertility

AU - Poley, Maria

AU - Mora-Raimundo, Patricia

AU - Shammai, Yael

AU - Kaduri, Maya

AU - Koren, Lilach

AU - Adir, Omer

AU - Shklover, Jeny

AU - Shainsky-Roitman, Janna

AU - Ramishetti, Srinivas

AU - Man, Francis

AU - T. M. de Rosales, Rafael

AU - Zinger, Assaf

AU - Peer, Dan

AU - Ben-Aharon, Irit

AU - Schroeder, Avi

N1 - Funding Information: This work was supported by the European Union’s Horizon 2020 research and innovation program under the grant agreement no. 680242-ERC [Next-Generation Personalized Diagnostic Nanotechnologies for Predicting Response to Cancer Medicine]; a Phospholipid Research Center grant (ASC-2018-062/1-1); the Israel Science Foundation (1881/21, 1778/13, 1421/17); the Israel Ministry of Science & Technology (3-16963, 3-17418); Ministry of Agriculture & Rural Development, Office of the Chief Scientist (323/19); Israel Innovation Authority for a Nofar grant (67967, 880326), the Israel Ministry of Economy for a Kamin grant (69230, 63379); the Israel Cancer Association (2015-0116); the German-Israeli Foundation for Scientific Research and Development for a GIF Young grant (I-2328-1139.10/2012); the European Union FP-7 IRG Program for a Career Integration grant (908049); the Louis Family Cancer Research Fund, Leventhal 2020 COVID19 Research Fund (ATS #11947); a Mallat Family Foundation grant; The Unger Family Fund; and the Carrie Rosenblatt Foundation for Cancer Research. A.S. acknowledges Alon and Taub Fellowships. Images in this paper were created with BioRender.com and Adobe Illustrator. The authors also acknowledge the support of the Technion Integrated Cancer Center (TICC), the Russell Berrie Nanotechnology Institute, and the Lorry I. Lokey Interdisciplinary Center for Life Sciences & Engineering. M.P. wishes to thank the Israeli Ministry of Science and Technology for the Shulamit Aloni Doctoral Fellowship. O.A. wishes to thank the Miriam and Aaron Gutwirth Memorial Fellowship. M.K. wishes to thank TEVA Pharmaceuticals–NFBI–The National Forum for BioInnovators for a doctoral grant and the Technion Integrated Cancer Center (TICC) Rubinstein scholarship. The SPECT-CT imaging studies were funded by a CRUK Multidisciplinary Project Award [C48390/A21153], the EPSRC program for next generation molecular imaging and therapy with radionuclides [EP/S032789/1], the Wellcome EPSRC Centre for Medical Engineering at King’s College London [WT 203148/Z/16/Z], a Wellcome Trust Multiuser Equipment Grant [212885/Z/18/Z], and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and KCL [IS-BRC-1215-20006]. Publisher Copyright: © 2022 American Chemical Society.

PY - 2022/4/26

Y1 - 2022/4/26

N2 - Throughout the female menstrual cycle, physiological changes occur that affect the biodistribution of nanoparticles within the reproductive system. We demonstrate a 2-fold increase in nanoparticle accumulation in murine ovaries and uterus during ovulation, compared to the nonovulatory stage, following intravenous administration. This biodistribution pattern had positive or negative effects when drug-loaded nanoparticles, sized 100 nm or smaller, were used to treat different cancers. For example, treating ovarian cancer with nanomedicines during mouse ovulation resulted in higher drug accumulation in the ovaries, improving therapeutic efficacy. Conversely, treating breast cancer during ovulation, led to reduced therapeutic efficacy, due to enhanced nanoparticle accumulation in the reproductive system rather than at the tumor site. Moreover, chemotherapeutic nanoparticles administered during ovulation increased ovarian toxicity and decreased fertility compared to the free drug. The menstrual cycle should be accounted for when designing and implementing nanomedicines for females.

AB - Throughout the female menstrual cycle, physiological changes occur that affect the biodistribution of nanoparticles within the reproductive system. We demonstrate a 2-fold increase in nanoparticle accumulation in murine ovaries and uterus during ovulation, compared to the nonovulatory stage, following intravenous administration. This biodistribution pattern had positive or negative effects when drug-loaded nanoparticles, sized 100 nm or smaller, were used to treat different cancers. For example, treating ovarian cancer with nanomedicines during mouse ovulation resulted in higher drug accumulation in the ovaries, improving therapeutic efficacy. Conversely, treating breast cancer during ovulation, led to reduced therapeutic efficacy, due to enhanced nanoparticle accumulation in the reproductive system rather than at the tumor site. Moreover, chemotherapeutic nanoparticles administered during ovulation increased ovarian toxicity and decreased fertility compared to the free drug. The menstrual cycle should be accounted for when designing and implementing nanomedicines for females.

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U2 - 10.1021/acsnano.1c07237

DO - 10.1021/acsnano.1c07237

M3 - Article

SN - 1936-0851

VL - 16

SP - 5246

EP - 5257

JO - ACS Nano

JF - ACS Nano

IS - 4

ER -

Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Cancer Treatment and Fertility

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