Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin

Yang Liu; Aftab Nadeem; Sujeesh Sebastian; Martin A. Olsson; Sun N. Wai; Emelie Styring; Jacob Engellau; Hanna Isaksson; Magnus Tägil; Lars Lidgren; Deepak Bushan Raina

doi:10.1016/j.mtbio.2022.100227

Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin

Yang Liu, Aftab Nadeem, Sujeesh Sebastian, Martin A. Olsson, Sun N. Wai, Emelie Styring, Jacob Engellau, Hanna Isaksson, Magnus Tägil, Lars Lidgren, Deepak Bushan Raina

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

Abstract

Efficient systemic pharmacological treatment of solid tumors is hampered by inadequate tumor concentration of cytostatics necessitating development of smart local drug delivery systems. To overcome this, we demonstrate that doxorubicin (DOX), a cornerstone drug used for osteosarcoma treatment, shows reversible accretion to hydroxyapatite (HA) of both nano (nHA) and micro (mHA) size. nHA particles functionalized with DOX get engulfed in the lysosome of osteosarcoma cells where the acidic microenvironment causes a disruption of the binding between DOX and HA. The released DOX then accumulates in the mitochondria causing cell starvation, reduced migration and apoptosis. The HA+DOX delivery system was also tested in-vivo on osteosarcoma bearing mice. Locally delivered DOX via the HA particles had a stronger tumor eradication effect compared to the controls as seen by PET-CT and immunohistochemical staining of proliferation and apoptosis markers. These results indicate that in addition to systemic chemotherapy, an adjuvant nHA could be used as a carrier for intracellular delivery of DOX for prevention of tumor recurrence after surgical resection in an osteosarcoma. Furthermore, we demonstrate that nHA particles are pivotal in this approach but a combination of nHA with mHA could increase the safety associated with particulate nanomaterials while maintaining similar therapeutic potential.

Original language	English
Article number	100227
Journal	Materials Today Bio
Volume	14
DOIs	https://doi.org/10.1016/j.mtbio.2022.100227
Publication status	Published - 2022 Mar

Bibliographical note

Funding Information:
Medical Faculty at Lund University and the Lund University Bioimaging Center (LBIC) are thanked for the infrastructure support. We also acknowledge the Biochemical Imaging Center at Umeå University and the National Microscopy Infrastructure, NMI (VR-RFI 2019–00217) for providing assistance with microscopy. Swedish Research Council (Vetenskapsrådet, Grant number: 2021-03447), Berta Kamprad foundation (Grant number: FBKS-2020-23-(269)), Maggie Stephens foundation (Grant number: 20202004), China Scholarship Council (grant number: 201806940015 ), and Cancerfonden (Grant number: 20 0711 PjF) are thanked for the financial support.

Funding Information:
Medical Faculty at Lund University and the Lund University Bioimaging Center (LBIC) are thanked for the infrastructure support. We also acknowledge the Biochemical Imaging Center at Ume? University and the National Microscopy Infrastructure, NMI (VR-RFI 2019?00217) for providing assistance with microscopy. Swedish Research Council (Vetenskapsr?det, Grant number: 2021-03447), Berta Kamprad foundation (Grant number: FBKS-2020-23-(269)), Maggie Stephens foundation (Grant number: 20202004), China Scholarship Council (grant number: 201806940015), and Cancerfonden (Grant number: 20 0711 PjF) are thanked for the financial support.

Publisher Copyright:
© 2022

Subject classification (UKÄ)

Biomaterials Science
Cancer and Oncology

Free keywords

Doxorubicin
Drug delivery
Nano and micro hydroxyapatite
Osteosarcoma
Solid tumor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.mtbio.2022.100227Licence: CC BY

1 Doctoral Thesis (compilation)

Hydroxyapatite – A trojan horse in the delivery of apatite-binding cytostatics in bone cancer
Liu, Y., 2022, Lund: Lund University, Faculty of Medicine. 77 p.
Research output: Thesis › Doctoral Thesis (compilation)

Open Access
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Liu, Y., Nadeem, A., Sebastian, S., Olsson, M. A., Wai, S. N., Styring, E., Engellau, J., Isaksson, H., Tägil, M., Lidgren, L., & Raina, D. B. (2022). Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin. Materials Today Bio, 14, Article 100227. https://doi.org/10.1016/j.mtbio.2022.100227

@article{2d72f71cfbf947e7a16790ba34812721,

title = "Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin",

abstract = "Efficient systemic pharmacological treatment of solid tumors is hampered by inadequate tumor concentration of cytostatics necessitating development of smart local drug delivery systems. To overcome this, we demonstrate that doxorubicin (DOX), a cornerstone drug used for osteosarcoma treatment, shows reversible accretion to hydroxyapatite (HA) of both nano (nHA) and micro (mHA) size. nHA particles functionalized with DOX get engulfed in the lysosome of osteosarcoma cells where the acidic microenvironment causes a disruption of the binding between DOX and HA. The released DOX then accumulates in the mitochondria causing cell starvation, reduced migration and apoptosis. The HA+DOX delivery system was also tested in-vivo on osteosarcoma bearing mice. Locally delivered DOX via the HA particles had a stronger tumor eradication effect compared to the controls as seen by PET-CT and immunohistochemical staining of proliferation and apoptosis markers. These results indicate that in addition to systemic chemotherapy, an adjuvant nHA could be used as a carrier for intracellular delivery of DOX for prevention of tumor recurrence after surgical resection in an osteosarcoma. Furthermore, we demonstrate that nHA particles are pivotal in this approach but a combination of nHA with mHA could increase the safety associated with particulate nanomaterials while maintaining similar therapeutic potential.",

keywords = "Doxorubicin, Drug delivery, Nano and micro hydroxyapatite, Osteosarcoma, Solid tumor",

author = "Yang Liu and Aftab Nadeem and Sujeesh Sebastian and Olsson, {Martin A.} and Wai, {Sun N.} and Emelie Styring and Jacob Engellau and Hanna Isaksson and Magnus T{\"a}gil and Lars Lidgren and Raina, {Deepak Bushan}",

note = "Funding Information: Medical Faculty at Lund University and the Lund University Bioimaging Center (LBIC) are thanked for the infrastructure support. We also acknowledge the Biochemical Imaging Center at Ume{\aa} University and the National Microscopy Infrastructure, NMI (VR-RFI 2019–00217) for providing assistance with microscopy. Swedish Research Council (Vetenskapsr{\aa}det, Grant number: 2021-03447), Berta Kamprad foundation (Grant number: FBKS-2020-23-(269)), Maggie Stephens foundation (Grant number: 20202004), China Scholarship Council (grant number: 201806940015 ), and Cancerfonden (Grant number: 20 0711 PjF) are thanked for the financial support. Funding Information: Medical Faculty at Lund University and the Lund University Bioimaging Center (LBIC) are thanked for the infrastructure support. We also acknowledge the Biochemical Imaging Center at Ume? University and the National Microscopy Infrastructure, NMI (VR-RFI 2019?00217) for providing assistance with microscopy. Swedish Research Council (Vetenskapsr?det, Grant number: 2021-03447), Berta Kamprad foundation (Grant number: FBKS-2020-23-(269)), Maggie Stephens foundation (Grant number: 20202004), China Scholarship Council (grant number: 201806940015), and Cancerfonden (Grant number: 20 0711 PjF) are thanked for the financial support. Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = mar,

doi = "10.1016/j.mtbio.2022.100227",

language = "English",

volume = "14",

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Liu, Y, Nadeem, A, Sebastian, S, Olsson, MA, Wai, SN, Styring, E , Engellau, J , Isaksson, H , Tägil, M , Lidgren, L & Raina, DB 2022, 'Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin', Materials Today Bio, vol. 14, 100227. https://doi.org/10.1016/j.mtbio.2022.100227

TY - JOUR

T1 - Bone mineral

T2 - A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin

AU - Liu, Yang

AU - Nadeem, Aftab

AU - Sebastian, Sujeesh

AU - Olsson, Martin A.

AU - Wai, Sun N.

AU - Styring, Emelie

AU - Engellau, Jacob

AU - Isaksson, Hanna

AU - Tägil, Magnus

AU - Lidgren, Lars

AU - Raina, Deepak Bushan

N1 - Funding Information: Medical Faculty at Lund University and the Lund University Bioimaging Center (LBIC) are thanked for the infrastructure support. We also acknowledge the Biochemical Imaging Center at Umeå University and the National Microscopy Infrastructure, NMI (VR-RFI 2019–00217) for providing assistance with microscopy. Swedish Research Council (Vetenskapsrådet, Grant number: 2021-03447), Berta Kamprad foundation (Grant number: FBKS-2020-23-(269)), Maggie Stephens foundation (Grant number: 20202004), China Scholarship Council (grant number: 201806940015 ), and Cancerfonden (Grant number: 20 0711 PjF) are thanked for the financial support. Funding Information: Medical Faculty at Lund University and the Lund University Bioimaging Center (LBIC) are thanked for the infrastructure support. We also acknowledge the Biochemical Imaging Center at Ume? University and the National Microscopy Infrastructure, NMI (VR-RFI 2019?00217) for providing assistance with microscopy. Swedish Research Council (Vetenskapsr?det, Grant number: 2021-03447), Berta Kamprad foundation (Grant number: FBKS-2020-23-(269)), Maggie Stephens foundation (Grant number: 20202004), China Scholarship Council (grant number: 201806940015), and Cancerfonden (Grant number: 20 0711 PjF) are thanked for the financial support. Publisher Copyright: © 2022

PY - 2022/3

Y1 - 2022/3

N2 - Efficient systemic pharmacological treatment of solid tumors is hampered by inadequate tumor concentration of cytostatics necessitating development of smart local drug delivery systems. To overcome this, we demonstrate that doxorubicin (DOX), a cornerstone drug used for osteosarcoma treatment, shows reversible accretion to hydroxyapatite (HA) of both nano (nHA) and micro (mHA) size. nHA particles functionalized with DOX get engulfed in the lysosome of osteosarcoma cells where the acidic microenvironment causes a disruption of the binding between DOX and HA. The released DOX then accumulates in the mitochondria causing cell starvation, reduced migration and apoptosis. The HA+DOX delivery system was also tested in-vivo on osteosarcoma bearing mice. Locally delivered DOX via the HA particles had a stronger tumor eradication effect compared to the controls as seen by PET-CT and immunohistochemical staining of proliferation and apoptosis markers. These results indicate that in addition to systemic chemotherapy, an adjuvant nHA could be used as a carrier for intracellular delivery of DOX for prevention of tumor recurrence after surgical resection in an osteosarcoma. Furthermore, we demonstrate that nHA particles are pivotal in this approach but a combination of nHA with mHA could increase the safety associated with particulate nanomaterials while maintaining similar therapeutic potential.

AB - Efficient systemic pharmacological treatment of solid tumors is hampered by inadequate tumor concentration of cytostatics necessitating development of smart local drug delivery systems. To overcome this, we demonstrate that doxorubicin (DOX), a cornerstone drug used for osteosarcoma treatment, shows reversible accretion to hydroxyapatite (HA) of both nano (nHA) and micro (mHA) size. nHA particles functionalized with DOX get engulfed in the lysosome of osteosarcoma cells where the acidic microenvironment causes a disruption of the binding between DOX and HA. The released DOX then accumulates in the mitochondria causing cell starvation, reduced migration and apoptosis. The HA+DOX delivery system was also tested in-vivo on osteosarcoma bearing mice. Locally delivered DOX via the HA particles had a stronger tumor eradication effect compared to the controls as seen by PET-CT and immunohistochemical staining of proliferation and apoptosis markers. These results indicate that in addition to systemic chemotherapy, an adjuvant nHA could be used as a carrier for intracellular delivery of DOX for prevention of tumor recurrence after surgical resection in an osteosarcoma. Furthermore, we demonstrate that nHA particles are pivotal in this approach but a combination of nHA with mHA could increase the safety associated with particulate nanomaterials while maintaining similar therapeutic potential.

KW - Doxorubicin

KW - Drug delivery

KW - Nano and micro hydroxyapatite

KW - Osteosarcoma

KW - Solid tumor

U2 - 10.1016/j.mtbio.2022.100227

DO - 10.1016/j.mtbio.2022.100227

M3 - Article

C2 - 35265825

AN - SCOPUS:85125537714

SN - 2590-0064

VL - 14

JO - Materials Today Bio

JF - Materials Today Bio

M1 - 100227

ER -

Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

Fingerprint

Research output

Hydroxyapatite – A trojan horse in the delivery of apatite-binding cytostatics in bone cancer

Cite this