Bone Tumor-Homing Nanotherapeutics for Prolonged Retention in Tumor Microenvironment and Facilitated Apoptotic Process Via Mevalonate Pathway Inhibition

34 Pages Posted: 11 Jul 2022

See all articles by Nae-Won Kang

Nae-Won Kang

Seoul National University

Voradanu Visetvichaporn

Seoul National University

Duy-Thuc Nguyen

Seoul National University

Da-Han Kim

Seoul National University

Min-Jae Kim

Seoul National University

So-Yeol Yoo

Seoul National University

Jae-Young Lee

Chungnam National University

Dae-Duk Kim

Seoul National University - Research Institute of Pharmaceutical Science

Abstract

Bone malignancy features a mineralized extracellular matrix primarily composed of hydroxyapatite, which interferes with the distribution and activity of antineoplastic agents. Herein, we report bone tumor-homing polymeric nanotherapeutics consisting of alendronate-decorated chondroitin sulfate A-graft-poly(lactide-co-glycolide) and doxorubicin (DOX), named PLCSA-AD, which displayed a prolonged retention profile in the tumor microenvironment and augmented therapeutic efficacy via inhibition of the mevalonate pathway. PLCSA-AD exhibited a 1.72-fold lower IC50 value than free DOX and a higher affinity for hydroxyapatite than PLCSA in HOS/MNNG cell-based 2D bone tumor-mimicking models. The inhibition of the mevalonate pathway by PLCSA-AD in tumor cells was verified by investigating the cytosolic fraction of unprenylated proteins, where blank PLCSA-AD significantly increased the expression of cytosolic Ras and RhoA without changing their total cellular amounts. In a bone tumor-mimicking xenografted mouse model, AD-decorated nanotherapeutics significantly increased tumor accumulation (1.73-fold) compared with PLCSA, and higher adsorption to hydroxyapatites was observed in the histological analysis of the tumor. As a result, inhibition of the mevalonate pathway and improvement in tumor accumulation led to markedly enhanced therapeutic efficacy in vivo, suggesting that PLCSA-AD could be promising nanotherapeutics for bone tumor treatment.

Note:
Funding Information: This work was supported by National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT [No. NRF-2018R1A5A2024425, NRF- 2018M3A7B4071203, NRF-2020R1A2C2099983, and NRF-2021R1C1C1009320].

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: The animal experimental protocol (SNU-210121-10-1) was approved by the Animal Care and Use Committee of Seoul National University.

Keywords: bone tumors, alendronate, mevalonate pathway inhibition, hydroxyapatites, tumor distribution, apoptosis

Suggested Citation

Kang, Nae-Won and Visetvichaporn, Voradanu and Nguyen, Duy-Thuc and Kim, Da-Han and Kim, Min-Jae and Yoo, So-Yeol and Lee, Jae-Young and Kim, Dae-Duk, Bone Tumor-Homing Nanotherapeutics for Prolonged Retention in Tumor Microenvironment and Facilitated Apoptotic Process Via Mevalonate Pathway Inhibition. Available at SSRN: https://ssrn.com/abstract=4155152 or http://dx.doi.org/10.2139/ssrn.4155152

Nae-Won Kang

Seoul National University ( email )

Kwanak-gu
Seoul, 151-742
Korea, Republic of (South Korea)

Voradanu Visetvichaporn

Seoul National University ( email )

Kwanak-gu
Seoul, 151-742
Korea, Republic of (South Korea)

Duy-Thuc Nguyen

Seoul National University ( email )

Kwanak-gu
Seoul, 151-742
Korea, Republic of (South Korea)

Da-Han Kim

Seoul National University ( email )

Kwanak-gu
Seoul, 151-742
Korea, Republic of (South Korea)

Min-Jae Kim

Seoul National University ( email )

Kwanak-gu
Seoul, 151-742
Korea, Republic of (South Korea)

So-Yeol Yoo

Seoul National University ( email )

Kwanak-gu
Seoul, 151-742
Korea, Republic of (South Korea)

Jae-Young Lee

Chungnam National University ( email )

Daejon, 34134
Korea, Republic of (South Korea)

Dae-Duk Kim (Contact Author)

Seoul National University - Research Institute of Pharmaceutical Science ( email )

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