A Theranostic Cellulose Nanocrystal-Based Drug Delivery System with Enhanced Retention in Pulmonary Metastasis of Melanoma

Surachet Imlimthan; You Cheng Khng; Outi Keinänen; Wenzhong Zhang; Anu J. Airaksinen; Mauri A. Kostiainen; Brian M. Zeglis; Hélder A. Santos; Mirkka Sarparanta

doi:10.1002/smll.202007705

A Theranostic Cellulose Nanocrystal-Based Drug Delivery System with Enhanced Retention in Pulmonary Metastasis of Melanoma

Surachet Imlimthan, You Cheng Khng, Outi Keinänen, Wenzhong Zhang, Anu J. Airaksinen, Mauri A. Kostiainen, Brian M. Zeglis, Hélder A. Santos, Mirkka Sarparanta^*

^*Corresponding author for this work

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Abstract

Metastatic melanoma can be difficult to detect until at the advanced state that decreases the survival rate of patients. Several FDA-approved BRAF inhibitors have been used for treatment of metastatic melanoma, but overall therapeutic efficacy has been limited. Lutetium-177 (¹⁷⁷Lu) enables simultaneous tracking of tracer accumulation with single-photon emission computed tomography and radiotherapy. Therefore, the codelivery of ¹⁷⁷Lu alongside chemotherapeutic agents using nanoparticles (NPs) might improve the therapeutic outcome in metastatic melanoma. Cellulose nanocrystals (CNC NPs) can particularly deliver payloads to lung capillaries in vivo. Herein, ¹⁷⁷Lu-labeled CNC NPs loaded with vemurafenib ([¹⁷⁷Lu]Lu-CNC-V NPs) is developed and the therapeutic effect in BRAF V600E mutation-harboring YUMM1.G1 murine model of lung metastatic melanoma is investigated. The [¹⁷⁷Lu]Lu-CNC-V NPs demonstrate favorable radiolabel stability, drug release profile, cellular uptake, and cell growth inhibition in vitro. In vivo biodistribution reveals significant retention of the [¹⁷⁷Lu]Lu-CNC-V NPs in the lung, liver, and spleen. Ultimately, the median survival time of animals is doubly increased after treatment with [¹⁷⁷Lu]Lu-CNC-V NPs compared to control groups. The enhanced therapeutic efficacy of [¹⁷⁷Lu]Lu-CNC-V NPs in the lung metastatic melanoma animal model provides convincing evidence for the potential of clinical translation for theranostic CNC NP-based drug delivery systems after intravenous administration.

Original language	English
Article number	2007705
Number of pages	13
Journal	Small
Volume	17
Issue number	18
Early online date	18 Mar 2021
DOIs	https://doi.org/10.1002/smll.202007705
Publication status	Published - 6 May 2021
MoE publication type	A1 Journal article-refereed

Keywords

cellulose nanocrystal
drug delivery system
Lutetium-177
metastatic melanoma
theranostic nanosystem
vemurafenib

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@article{0c691f7cf3f8416aa4ade652568a792b,

title = "A Theranostic Cellulose Nanocrystal-Based Drug Delivery System with Enhanced Retention in Pulmonary Metastasis of Melanoma",

abstract = "Metastatic melanoma can be difficult to detect until at the advanced state that decreases the survival rate of patients. Several FDA-approved BRAF inhibitors have been used for treatment of metastatic melanoma, but overall therapeutic efficacy has been limited. Lutetium-177 (177Lu) enables simultaneous tracking of tracer accumulation with single-photon emission computed tomography and radiotherapy. Therefore, the codelivery of 177Lu alongside chemotherapeutic agents using nanoparticles (NPs) might improve the therapeutic outcome in metastatic melanoma. Cellulose nanocrystals (CNC NPs) can particularly deliver payloads to lung capillaries in vivo. Herein, 177Lu-labeled CNC NPs loaded with vemurafenib ([177Lu]Lu-CNC-V NPs) is developed and the therapeutic effect in BRAF V600E mutation-harboring YUMM1.G1 murine model of lung metastatic melanoma is investigated. The [177Lu]Lu-CNC-V NPs demonstrate favorable radiolabel stability, drug release profile, cellular uptake, and cell growth inhibition in vitro. In vivo biodistribution reveals significant retention of the [177Lu]Lu-CNC-V NPs in the lung, liver, and spleen. Ultimately, the median survival time of animals is doubly increased after treatment with [177Lu]Lu-CNC-V NPs compared to control groups. The enhanced therapeutic efficacy of [177Lu]Lu-CNC-V NPs in the lung metastatic melanoma animal model provides convincing evidence for the potential of clinical translation for theranostic CNC NP-based drug delivery systems after intravenous administration.",

keywords = "cellulose nanocrystal, drug delivery system, Lutetium-177, metastatic melanoma, theranostic nanosystem, vemurafenib",

author = "Surachet Imlimthan and Khng, {You Cheng} and Outi Kein{\"a}nen and Wenzhong Zhang and Airaksinen, {Anu J.} and Kostiainen, {Mauri A.} and Zeglis, {Brian M.} and Santos, {H{\'e}lder A.} and Mirkka Sarparanta",

note = "Funding Information: Financial support from the Finnish Cultural Foundation (grant no. 00190375), the Academy of Finland (decision nos. 318422, 278056, 298481, 302102, and 331659), and the University of Helsinki Research Funds are gratefully acknowledged. Finnish Center for Laboratory Animal Pathology (FCLAP) at HiLIFE, University of Helsinki, is acknowledged for the tissue preparation and staining services. The authors also thank Dr. Jaakko Sarparanta for help with phospho‐MEK western blot, Ms. Karina Moslova for assistance with the elemental analysis, Ms. Alexandra Correia for assistance with cell culture, and Ms. Phetcharada Imlimthan for the assistance with the images. Publisher Copyright: {\textcopyright} 2021 The Authors. Small published by Wiley-VCH GmbH Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = may,

day = "6",

doi = "10.1002/smll.202007705",

language = "English",

volume = "17",

journal = "Small",

issn = "1613-6810",

publisher = "Wiley-VCH Verlag",

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T1 - A Theranostic Cellulose Nanocrystal-Based Drug Delivery System with Enhanced Retention in Pulmonary Metastasis of Melanoma

AU - Imlimthan, Surachet

AU - Khng, You Cheng

AU - Keinänen, Outi

AU - Zhang, Wenzhong

AU - Airaksinen, Anu J.

AU - Kostiainen, Mauri A.

AU - Zeglis, Brian M.

AU - Santos, Hélder A.

AU - Sarparanta, Mirkka

N1 - Funding Information: Financial support from the Finnish Cultural Foundation (grant no. 00190375), the Academy of Finland (decision nos. 318422, 278056, 298481, 302102, and 331659), and the University of Helsinki Research Funds are gratefully acknowledged. Finnish Center for Laboratory Animal Pathology (FCLAP) at HiLIFE, University of Helsinki, is acknowledged for the tissue preparation and staining services. The authors also thank Dr. Jaakko Sarparanta for help with phospho‐MEK western blot, Ms. Karina Moslova for assistance with the elemental analysis, Ms. Alexandra Correia for assistance with cell culture, and Ms. Phetcharada Imlimthan for the assistance with the images. Publisher Copyright: © 2021 The Authors. Small published by Wiley-VCH GmbH Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/5/6

Y1 - 2021/5/6

N2 - Metastatic melanoma can be difficult to detect until at the advanced state that decreases the survival rate of patients. Several FDA-approved BRAF inhibitors have been used for treatment of metastatic melanoma, but overall therapeutic efficacy has been limited. Lutetium-177 (177Lu) enables simultaneous tracking of tracer accumulation with single-photon emission computed tomography and radiotherapy. Therefore, the codelivery of 177Lu alongside chemotherapeutic agents using nanoparticles (NPs) might improve the therapeutic outcome in metastatic melanoma. Cellulose nanocrystals (CNC NPs) can particularly deliver payloads to lung capillaries in vivo. Herein, 177Lu-labeled CNC NPs loaded with vemurafenib ([177Lu]Lu-CNC-V NPs) is developed and the therapeutic effect in BRAF V600E mutation-harboring YUMM1.G1 murine model of lung metastatic melanoma is investigated. The [177Lu]Lu-CNC-V NPs demonstrate favorable radiolabel stability, drug release profile, cellular uptake, and cell growth inhibition in vitro. In vivo biodistribution reveals significant retention of the [177Lu]Lu-CNC-V NPs in the lung, liver, and spleen. Ultimately, the median survival time of animals is doubly increased after treatment with [177Lu]Lu-CNC-V NPs compared to control groups. The enhanced therapeutic efficacy of [177Lu]Lu-CNC-V NPs in the lung metastatic melanoma animal model provides convincing evidence for the potential of clinical translation for theranostic CNC NP-based drug delivery systems after intravenous administration.

AB - Metastatic melanoma can be difficult to detect until at the advanced state that decreases the survival rate of patients. Several FDA-approved BRAF inhibitors have been used for treatment of metastatic melanoma, but overall therapeutic efficacy has been limited. Lutetium-177 (177Lu) enables simultaneous tracking of tracer accumulation with single-photon emission computed tomography and radiotherapy. Therefore, the codelivery of 177Lu alongside chemotherapeutic agents using nanoparticles (NPs) might improve the therapeutic outcome in metastatic melanoma. Cellulose nanocrystals (CNC NPs) can particularly deliver payloads to lung capillaries in vivo. Herein, 177Lu-labeled CNC NPs loaded with vemurafenib ([177Lu]Lu-CNC-V NPs) is developed and the therapeutic effect in BRAF V600E mutation-harboring YUMM1.G1 murine model of lung metastatic melanoma is investigated. The [177Lu]Lu-CNC-V NPs demonstrate favorable radiolabel stability, drug release profile, cellular uptake, and cell growth inhibition in vitro. In vivo biodistribution reveals significant retention of the [177Lu]Lu-CNC-V NPs in the lung, liver, and spleen. Ultimately, the median survival time of animals is doubly increased after treatment with [177Lu]Lu-CNC-V NPs compared to control groups. The enhanced therapeutic efficacy of [177Lu]Lu-CNC-V NPs in the lung metastatic melanoma animal model provides convincing evidence for the potential of clinical translation for theranostic CNC NP-based drug delivery systems after intravenous administration.

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A Theranostic Cellulose Nanocrystal-Based Drug Delivery System with Enhanced Retention in Pulmonary Metastasis of Melanoma

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