HPMA copolymer conjugated 5-aminolevulinic acid exhibits superior efficacy for photodynamic therapy with tumor-responsive and targeting properties

Rayhanul Islam; Kevin Kotalík; Vladimír Šubr; Shanghui Gao; Kazumi Yokomizo; Tomáš Etrych; Jun Fang

doi:10.1016/j.nano.2022.102636

HPMA copolymer conjugated 5-aminolevulinic acid exhibits superior efficacy for photodynamic therapy with tumor-responsive and targeting properties

Rayhanul Islam, Kevin Kotalík, Vladimír Šubr, Shanghui Gao, Kazumi Yokomizo, Tomáš Etrych^*, Jun Fang^*

^*Corresponding author for this work

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

2 Citations (Scopus)

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Abstract

In this study, we developed a nanoformulation of 5-aminolevulinic acid (5-ALA) for tumor-targeted photodynamic therapy, in which 5-ALA was conjugated with a biocompatible polymer N-(2-hydroxypropyl)methacrylamide (HPMA) through the hydrazone bond, i.e., P-ALA. P-ALA behaves as the nano-sized molecule with an average size of 5.5 nm in aqueous solution. P-ALA shows a largely increased release rate in acidic pH than physiological pH, suggesting the rapid release profile in acidic tumor environment. P-ALA did not show apparent cytotoxicity up to 0.1 mg/ml, however, under light irradiation, remarkable cell death was induced with the IC₅₀ of 20–30 μg/ml. More importantly, we found significantly higher tumor accumulation of P-ALA than 5-ALA which benefit from its nano-size by taking advantage of the enhanced permeability and retention (EPR) effect. Consequently, P-ALA exhibited much improved in vivo antitumor efficacy without any apparent side effects. We thus anticipate the application of P-ALA as a nano-designed photosensitizer for anticancer photodynamic therapy.

Original language	English
Article number	102636
Journal	Nanomedicine: Nanotechnology, Biology, and Medicine
Volume	48
Early online date	23 Dec 2022
DOIs	https://doi.org/10.1016/j.nano.2022.102636
Publication status	Published - Feb 2023
Externally published	Yes

Bibliographical note

Funding Information:
Funding sources: This work was supported by the research fund from Sojo University to J. Fang. and partly by a Grant-in-Aid for Scientific Research on Scientific Research (C) (JSPS KAKENHI grant numbers 19K09806 and 19K07743 ) to J. Fang. This work was also supported by the Czech Academy of Sciences [Mobility plus project JSPS-22-01 ] and by the project National Institute for Cancer Research (Programme EXCELES, ID project no. LX22NPO5102 ) - Funded by the European Union – Next Generation E.

Publisher Copyright:
© 2022 The Authors

Keywords

5-Aminolevulinic acid
EPR effect
HPMA copolymer
Photodynamic therapy
Tumor targeting

ASJC Scopus subject areas

Bioengineering
Medicine (miscellaneous)
Molecular Medicine
Biomedical Engineering
General Materials Science
Pharmaceutical Science

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HPMA copolymer conjugated 5-aminolevulinic acid exhibits superior efficacy for photodynamic therapy with tumor-responsive and targeting properties
Copyright 2023 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 1.45 MBLicence: CC BY

Cite this

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title = "HPMA copolymer conjugated 5-aminolevulinic acid exhibits superior efficacy for photodynamic therapy with tumor-responsive and targeting properties",

abstract = "In this study, we developed a nanoformulation of 5-aminolevulinic acid (5-ALA) for tumor-targeted photodynamic therapy, in which 5-ALA was conjugated with a biocompatible polymer N-(2-hydroxypropyl)methacrylamide (HPMA) through the hydrazone bond, i.e., P-ALA. P-ALA behaves as the nano-sized molecule with an average size of 5.5 nm in aqueous solution. P-ALA shows a largely increased release rate in acidic pH than physiological pH, suggesting the rapid release profile in acidic tumor environment. P-ALA did not show apparent cytotoxicity up to 0.1 mg/ml, however, under light irradiation, remarkable cell death was induced with the IC50 of 20–30 μg/ml. More importantly, we found significantly higher tumor accumulation of P-ALA than 5-ALA which benefit from its nano-size by taking advantage of the enhanced permeability and retention (EPR) effect. Consequently, P-ALA exhibited much improved in vivo antitumor efficacy without any apparent side effects. We thus anticipate the application of P-ALA as a nano-designed photosensitizer for anticancer photodynamic therapy.",

keywords = "5-Aminolevulinic acid, EPR effect, HPMA copolymer, Photodynamic therapy, Tumor targeting",

author = "Rayhanul Islam and Kevin Kotal{\'i}k and Vladim{\'i}r {\v S}ubr and Shanghui Gao and Kazumi Yokomizo and Tom{\'a}{\v s} Etrych and Jun Fang",

note = "Funding Information: Funding sources: This work was supported by the research fund from Sojo University to J. Fang. and partly by a Grant-in-Aid for Scientific Research on Scientific Research (C) (JSPS KAKENHI grant numbers 19K09806 and 19K07743 ) to J. Fang. This work was also supported by the Czech Academy of Sciences [Mobility plus project JSPS-22-01 ] and by the project National Institute for Cancer Research (Programme EXCELES, ID project no. LX22NPO5102 ) - Funded by the European Union – Next Generation E. Publisher Copyright: {\textcopyright} 2022 The Authors",

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language = "English",

volume = "48",

journal = "Nanomedicine: Nanotechnology, Biology, and Medicine",

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AU - Islam, Rayhanul

AU - Kotalík, Kevin

AU - Šubr, Vladimír

AU - Gao, Shanghui

AU - Yokomizo, Kazumi

AU - Etrych, Tomáš

AU - Fang, Jun

N1 - Funding Information: Funding sources: This work was supported by the research fund from Sojo University to J. Fang. and partly by a Grant-in-Aid for Scientific Research on Scientific Research (C) (JSPS KAKENHI grant numbers 19K09806 and 19K07743 ) to J. Fang. This work was also supported by the Czech Academy of Sciences [Mobility plus project JSPS-22-01 ] and by the project National Institute for Cancer Research (Programme EXCELES, ID project no. LX22NPO5102 ) - Funded by the European Union – Next Generation E. Publisher Copyright: © 2022 The Authors

PY - 2023/2

Y1 - 2023/2

N2 - In this study, we developed a nanoformulation of 5-aminolevulinic acid (5-ALA) for tumor-targeted photodynamic therapy, in which 5-ALA was conjugated with a biocompatible polymer N-(2-hydroxypropyl)methacrylamide (HPMA) through the hydrazone bond, i.e., P-ALA. P-ALA behaves as the nano-sized molecule with an average size of 5.5 nm in aqueous solution. P-ALA shows a largely increased release rate in acidic pH than physiological pH, suggesting the rapid release profile in acidic tumor environment. P-ALA did not show apparent cytotoxicity up to 0.1 mg/ml, however, under light irradiation, remarkable cell death was induced with the IC50 of 20–30 μg/ml. More importantly, we found significantly higher tumor accumulation of P-ALA than 5-ALA which benefit from its nano-size by taking advantage of the enhanced permeability and retention (EPR) effect. Consequently, P-ALA exhibited much improved in vivo antitumor efficacy without any apparent side effects. We thus anticipate the application of P-ALA as a nano-designed photosensitizer for anticancer photodynamic therapy.

AB - In this study, we developed a nanoformulation of 5-aminolevulinic acid (5-ALA) for tumor-targeted photodynamic therapy, in which 5-ALA was conjugated with a biocompatible polymer N-(2-hydroxypropyl)methacrylamide (HPMA) through the hydrazone bond, i.e., P-ALA. P-ALA behaves as the nano-sized molecule with an average size of 5.5 nm in aqueous solution. P-ALA shows a largely increased release rate in acidic pH than physiological pH, suggesting the rapid release profile in acidic tumor environment. P-ALA did not show apparent cytotoxicity up to 0.1 mg/ml, however, under light irradiation, remarkable cell death was induced with the IC50 of 20–30 μg/ml. More importantly, we found significantly higher tumor accumulation of P-ALA than 5-ALA which benefit from its nano-size by taking advantage of the enhanced permeability and retention (EPR) effect. Consequently, P-ALA exhibited much improved in vivo antitumor efficacy without any apparent side effects. We thus anticipate the application of P-ALA as a nano-designed photosensitizer for anticancer photodynamic therapy.

KW - 5-Aminolevulinic acid

KW - EPR effect

KW - HPMA copolymer

KW - Photodynamic therapy

KW - Tumor targeting

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DO - 10.1016/j.nano.2022.102636

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SN - 1549-9634

VL - 48

JO - Nanomedicine: Nanotechnology, Biology, and Medicine

JF - Nanomedicine: Nanotechnology, Biology, and Medicine

M1 - 102636

ER -

HPMA copolymer conjugated 5-aminolevulinic acid exhibits superior efficacy for photodynamic therapy with tumor-responsive and targeting properties

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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