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'Prodrug-Like' Acetylmannosamine Modified Liposomes Loaded with Arsenic Trioxide for the Treatment of Orthotopic Glioma in Mice.
J Pharm Sci. 2020 Jun 11 [Online ahead of print]JP

Abstract

Glioma is one of the fatal intracranial cancers that is a huge challenge to decrease the death rate currently. The deep penetration and high accumulation of therapeutic inorganic ions into the tumor site are extremely impeded due to the existence of physiological barriers, which limits to widen the indication of some drugs such as arsenic trioxide. The previous data have confirmed that the mannose substrate (MAN) without acetyl groups facilitates vesicles to go into the brain. Given that deacetylation of Ac4MAN groups on the surface of liposomes under the enzyme incubation occurred, namely 'prodrug-like' features of vesicles, the liposomes could more easily penetrate the BBB, target the glioma site, release arsenic trioxide, and inhibit the growth of glioma cells in the brain. Besides, the possibility of Ac4MAN binding to Gluts could be reduced due to the steric hindrance of acetyl groups, decreasing the off-target effects of vesicles. Here, we developed 'prodrug-like' arsenic trioxide (As2O3, ATO)-loaded liposomes inserted with distearoyl phospho-ethanolamine-polyethylene glycol-1000-p-carboxylpheny-α-d-acetylmannosamine (DSPE-PEG-1000-Ac4MAN), which was named Ac4MAN-ATO-LIP. Cytotoxic experiments of liposomes indicated that the toxicity of Ac4MAN-ATO-LIP was lower than that of free ATO but stronger than that of ATO-LIP (without insertion of DSPE-PEG-1000-Ac4MAN). The uptake of vesicles by U87 glioma cells displayed that the cellular uptake of Ac4MAN-Rho-LIP (labeled by rhodamine) was remarkably improved, compared with Rho-LIP. The in vivo biodistribution results showed the superiority of Ac4MAN-Rho-LIP in enhanced intracranial accumulation. Furthermore, the treatment of orthotopic glioma in Balb/c nude mice with Ac4MAN-ATO-LIP elongated the survival time of the animals than that with physiological saline, free ATO, or ATO-LIP, respectively. All the results suggested that the Ac4MAN-ATO-LIP had stronger anti-glioma effects as well as lower toxicities, and may be a promising approach for the treatment of brain cancer.

Authors+Show Affiliations

Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China.Department of Pharmaceutics, Daqing Campus, Harbin Medical University, Key Laboratory of Research and Development of Natural Products at Harbin Medical University, 39 Xin Yang Road, Daqing 163319, China. Electronic address: fisher1688@163.com.Department of Pharmacology, Harbin Medical University, 157 Baojian Road, Harbin, China. Electronic address: 88982194@qq.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32534027

Citation

Wang, Na, et al. "'Prodrug-Like' Acetylmannosamine Modified Liposomes Loaded With Arsenic Trioxide for the Treatment of Orthotopic Glioma in Mice." Journal of Pharmaceutical Sciences, 2020.
Wang N, Zhang W, Hu D, et al. 'Prodrug-Like' Acetylmannosamine Modified Liposomes Loaded with Arsenic Trioxide for the Treatment of Orthotopic Glioma in Mice. J Pharm Sci. 2020.
Wang, N., Zhang, W., Hu, D., Jiang, L., Liu, X., Tang, S., Zhou, X., Liu, T., Tang, X., Chai, Y., Li, M., Peng, H., & Du, Z. (2020). 'Prodrug-Like' Acetylmannosamine Modified Liposomes Loaded with Arsenic Trioxide for the Treatment of Orthotopic Glioma in Mice. Journal of Pharmaceutical Sciences. https://doi.org/10.1016/j.xphs.2020.06.001
Wang N, et al. 'Prodrug-Like' Acetylmannosamine Modified Liposomes Loaded With Arsenic Trioxide for the Treatment of Orthotopic Glioma in Mice. J Pharm Sci. 2020 Jun 11; PubMed PMID: 32534027.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 'Prodrug-Like' Acetylmannosamine Modified Liposomes Loaded with Arsenic Trioxide for the Treatment of Orthotopic Glioma in Mice. AU - Wang,Na, AU - Zhang,Wenyuan, AU - Hu,Dandan, AU - Jiang,Lei, AU - Liu,Xiaoying, AU - Tang,Shukun, AU - Zhou,Xuegang, AU - Liu,Ting, AU - Tang,Xuefeng, AU - Chai,Yanqun, AU - Li,Minghui, AU - Peng,Haisheng, AU - Du,Zhimin, Y1 - 2020/06/11/ PY - 2020/03/02/received PY - 2020/05/06/revised PY - 2020/06/01/accepted PY - 2020/6/14/pubmed PY - 2020/6/14/medline PY - 2020/6/14/entrez KW - Ac(4)MAN-ATO-LIP KW - Arsenic trioxide KW - Blood brain barrier (BBB) KW - Brain-targeting liposomes KW - Gluts JF - Journal of pharmaceutical sciences JO - J Pharm Sci N2 - Glioma is one of the fatal intracranial cancers that is a huge challenge to decrease the death rate currently. The deep penetration and high accumulation of therapeutic inorganic ions into the tumor site are extremely impeded due to the existence of physiological barriers, which limits to widen the indication of some drugs such as arsenic trioxide. The previous data have confirmed that the mannose substrate (MAN) without acetyl groups facilitates vesicles to go into the brain. Given that deacetylation of Ac4MAN groups on the surface of liposomes under the enzyme incubation occurred, namely 'prodrug-like' features of vesicles, the liposomes could more easily penetrate the BBB, target the glioma site, release arsenic trioxide, and inhibit the growth of glioma cells in the brain. Besides, the possibility of Ac4MAN binding to Gluts could be reduced due to the steric hindrance of acetyl groups, decreasing the off-target effects of vesicles. Here, we developed 'prodrug-like' arsenic trioxide (As2O3, ATO)-loaded liposomes inserted with distearoyl phospho-ethanolamine-polyethylene glycol-1000-p-carboxylpheny-α-d-acetylmannosamine (DSPE-PEG-1000-Ac4MAN), which was named Ac4MAN-ATO-LIP. Cytotoxic experiments of liposomes indicated that the toxicity of Ac4MAN-ATO-LIP was lower than that of free ATO but stronger than that of ATO-LIP (without insertion of DSPE-PEG-1000-Ac4MAN). The uptake of vesicles by U87 glioma cells displayed that the cellular uptake of Ac4MAN-Rho-LIP (labeled by rhodamine) was remarkably improved, compared with Rho-LIP. The in vivo biodistribution results showed the superiority of Ac4MAN-Rho-LIP in enhanced intracranial accumulation. Furthermore, the treatment of orthotopic glioma in Balb/c nude mice with Ac4MAN-ATO-LIP elongated the survival time of the animals than that with physiological saline, free ATO, or ATO-LIP, respectively. All the results suggested that the Ac4MAN-ATO-LIP had stronger anti-glioma effects as well as lower toxicities, and may be a promising approach for the treatment of brain cancer. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/32534027/'Prodrug-like'_acetylmannosamine_modified_liposomes_loaded_with_arsenic_trioxide_for_the_treatment_of_orthotopic_glioma_in_mice L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(20)30309-9 DB - PRIME DP - Unbound Medicine ER -
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