Direct Polymerization of the Arsenic Drug PENAO to Obtain Nanoparticles with High Thiol-Reactivity and Anti-Cancer Efficiency

Noy, JM; Lu, H; Hogg, PJ; Yang, JL; Stenzel, M

Direct Polymerization of the Arsenic Drug PENAO to Obtain Nanoparticles with High Thiol-Reactivity and Anti-Cancer Efficiency

Noy, JM Lu, H

Hogg, PJ Yang, JL Stenzel, M

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Publication Type:: Journal Article
Citation:: Bioconjugate Chemistry, 2018, 29 (2), pp. 546 - 558
Issue Date:: 2018-02-21

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Field	Value	Language
dc.contributor.author	Noy, JM	en_US
dc.contributor.author	Lu, H https://orcid.org/0000-0001-6932-1900	en_US
dc.contributor.author	Hogg, PJ	en_US
dc.contributor.author	Yang, JL	en_US
dc.contributor.author	Stenzel, M https://orcid.org/0000-0002-6433-4419	en_US
dc.date.issued	2018-02-21	en_US
dc.identifier.citation	Bioconjugate Chemistry, 2018, 29 (2), pp. 546 - 558	en_US
dc.identifier.issn	1043-1802	en_US
dc.identifier.uri	http://hdl.handle.net/10453/130273
dc.description.abstract	© 2018 American Chemical Society. PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid), which is a mitochondria inhibitor that reacts with adenine nucleotide translocator (ANT), is currently being trialed in patients with solid tumors. To increase the stability of the drug, the formation of nanoparticles has been proposed. Herein, the direct synthesis of polymeric micelles based on the anticancer drug PENAO is presented. PENAO is readily available for amidation reaction to form PENAO MA (4-(N-(S-penicillaminylacetyl) amino) phenylarsonous acid methacrylamide) which undergoes RAFT (reversible addition-fragmentation chain transfer) polymerization with poly(ethylene glycol methyl ether methacrylate) as comonomer and poly(methyl methacrylate) (pMMA) as chain transfer agent, resulting in p(MMA)-b-p(PEG-co-PENAO) block copolymers with 3-15 wt % of PENAO MA. The different block copolymers self-assembled into micelle structures, varying in size and stability (Dh = 84-234 nm, cmc = 0.5-82 μg mol-1) depending on the hydrophilic to hydrophobic ratio of the polymer blocks and the amount of drug in the corona of the particle. The more stable micelle structures were investigated toward 143B human osteosarcoma cells, showing an enhanced cytotoxicity and cellular uptake compared to the free drug PENAO (IC50 (PENAO) = 2.7 ± 0.3 μM; IC50 (micelle M4) = 0.8 ± 0.02 μM). Furthermore, PENAOs arsonous acid residue remains active when incorporated into a polymer matrix and conjugates to small mono and closely spaced dithiols and is able to actively target the mitochondria, which is PENAO's main target to introduce growth inhibition in cancer cells. As a result, no cleavable linker between drug and polymer was necessary for the delivery of PENAO to osteosarcoma cells. These findings provide a rationale for in vivo studies of micelle M4 versus PENAO in an osteosarcoma animal model.	en_US
dc.relation.ispartof	Bioconjugate Chemistry	en_US
dc.relation.isbasedon	10.1021/acs.bioconjchem.8b00032	en_US
dc.subject.classification	Organic Chemistry	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Mitochondria	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Osteosarcoma	en_US
dc.subject.mesh	Arsenicals	en_US
dc.subject.mesh	Sulfhydryl Compounds	en_US
dc.subject.mesh	Polymers	en_US
dc.subject.mesh	Antineoplastic Agents	en_US
dc.subject.mesh	Drug Carriers	en_US
dc.subject.mesh	Cell Proliferation	en_US
dc.subject.mesh	Nanoparticles	en_US
dc.subject.mesh	Polymerization	en_US
dc.title	Direct Polymerization of the Arsenic Drug PENAO to Obtain Nanoparticles with High Thiol-Reactivity and Anti-Cancer Efficiency	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	29	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - IBMD - Initiative for Biomedical Devices
utslib.copyright.status	closed_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	29	en_US

Abstract:

© 2018 American Chemical Society. PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid), which is a mitochondria inhibitor that reacts with adenine nucleotide translocator (ANT), is currently being trialed in patients with solid tumors. To increase the stability of the drug, the formation of nanoparticles has been proposed. Herein, the direct synthesis of polymeric micelles based on the anticancer drug PENAO is presented. PENAO is readily available for amidation reaction to form PENAO MA (4-(N-(S-penicillaminylacetyl) amino) phenylarsonous acid methacrylamide) which undergoes RAFT (reversible addition-fragmentation chain transfer) polymerization with poly(ethylene glycol methyl ether methacrylate) as comonomer and poly(methyl methacrylate) (pMMA) as chain transfer agent, resulting in p(MMA)-b-p(PEG-co-PENAO) block copolymers with 3-15 wt % of PENAO MA. The different block copolymers self-assembled into micelle structures, varying in size and stability (Dh = 84-234 nm, cmc = 0.5-82 μg mol-1) depending on the hydrophilic to hydrophobic ratio of the polymer blocks and the amount of drug in the corona of the particle. The more stable micelle structures were investigated toward 143B human osteosarcoma cells, showing an enhanced cytotoxicity and cellular uptake compared to the free drug PENAO (IC50 (PENAO) = 2.7 ± 0.3 μM; IC50 (micelle M4) = 0.8 ± 0.02 μM). Furthermore, PENAOs arsonous acid residue remains active when incorporated into a polymer matrix and conjugates to small mono and closely spaced dithiols and is able to actively target the mitochondria, which is PENAO's main target to introduce growth inhibition in cancer cells. As a result, no cleavable linker between drug and polymer was necessary for the delivery of PENAO to osteosarcoma cells. These findings provide a rationale for in vivo studies of micelle M4 versus PENAO in an osteosarcoma animal model.

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http://hdl.handle.net/10453/130273