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Article ; Online: Efficient Combination Chemo-Sonodynamic Cancer Therapy Using Mitochondria-Targeting Sonosensitizer-Loaded Polysorbate-Based Micelles.

Kang, Hyeon Ju / Truong Hoang, Quan / Min, Jun / Son, Min Soo / Tram, Le Thi Hong / Kim, Byoung Choul / Song, Youngjun / Shim, Min Suk

International journal of molecular sciences

2024 Volume 25, Issue 6

Abstract: Sonodynamic therapy (SDT), utilizing ultrasound (US) and sonosensitizers, holds immense potential as a noninvasive and targeted treatment for a variety of deep-seated tumors. However, the clinical translation of SDT is hampered by several key limitations ...

Abstract	Sonodynamic therapy (SDT), utilizing ultrasound (US) and sonosensitizers, holds immense potential as a noninvasive and targeted treatment for a variety of deep-seated tumors. However, the clinical translation of SDT is hampered by several key limitations in sonosensitizers, especially their low aqueous stability and poor cellular uptake. In this study, non-ionic polysorbate (Tween 80, T80) was adopted to formulate effective nanocarriers for the safe and efficient delivery of sonosensitizers to cancer cells. Mitochondria-targeting triphenylphosphonium (TPP)-conjugated chlorin e6 (Ce6) sonosensitizer was loaded into T80-based micelles for efficient SDT. Pro-oxidant piperlongumine (PL) was co-encapsulated with TPP-conjugated Ce6 (T-Ce6) in T80 micelles to enable combination chemo-SDT. T80 micelles substantially enhanced the cellular internalization of T-Ce6. As a result, T80 micelles loaded with T-Ce6 and PL [T80(T-Ce6/PL)] significantly elevated intracellular reactive oxygen species (ROS) generation in MCF-7 human breast cancer cells upon US exposure. Moreover, T-Ce6 exhibited selective accumulation within the mitochondria, leading to efficient cell death under US irradiation. Importantly, T80(T-Ce6/PL) micelles caused cancer-specific cell death by selectively triggering apoptosis in cancer cells through PL. This study demonstrated the feasibility of using T80(T-Ce6/PL) micelles for efficient and cancer-specific combination chemo-SDT.
MeSH term(s)	Humans ; Polysorbates ; Cell Line, Tumor ; Micelles ; Reactive Oxygen Species/metabolism ; Mitochondria/metabolism ; Porphyrins/metabolism ; Nanoparticles ; Neoplasms/drug therapy ; Organophosphorus Compounds
Chemical Substances	Polysorbates ; Micelles ; triphenylphosphonium ; Reactive Oxygen Species ; Porphyrins ; Organophosphorus Compounds
Language	English
Publishing date	2024-03-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25063474
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Beyond Nanoparticle-Based Intracellular Drug Delivery: Cytosol/Organelle-Targeted Drug Release and Therapeutic Synergism.

Cho, Hana / Huh, Kang Moo / Shim, Min Suk / Cho, Yong-Yeon / Lee, Joo Young / Lee, Hye Suk / Kang, Han Chang

Macromolecular bioscience

2024 , Page(s) e2300590

Abstract: Nanoparticle (NP)-based drug delivery systems are conceived to solve poor water-solubility and chemical/physical instability, and their purpose expanded to target specific sites for maximizing therapeutic effects and minimizing unwanted events of ... ...

Abstract	Nanoparticle (NP)-based drug delivery systems are conceived to solve poor water-solubility and chemical/physical instability, and their purpose expanded to target specific sites for maximizing therapeutic effects and minimizing unwanted events of payloads. Targeted sites are also narrowed from organs/tissues and cells to cytosol/organelles. Beyond specific site targeting, the particular release of payloads at the target sites is growing in importance. This review overviews various issues and their general strategies during multiple steps, from the preparation of drug-loaded NPs to their drug release at the target cytosol/organelles. In particular, this review focuses on current strategies for "first" delivery and "later" release of drugs to the cytosol or organelles of interest using specific stimuli in the target sites. Recognizing or distinguishing the presence/absence of stimuli or their differences in concentration/level/activity in one place from those in another is applied to stimuli-triggered release via bond cleavage or nanostructural transition. In addition, future directions on understanding the intracellular balance of stimuli and their counter-stimuli are demonstrated to synergize the therapeutic effects of payloads released from stimuli-sensitive NPs.
Language	English
Publishing date	2024-03-15
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2039130-4
ISSN	1616-5195 ; 1616-5187
ISSN (online)	1616-5195
ISSN	1616-5187
DOI	10.1002/mabi.202300590
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Article: Pro-oxidant drug-loaded porphyrinic zirconium metal-organic-frameworks for cancer-specific sonodynamic therapy

Truong Hoang, Quan / Kim, Miyeon / Kim, Byoung Choul / Lee, Chang Yeon / Shim, Min Suk

Colloids and surfaces. 2022 Jan., v. 209

2022

Abstract: Sonodynamic therapy, which utilizes ultrasound (US) to produce cytotoxic reactive oxygen species (ROS), can overcome the critical drawbacks of photodynamic therapy, such as limited tissue penetration depth. However, the development of sonosensitizers ... ...

Abstract	Sonodynamic therapy, which utilizes ultrasound (US) to produce cytotoxic reactive oxygen species (ROS), can overcome the critical drawbacks of photodynamic therapy, such as limited tissue penetration depth. However, the development of sonosensitizers having superior sonodynamic effects and desirable biocompatibility remains a major challenge. In this study, nanoscale zirconium-based porphyrinic metal organic frameworks (MOFs) (PCN-222) were developed as safe and effective nanosonosensitizers. Polyethylene glycol (PEG)-coated PCN-222 (PEG-PCN) was loaded with a pro-oxidant drug, piperlongumine (PL), to enable tumor-specific chemo-photodynamic combination therapy. Both PEG-PCN and PL-incorporated PEG-PCN (PL-PEG-PCN) showed high colloidal stability in biological media. In addition, nanoscale PL-PEG-PCN was efficiently internalized by breast cancer cells, leading to substantially increased ROS generation under US exposure. The effective intracellular delivery of PL by PEG-PCN further elevated the level of intracellular ROS in breast cancer cells owing to the pro-oxidative activity of PL. Therefore, PL-PEG-PCN revealed significantly higher sonotoxicity than free PL and PEG-PCN. Owing to the cancer-specific apoptosis triggered by PL, PL-PEG-PCN showed cancer-selective cell death in breast cancer cells compared with normal fibroblast cells. This study demonstrates that pro-oxidant drug-loaded porphyrinic MOFs are biocompatible and effective sonosensitizers for cancer-targeted chemo-sonodynamic combination therapy.
Keywords	apoptosis ; biocompatibility ; breast neoplasms ; cytotoxicity ; drugs ; fibroblasts ; photochemotherapy ; polyethylene glycol ; reactive oxygen species ; ultrasonics ; zirconium
Language	English
Dates of publication	2022-01
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	1500523-9
ISSN	1873-4367 ; 0927-7765
ISSN (online)	1873-4367
ISSN	0927-7765
DOI	10.1016/j.colsurfb.2021.112189
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Selective Anticancer Therapy Using Pro-Oxidant Drug-Loaded Chitosan-Fucoidan Nanoparticles.

Choi, Dae Gun / Venkatesan, Jayachandran / Shim, Min Suk

International journal of molecular sciences

2019 Volume 20, Issue 13

Abstract: Pro-oxidant therapy exploiting pro-oxidant drugs that can trigger cytotoxic oxidative stress in cancer cells has emerged as an innovative strategy for cancer-specific therapy. Piperlongumine (PL) has gained great interest as a novel pro-oxidant agent, ... ...

Abstract	Pro-oxidant therapy exploiting pro-oxidant drugs that can trigger cytotoxic oxidative stress in cancer cells has emerged as an innovative strategy for cancer-specific therapy. Piperlongumine (PL) has gained great interest as a novel pro-oxidant agent, because it has an ability to trigger cancer-specific apoptosis through the increase of oxidative stress in cancer cells. However, the use of PL is limited in the clinic because of its hydrophobic nature. In this study, chitosan- and fucoidan-based nanoparticles were prepared for the effective intracellular delivery of PL into cancer cells. Chitosan and fucoidan formed nanoparticles by ionic gelation. The chitosan- and fucoidan-based nanoparticles (CS-F NPs) effectively encapsulated PL, and increased its water solubility and bioavailability. CS-F NPs showed very low cytotoxicity in human prostate cancer cells, demonstrating its high potential for in vivo applications. The PL-loaded chitosan-fucoidan nanoparticles (PL-CS-F NPs) efficiently killed human prostate cancer cells via PL-induced intracellular reactive oxygen species (ROS) generation. This study demonstrates that CS-F NPs are promising natural polymer-based drug carriers for safe and effective PL delivery.
MeSH term(s)	Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Cell Death/drug effects ; Cell Line ; Cell Line, Tumor ; Chitosan/analogs & derivatives ; Dioxolanes/administration & dosage ; Dioxolanes/pharmacology ; Humans ; Nanoparticles/adverse effects ; Nanoparticles/chemistry ; Oxidants/administration & dosage ; Oxidants/pharmacology ; Polysaccharides/chemistry
Chemical Substances	Antineoplastic Agents ; Dioxolanes ; Oxidants ; Polysaccharides ; Chitosan (9012-76-4) ; fucoidan (9072-19-9) ; piperlongumine (SGD66V4SVJ)
Language	English
Publishing date	2019-06-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20133220
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Beyond nanoparticle-based oral drug delivery: transporter-mediated absorption and disease targeting.

Cho, Hana / Huh, Kang Moo / Cho, Hyun Ji / Kim, Bogeon / Shim, Min Suk / Cho, Yong-Yeon / Lee, Joo Young / Lee, Hye Suk / Kwon, Young Jik / Kang, Han Chang

Biomaterials science

2024

Abstract: Various strategies at the microscale/nanoscale have been developed to improve oral absorption of therapeutics. Among them, gastrointestinal (GI)-transporter/receptor-mediated nanosized drug delivery systems (NDDSs) have drawn attention due to their many ... ...

Abstract	Various strategies at the microscale/nanoscale have been developed to improve oral absorption of therapeutics. Among them, gastrointestinal (GI)-transporter/receptor-mediated nanosized drug delivery systems (NDDSs) have drawn attention due to their many benefits, such as improved water solubility, improved chemical/physical stability, improved oral absorption, and improved targetability of their payloads. Their therapeutic potential in disease animal models (
Language	English
Publishing date	2024-05-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/d4bm00313f
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Solvent-driven, self-assembled acid-responsive poly(ketalized serine)/siRNA complexes for RNA interference.

Wong, Shirley / Kemp, Jessica A / Shim, Min Suk / Kwon, Young Jik

Biomaterials science

2020 Volume 8, Issue 23, Page(s) 6718–6729

Abstract: Advances in bionanotechnology aim to develop smart nucleic acid delivery carriers with stimuli-responsive features to overcome challenges such as non-biodegradability, rapid clearance, immune response, and reaching intracellular targets. Peptide-based ... ...

Abstract	Advances in bionanotechnology aim to develop smart nucleic acid delivery carriers with stimuli-responsive features to overcome challenges such as non-biodegradability, rapid clearance, immune response, and reaching intracellular targets. Peptide-based nanomaterials have become widely used in the field of gene and drug delivery due to their structural versatility and biomimetic properties. Particularly, polypeptide gene vectors that respond to biological stimuli, such as acidic intracellular environments, have promising applications in mediating efficient endosomal escape and drug release. Unfortunately, synthesis strategies for efficient polymerization of acid-labile peptides have been limited due to conditions that fail to preserve acid-degradable functional groups. Stable urethane derivatives of the acid-labile amino acid ketalized serine (kSer) were synthesized and polymerized to a high molecular weight under permissive conditions independent of elevated temperature, restrictive solvents, or an inert atmosphere. A new formulation strategy utilizing solvent-driven self-assembly of poly(kSer) peptides with small interfering RNA (siRNA) was developed, and the resulting poly(kSer)/siRNA complexes were further cross-linked for reinforced stability under physiological conditions. The complexes were highly monodisperse and precisely spherical in morphology, which has significant clinical implications in definitive biodistribution, cellular internalization, and intracellular trafficking patterns. Self-assembled, cross-linked poly(kSer)/siRNA complexes demonstrated efficient nucleic acid encapsulation, internalization, endosomal escape, and acid-triggered cargo release, tackling multiple hurdles in siRNA delivery. The acid-responsive polypeptides and solvent-driven self-assembly strategies demonstrated in this study could be applicable to developing other efficient and safe delivery systems for gene and drug delivery.
MeSH term(s)	RNA Interference ; RNA, Small Interfering/metabolism ; Serine ; Solvents ; Tissue Distribution
Chemical Substances	RNA, Small Interfering ; Solvents ; Serine (452VLY9402)
Language	English
Publishing date	2020-10-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/d0bm01478h
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Pro-oxidant drug-loaded porphyrinic zirconium metal-organic-frameworks for cancer-specific sonodynamic therapy.

Truong Hoang, Quan / Kim, Miyeon / Kim, Byoung Choul / Lee, Chang Yeon / Shim, Min Suk

Colloids and surfaces. B, Biointerfaces

2021 Volume 209, Issue Pt 1, Page(s) 112189

Abstract	Sonodynamic therapy, which utilizes ultrasound (US) to produce cytotoxic reactive oxygen species (ROS), can overcome the critical drawbacks of photodynamic therapy, such as limited tissue penetration depth. However, the development of sonosensitizers having superior sonodynamic effects and desirable biocompatibility remains a major challenge. In this study, nanoscale zirconium-based porphyrinic metal organic frameworks (MOFs) (PCN-222) were developed as safe and effective nanosonosensitizers. Polyethylene glycol (PEG)-coated PCN-222 (PEG-PCN) was loaded with a pro-oxidant drug, piperlongumine (PL), to enable tumor-specific chemo-photodynamic combination therapy. Both PEG-PCN and PL-incorporated PEG-PCN (PL-PEG-PCN) showed high colloidal stability in biological media. In addition, nanoscale PL-PEG-PCN was efficiently internalized by breast cancer cells, leading to substantially increased ROS generation under US exposure. The effective intracellular delivery of PL by PEG-PCN further elevated the level of intracellular ROS in breast cancer cells owing to the pro-oxidative activity of PL. Therefore, PL-PEG-PCN revealed significantly higher sonotoxicity than free PL and PEG-PCN. Owing to the cancer-specific apoptosis triggered by PL, PL-PEG-PCN showed cancer-selective cell death in breast cancer cells compared with normal fibroblast cells. This study demonstrates that pro-oxidant drug-loaded porphyrinic MOFs are biocompatible and effective sonosensitizers for cancer-targeted chemo-sonodynamic combination therapy.
MeSH term(s)	Metal-Organic Frameworks ; Neoplasms ; Oxidants ; Prodrugs ; Reactive Oxygen Species ; Zirconium
Chemical Substances	Metal-Organic Frameworks ; Oxidants ; Prodrugs ; Reactive Oxygen Species ; Zirconium (C6V6S92N3C)
Language	English
Publishing date	2021-10-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1500523-9
ISSN	1873-4367 ; 0927-7765
ISSN (online)	1873-4367
ISSN	0927-7765
DOI	10.1016/j.colsurfb.2021.112189
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Solvent-driven, self-assembled acid-responsive poly(ketalized serine)/siRNA complexes for RNA interference

Wong, Shirley / Kemp, Jessica A / Shim, Min Suk / Kwon, Young Jik

Biomaterials science. 2020 Nov. 24, v. 8, no. 23

2020

Abstract	Advances in bionanotechnology aim to develop smart nucleic acid delivery carriers with stimuli-responsive features to overcome challenges such as non-biodegradability, rapid clearance, immune response, and reaching intracellular targets. Peptide-based nanomaterials have become widely used in the field of gene and drug delivery due to their structural versatility and biomimetic properties. Particularly, polypeptide gene vectors that respond to biological stimuli, such as acidic intracellular environments, have promising applications in mediating efficient endosomal escape and drug release. Unfortunately, synthesis strategies for efficient polymerization of acid-labile peptides have been limited due to conditions that fail to preserve acid-degradable functional groups. Stable urethane derivatives of the acid-labile amino acid ketalized serine (kSer) were synthesized and polymerized to a high molecular weight under permissive conditions independent of elevated temperature, restrictive solvents, or an inert atmosphere. A new formulation strategy utilizing solvent-driven self-assembly of poly(kSer) peptides with small interfering RNA (siRNA) was developed, and the resulting poly(kSer)/siRNA complexes were further cross-linked for reinforced stability under physiological conditions. The complexes were highly monodisperse and precisely spherical in morphology, which has significant clinical implications in definitive biodistribution, cellular internalization, and intracellular trafficking patterns. Self-assembled, cross-linked poly(kSer)/siRNA complexes demonstrated efficient nucleic acid encapsulation, internalization, endosomal escape, and acid-triggered cargo release, tackling multiple hurdles in siRNA delivery. The acid-responsive polypeptides and solvent-driven self-assembly strategies demonstrated in this study could be applicable to developing other efficient and safe delivery systems for gene and drug delivery.
Keywords	RNA interference ; biocompatible materials ; biomimetics ; crosslinking ; encapsulation ; genes ; immune response ; molecular weight ; nanobiotechnology ; polymerization ; polypeptides ; serine ; temperature ; urethane
Language	English
Dates of publication	2020-1124
Size	p. 6718-6729.
Publishing place	The Royal Society of Chemistry
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/d0bm01478h
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Guanidinium-functionalized Block Copolyelectrolyte Micelleplexes for Safe and Efficient siRNA Delivery

Heo, Tae-Young / Hoang, Quan Truong / Cao, Thuy Giang Nguyen / O, Sŭng-hwan / Ryu, Moon-Chul / Shim, Min Suk / Choi, Soo-Hyung

Biotechnol Bioproc E. 2022 Dec., v. 27, no. 6 p.1004-1013

2022

Abstract: RNAi-based therapeutics utilizing small interfering RNAs (siRNAs) are of significance in the clinic as it serves great potentials for gene-based treatment of human diseases. Currently, siRNA-based RNAi efficiency has been limited by facile degradation, ... ...

Abstract	RNAi-based therapeutics utilizing small interfering RNAs (siRNAs) are of significance in the clinic as it serves great potentials for gene-based treatment of human diseases. Currently, siRNA-based RNAi efficiency has been limited by facile degradation, poor cell membrane penetration, and short half-life time of siRNA. In this study, block copolyelectrolytes containing a poly(ethylene oxide) (PEO) neutral block and a cationic block were synthesized by anionic polymerization and post-polymerization modification. In the cationic block, guanidinium and ammonium groups were randomly incorporated with various fractions to achieve micelleplexes for safe and efficient siRNA delivery. Compared to traditional polyethylenimine-based polyplexes, all micelleplexes exhibited enhanced cellular internalization and better gene silencing efficiency with higher stability. As the fraction of guanidinium groups increased, the uptake level and siRNA transfection were enhanced due to stronger binding of guanidinium groups with siRNA. However, the trade-off between cellular internalization and toxicity was inevitable with increasing guanidinium fraction. The fraction of guanidinium group in block copolyelectrolytes was optimized by the systemic evaluation of cytotoxicity and gene silencing efficiency of the micelleplexes.
Keywords	ammonium ; cell membranes ; cytotoxicity ; genes ; guanidinium ; half life ; humans ; polymerization ; therapeutics ; transfection
Language	English
Dates of publication	2022-12
Size	p. 1004-1013.
Publishing place	The Korean Society for Biotechnology and Bioengineering
Document type	Article ; Online
ZDB-ID	2125481-3
ISSN	1976-3816 ; 1226-8372
ISSN (online)	1976-3816
ISSN	1226-8372
DOI	10.1007/s12257-022-0222-6
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Bioreducible exosomes encapsulating glycolysis inhibitors potentiate mitochondria-targeted sonodynamic cancer therapy via cancer-targeted drug release and cellular energy depletion

Nguyen Cao, Thuy Giang / Truong Hoang, Quan / Kang, Ji Hee / Kang, Su Jin / Ravichandran, Vasanthan / Rhee, Won Jong / Lee, Minjong / Ko, Young Tag / Shim, Min Suk

Biomaterials. 2023 July 11, p.122242-

2023 , Page(s) 122242–

Abstract: Nanocarrier-assisted sonodynamic therapy (SDT) has shown great potential for the effective and targeted treatment of deep-seated tumors by overcoming the critical limitations of sonosensitizers. However, in vivo SDT using nanocarriers is still ... ...

Abstract	Nanocarrier-assisted sonodynamic therapy (SDT) has shown great potential for the effective and targeted treatment of deep-seated tumors by overcoming the critical limitations of sonosensitizers. However, in vivo SDT using nanocarriers is still constrained by their intrinsic toxicity and nonspecific cargo release. In this study, we developed bioreducible exosomes for the safe and tumor-specific delivery of mitochondria-targeting sonosensitizers [triphenylphosphonium-conjugated chlorin e6 (T-Ce6)] and glycolysis inhibitors (FX11). Redox-cleavable diselenide linker-bearing lipids were embedded into exosomes to trigger drug release in response to overexpressed glutathione in the tumor microenvironment. Bioreducible exosomes facilitate the cytoplasmic release of their payload in the reducing environment of tumor cells. They significantly enhance drug release and sonodynamic effects when irradiated with ultrasound (US). The mitochondria-targeted accumulation of T-Ce6 efficiently damaged the mitochondria of the cells under US irradiation, accelerating apoptotic cell death. FX11 substantially inhibited cellular energy metabolism, potentiating the antitumor efficacy of mitochondria-targeted SDT. Bioreducible exosomes effectively suppressed tumor growth in mice without significant systemic toxicity, via a combination of mitochondria-targeted SDT and energy metabolism-targeted therapy. This study offers new insights into the use of dual stimuli-responsive exosomes encapsulating sonosensitizers for safe and targeted sonodynamic cancer therapy.
Keywords	apoptosis ; biocompatible materials ; cancer therapy ; chlorins ; drugs ; energy ; energy metabolism ; exosomes ; glutathione ; glycolysis ; irradiation ; mitochondria ; nanocarriers ; neoplasms ; toxicity ; ultrasonics ; Sonodynamic therapy ; Bioreducible exosomes ; Diselenide ; Glycolysis inhibition
Language	English
Dates of publication	2023-0711
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	603079-8
ISSN	0142-9612
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2023.122242
Database	NAL-Catalogue (AGRICOLA)

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