Triphenylphosphine-docetaxel conjugate-incorporated albumin nanoparticles for cancer treatment

Battogtokh, Gantumur,Gotov, Oyuntuya,Kang, Jee He,Cho, Jinsung,Jeong, Tae Ho,Chimed, Ganzorig,Ko, Young Tag Future Medicine 2018 Nanomedicine Vol.13 No.3

Self-Assembling Micelle-like Nanoparticles with Detachable Envelopes for Enhanced Delivery of Nucleic Acid Therapeutics

Battogtokh, Gantumur,Ko, Young Tag American Chemical Society 2014 Molecular pharmaceutics Vol.11 No.3

<P>In spite of the great potential of nucleic acids as therapeutic agents, the clinical application of nucleic acid therapeutics requires the development of effective systemic delivery strategies. In an effort to develop effective nucleic acid delivery systems suitable for clinical application, we previously reported a self-assembling micelle-like nanoparticle that was based on phospholipid–polyethylenimine conjugates, i.e., “micelle-like nanoparticles” (MNPs). In this study, we aimed to improve the system by enhancing the efficiency of intracellular delivery of the payload via pH-responsive detachment of the monolayer envelope and release of the nucleic acid therapeutics upon reaching the target tissues with an acidic pH, e.g., tumors. The acid-cleavable phospholipid–polyethylenimine conjugate was synthesized via hydrazone bond, and acid-cleavable MNPs were then prepared and characterized as before. We evaluated the acid-cleavable MNP construct for <I>in vitro</I> and <I>in vivo</I> nucleic acid delivery efficiency using cultured tumor cells and tumor-bearing mice. The acid-cleavable nanocarrier showed an enhanced cellular delivery at pH 6.5 as compared to pH 7.4, whereas the noncleavable nanocarrier did not show any differences. Tail vein injections also led to enhanced intracellular uptake of the acid-cleavable nanocarrier compared to the noncleavable nanocarrier into tumor cells of tumor-bearing mice although no significant difference was observed in total tumor accumulation.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/mpohbp/2014/mpohbp.2014.11.issue-3/mp400579h/production/images/medium/mp-2013-00579h_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/mp400579h'>ACS Electronic Supporting Info</A></P>

Mitochondrial-targeted photosensitizer-loaded folate-albumin nanoparticle for photodynamic therapy of cancer

Battogtokh, Gantumur,Ko, Young Tag Elsevier 2017 NANOMEDICINE Vol.13 No.2

<P><B>Abstract</B></P> <P>The objective of this study was to develop a mitochondria-targeted photosensitizer (PS) for photodynamic therapy (PDT). Herein, a porphyrin-derivative photosensitizer, pheophorbide-a (PheoA), was conjugated to carboxybutyltriphenylphosphonium (TPP) <I>via</I> a carbodiimide linkage to enhance mitochondrial targeting and TPP-PheoA conjugate was further loaded into folate-cholesteryl albumin (FA-chol-BSA) nanoparticles (NPs) to improve its biocompatibility. Cellular uptake results showed that TPP-PheoA and TPP-PheoA@FA-chol-BSA NPs were readily taken up by B16F10 and HeLa cells. Further <I>in vitro</I> studies exhibited that TPP-PheoA and its nanoparticle primarily accumulate in the mitochondria, greatly generate ROS, lead mitochondrial disruption and cell apoptosis, and have higher phototoxicity against cancer cells. <I>In vivo</I> bioimaging and the <I>in vivo</I> antitumor studies indicated that TPP-PheoA@FA-chol-BSA NP greatly accumulated in the tumor area and significantly suppress the tumor growth as compared to PheoA@FA-chol-BSA NP in tumor-bearing mice. Taken together, TPP-PheoA@FA-chol-BSA NP could be a promising mitochondria-targeted PS for image-guided PDT.</P> <P><B>Graphical Abstract</B></P> <P>This study demonstrated that TPP-PheoA@FA-chol-BSA NP was internalized upon cells by endocytosis mechanism due to its active targeting ligand and further reached to mitochondria owing to TPP moiety in TPP-PheoA conjugate. Overall, the antitumor PDT efficacy of TPP-PheoA significantly increased.</P> <P>[DISPLAY OMISSION]</P>

Active-targeted pH-responsive albumin-photosensitizer conjugate nanoparticles as theranostic agents

Battogtokh, Gantumur,Ko, Young Tag The Royal Society of Chemistry 2015 Journal of Materials Chemistry B Vol.3 No.48

<P>The objective of this study was to develop an active-targeted, pH-responsive albumin-photosensitizer conjugate as a theranostic agent. Herein, a porphyrin derivative photosensitizer, pheophorbide-a (PheoA), was conjugated to bovine serum albumin (BSA) <I>via</I> a <I>cis</I>-aconityl linkage, and the conjugate was then linked with polyethylene glycosylated folate to improve targeting ability. Further, BSA-<I>c</I>-PheoA and folate (FA)-BSA-<I>c</I>-PheoA at a ratio of 2 : 1 were self-assembled to form nanoparticles with a mean hydrodynamic diameter of 121.47 ± 11.60 nm. The release study exhibited that the photosensitizer was released 4.5-fold faster at pH 5.0 than at pH 7.4 when incubated for 24 h. Cellular uptake results showed that the FA-BSA-<I>c</I>-PheoA nanoparticles were readily taken up by B16F10 and MCF7 cancer cells. <I>In vitro</I> phototoxicity results showed that FA-BSA-<I>c</I>-PheoA NPs have higher efficacy on cancer cells compared to simple BSA-<I>c</I>-PheoA NPs. <I>In vivo</I> bioimaging results exhibited that FA-BSA-<I>c</I>-PheoA NPs greatly accumulated into the tumor area as compared to free PheoA. These results show that our prepared FA-BSA-<I>c</I>-PheoA NPs have the potential to be applied as theranostic agents in photodynamic therapy and photodiagnosis of cancer.</P>

Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives

Battogtokh, Gantumur,Choi, Yeon Su,Kang, Dong Seop,Park, Sang Jun,Shim, Min Suk,Huh, Kang Moo,Cho, Yong-Yeon,Lee, Joo Young,Lee, Hye Suk,Kang, Han Chang Elsevier 2018 Acta pharmaceutica Sinica. B Vol.8 No.6

<P>Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated <I>in vitro</I> and <I>in vivo</I>, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.</P>

Hyaluronic acid-coated cisplatin conjugated gold nanoparticles for combined cancer treatment

Oyuntuya Gotov,Gantumur Battogtokh,신동윤,고영탁 한국공업화학회 2018 Journal of Industrial and Engineering Chemistry Vol.65 No.-

Gold nanoparticles are widely utilized for medical applications such as drug carriers and therapeutic and diagnostic agents due to their small size and great surface area. In the present study, we prepared hyaluronic acid-coated cisplatin conjugated gold nanoparticles to selectively deliver cisplatin into a tumor, and obtain synergistic effects using laser treatment. Our prepared hyaluronic acid-coated cisplatin conjugated gold nanoparticles were found to have a mean hydrodynamic diameter of approximately 140 nm and negative surface charge. The nanoparticles showed greater cytotoxicity than free cisplatin and in vivo antitumor efficacy in tumor models when near infra-red laser was applied. Therefore, this formulation could be applied for combined cancer therapy.

Hyaluronic acid-coated cisplatin conjugated gold nanoparticles for combined cancer treatment

Gotov, Oyuntuya,Battogtokh, Gantumur,Shin, Dongyun,Ko, Young Tag Elsevier 2018 Journal of industrial and engineering chemistry Vol.65 No.-

<P><B>Abstract</B></P> <P>Gold nanoparticles are widely utilized for medical applications such as drug carriers and therapeutic and diagnostic agents due to their small size and great surface area. In the present study, we prepared hyaluronic acid-coated cisplatin conjugated gold nanoparticles to selectively deliver cisplatin into a tumor, and obtain synergistic effects using laser treatment. Our prepared hyaluronic acid-coated cisplatin conjugated gold nanoparticles were found to have a mean hydrodynamic diameter of approximately 140nm and negative surface charge. The nanoparticles showed greater cytotoxicity than free cisplatin and in vivo antitumor efficacy in tumor models when near infra-red laser was applied. Therefore, this formulation could be applied for combined cancer therapy.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Docetaxel-Loaded Hyaluronic Acid-Cathepsin B-Cleavable-Peptide-Gold Nanoparticles for the Treatment of Cancer

Gotov, Oyuntuya,Battogtokh, Gantumur,Ko, Young Tag American Chemical Society 2018 MOLECULAR PHARMACEUTICS Vol.15 No.10

<P>Gold nanoparticles are commonly used for medical applications such as drug delivery and as therapeutic and diagnostic materials because of their unique properties. In this study, we prepared docetaxel (DTX)-loaded hyaluronic acid-cleavable-peptide-gold nanoparticles for the treatment of cancer by selectively delivering DTX into the tumor and, thus, enhancing the therapeutic effect of DTX; further, we determined synergistic effects of the nanoparticles using laser treatment. The DTX-loaded hyaluronic acid-cleavable-peptide-gold nanoparticles prepared in this study had an average size of 75 nm and negative surface charge. The nanoparticles revealed greater cytotoxicity and higher tumor suppression efficacy in tumor models than free DTX under near-infrared laser irradiation. Therefore, the nanoparticle formulation prepared in this study could be utilized for targeted drug delivery and in combination with other cancer therapies.</P> [FIG OMISSION]</BR>

Self-Assembling Lipid–Peptide Hybrid Nanoparticles of Phospholipid–Nonaarginine Conjugates for Enhanced Delivery of Nucleic Acid Therapeutics

Kang, Ji Hee,Battogtokh, Gantumur,Ko, Young Tag American Chemical Society 2017 Biomacromolecules Vol.18 No.11

<P>Despite potential applications of nucleic acid therapeutics, the lack of effective delivery systems hinders their clinical application. To overcome the barriers to nucleic acid delivery, we previously reported nanoparticles using phospholipid–polyethylenimine conjugates. However, toxicity of polyethylenimine remains as a problematic issue. Herein, we proposed to substitute the polyethylenimine with arginine-rich peptide to obtain a less-toxic carrier system. Nonaarginine was conjugated to the distal end of phospholipid hydrocarbon chains leading to phospholipid–nonaarginine conjugates (PL9R) and then lipid–peptide hybrid nanoparticles carrying oligonucleotide therapeutics (hNP) were constructed by self-assembly process. The hNP were further modified with cell penetrating Tat peptide (T-hNP) to enhance cellular uptake. The PL9R was less cytotoxic, and the hNP showed high loading capacity and colloidal stability. The T-hNP showed higher cellular uptake and transfection efficiency and effective accumulation to tumor tissue and silencing effect in tumor bearing mice. Altogether, T-hNP could provide a promising nanocarrier for nucleic acid therapeutics.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/bomaf6/2017/bomaf6.2017.18.issue-11/acs.biomac.7b01084/production/images/medium/bm-2017-01084g_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/bm7b01084'>ACS Electronic Supporting Info</A></P>

The Chronic and Acute Toxicity of Traditional Medicines Containing Terminalia chebula

ARONGQIQIGE,Enebish Gerelmaa,Song Wang,Xi Wei Cheng,Gantumur Anuujin,Altanbayar Oyunbaatar,Shimomura Hirofumi,Chimeddorj Battogtokh,Chuluun Batnairamdal,Amgalanbaatar Avarzed 대한약침학회 2023 Journal of pharmacopuncture Vol.26 No.1

Objectives: Terminalia chebula, the main ingredient of Altan Arur 5, has been used for many years in traditional medicine. This medicine is more effective than other drugs and is used to treat chronic gastritis and gastrointestinal disorders such as peptic ulcers and esophageal reflux. Other ingredients of Altan Arur 5 are Punica granatum (pomegranate), tulip seeds, black balm, and excreta of Trogopterus xanthipes. The main ingredients of T. chebula are antibacterial and analgesic in traditional medicine. Despite having been used for many years and although many studies have been conducted on the beneficial effects of this medicine and its ingredients, the toxicity of Altan Arur 5 has not yet been elucidated. Therefore, we aimed to study the toxicity of Altan Arur 5 to ensure that it is safe to use. Methods: Acute and chronic toxicity of Altan Arur 5 were assessed in 10 Kunming mice and 8 Sprague-Dawley rats, respectively, in different doses. In the acute toxicity study, Altan Arur 5 was orally administered to Kunming mice in doses of 12 g/kg, 24 g/kg, and 48 g/kg for 14 days. In the chronic toxicity study, it was orally administered to Sprague-Dawley rats in doses of 1.25 g/kg, 2.5 g/kg, and 5 g/kg for 12 weeks. Results: No significant differences were observed in the relative organ weights for mice treated with Altan Arur 5 compared with those in the control group. Furthermore, no macro- or microstructural changes were noted in the organs of any group. Conclusion: Our toxicity testing revealed that the traditional medicine Altan Arur 5 has no toxic effects in vivo.