All Publications

  • Selective Targeting of alpha4beta7/MAdCAM-1 Axis Suppresses Fibrosis Progression by Reducing Proinflammatory T Cell Recruitment to the Liver. Cells Gupta, B., Rai, R. P., Pal, P. B., Rossmiller, D., Chaudhary, S., Chiaro, A., Seaman, S., Singhi, A. D., Liu, S., Monga, S. P., Iyer, S. S., Raeman, R. 2024; 13 (9)


    Integrin alpha4beta7+ T cells perpetuate tissue injury in chronic inflammatory diseases, yet their role in hepatic fibrosis progression remains poorly understood. Here, we report increased accumulation of alpha4beta7+ T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl4-induced liver fibrosis was associated with enrichment of intrahepatic alpha4beta7+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of alpha4beta7 or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl4-treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of alpha4beta7+ CD4 and CD8 T cells, suggesting that alpha4beta7/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and alpha4beta7+ T cells promote hepatic fibrosis progression. Analysis of hepatic alpha4beta7+ and alpha4beta7- CD4 T cells revealed that alpha4beta7+ CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that alpha4beta7+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of alpha4beta7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.

    View details for DOI 10.3390/cells13090756

    View details for PubMedID 38727292

  • Heterogeneity of Human Invariant Natural Killer T Cells, Including Novel Naive-like CD8+and Temra-like CD4-CD8-Populations, Revealed through Single Cell RNA-Sequencing Mavers, M., Hollingsworth, D., Jayasinghe, R. G., Boonchalermvichian, C., Gupta, B., Yan, H., Baker, J., Dejene, B., Weinberg, K. I., Negrin, R. S. AMER SOC HEMATOLOGY. 2023
  • Intestinal Barrier Dysfunction in Fatty Liver Disease: Roles of Microbiota, Mucosal Immune System, and Bile Acids. Seminars in liver disease Gupta, B., Rai, R., Oertel, M., Raeman, R. 2022; 42 (2): 122-137


    Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality associated with chronic liver disease, and NAFLD patients are at a higher risk of developing cirrhosis and hepatocellular carcinoma. While there is a consensus that inflammation plays a key role in promoting NAFLD progression, the underlying mechanisms are not well understood. Recent clinical and experimental evidence suggest that increased hepatic translocation of gut microbial antigens, secondary to diet-induced impairment of the intestinal barrier may be important in driving hepatic inflammation in NAFLD. Here, we briefly review various endogenous and exogenous factors influencing the intestinal barrier and present recent advances in our understanding of cellular and molecular mechanisms underlying intestinal barrier dysfunction in NAFLD.

    View details for DOI 10.1055/s-0042-1748037

    View details for PubMedID 35738255

  • Recent progress in cancer immunotherapy approaches based on nanoparticle delivery devices JOURNAL OF PHARMACEUTICAL INVESTIGATION Gupta, B., Kim, J. 2021; 51 (4): 399-412
  • Blocking integrin alpha(4)beta(7)-mediated CD4 T cell recruitment to the intestine and liver protects mice from western diet-induced non-alcoholic steatohepatitis JOURNAL OF HEPATOLOGY Rai, R. P., Liu, Y., Iyer, S. S., Liu, S., Gupta, B., Desai, C., Kumar, P., Smith, T., Singhi, A. D., Nusrat, A., Parkos, C. A., Monga, S. P., Czaja, M. J., Anania, F. A., Raeman, R. 2020; 73 (5): 1013-1022


    The heterodimeric integrin receptor α4β7 regulates CD4 T cell recruitment to inflamed tissues, but its role in the pathogenesis of non-alcoholic steatohepatitis (NASH) is unknown. Herein, we examined the role of α4β7-mediated recruitment of CD4 T cells to the intestine and liver in NASH.Male littermate F11r+/+ (control) and junctional adhesion molecule A knockout F11r-/- mice were fed a normal diet or a western diet (WD) for 8 weeks. Liver and intestinal tissues were analyzed by histology, quantitative reverse transcription PCR (qRT-PCR), 16s rRNA sequencing and flow cytometry. Colonic mucosa-associated microbiota were analyzed using 16s rRNA sequencing. Liver biopsies from patients with NASH were analyzed by confocal imaging and qRT-PCR.WD-fed knockout mice developed NASH and had increased hepatic and intestinal α4β7+ CD4 T cells relative to control mice who developed mild hepatic steatosis. The increase in α4β7+ CD4 T cells was associated with markedly higher expression of the α4β7 ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the colonic mucosa and livers of WD-fed knockout mice. Elevated MAdCAM-1 expression correlated with increased mucosa-associated Proteobacteria in the WD-fed knockout mice. Antibiotics reduced MAdCAM-1 expression indicating that the diet-altered microbiota promoted colonic and hepatic MAdCAM-1 expression. α4β7 blockade in WD-fed knockout mice significantly decreased α4β7+ CD4 T cell recruitment to the intestine and liver, attenuated hepatic inflammation and fibrosis, and improved metabolic indices. MAdCAM-1 blockade also reduced hepatic inflammation and fibrosis in WD-fed knockout mice. Hepatic MAdCAM-1 expression was elevated in patients with NASH and correlated with higher expression of α4 and β7 integrins.These findings establish α4β7/MAdCAM-1 as a critical axis regulating NASH development through colonic and hepatic CD4 T cell recruitment.Non-alcoholic steatohepatitis (NASH) is an advanced and progressive form of non-alcoholic fatty liver disease (NAFLD), and despite its growing incidence no therapies currently exist to halt NAFLD progression. Herein, we show that blocking integrin receptor α4β7-mediated recruitment of CD4 T cells to the intestine and liver not only attenuates hepatic inflammation and fibrosis, but also improves metabolic derangements associated with NASH. These findings provide evidence for the potential therapeutic application of α4β7 antibody in the treatment of human NASH.

    View details for DOI 10.1016/j.jhep.2020.05.047

    View details for Web of Science ID 000579809700005

    View details for PubMedID 32540177

    View details for PubMedCentralID PMC7839272

  • Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic activities JOURNAL OF HEMATOLOGY & ONCOLOGY Choi, Y., Jang, H., Gupta, B., Jeong, J., Ge, Y., Yong, C., Kim, J., Bae, J., Song, I., Kim, I., Lee, Y. 2020; 13 (1): 123


    Conventional therapeutic approaches for tumor angiogenesis, which are primarily focused on the inhibition of active angiogenesis to starve cancerous cells, target the vascular endothelial growth factor signaling pathway. This aggravates hypoxia within the tumor core and ultimately leads to increased tumor proliferation and metastasis. To overcome this limitation, we developed nanoparticles with antiseptic activity that target tumor vascular abnormalities.Ferritin-based protein C nanoparticles (PCNs), known as TFG and TFMG, were generated and tested in Lewis lung carcinoma (LLC) allograft and MMTV-PyMT spontaneous breast cancer models. Immunohistochemical analysis was performed on tumor samples to evaluate the tumor vasculature. Western blot and permeability assays were used to explore the role and mechanism of the antitumor effects of PCNs in vivo. For knocking down proteins of interest, endothelial cells were transfected with siRNAs. Statistical analysis was performed using one-way ANOVA followed by post hoc Dunnett's multiple comparison test.PCNs significantly inhibited hypoxia and increased pericyte coverage, leading to the inhibition of tumor growth and metastasis, while increasing survival in LLC allograft and MMTV-PyMT spontaneous breast cancer models. The coadministration of cisplatin with PCNs induced a synergistic suppression of tumor growth by improving drug delivery as evidenced by increased blood prefusion and decreased vascular permeability. Moreover, PCNs altered the immune cell profiles within the tumor by increasing cytotoxic T cells and M1-like macrophages with antitumor activity. PCNs induced PAR-1/PAR-3 heterodimerization through EPCR occupation and PAR-1 activation, which resulted in Gα13-RhoA-mediated-Tie2 activation and stabilized vascular tight junctions via the Akt-FoxO3a signaling pathway.Cancer treatment targeting the tumor vasculature by inducing antitumor immune responses and enhancing the delivery of a chemotherapeutic agent with PCNs resulted in tumor regression and may provide an effective therapeutic strategy.

    View details for DOI 10.1186/s13045-020-00952-9

    View details for Web of Science ID 000571957600001

    View details for PubMedID 32928251

    View details for PubMedCentralID PMC7489044

  • Stealth Polymer-Coated Graphene Oxide Decorated Mesoporous Titania Nanoplatforms for In Vivo Chemo-Photodynamic Cancer Therapy PHARMACEUTICAL RESEARCH Gautam, M., Gupta, B., Soe, Z., Poudel, K., Maharjan, S., Jeong, J., Choi, H., Ku, S., Yong, C., Kim, J. 2020; 37 (8): 162


    The goal of this study was to develop chemotherapeutic drug-loaded photoactivable stealth polymer-coated silica based- mesoporous titania nanoplatforms for enhanced antitumor activity.Both in vitro and in vivo models of solvothermal treated photoactivable nanoplatforms were evaluated for efficient chemo-photothermal activity. A versatile nanocomposite that combined silica based- mesoporous titania nanocarriers (S-MTN) with the promising photoactivable agent, graphene oxide (G) modified with a stealth polymer (P) was fabricated to deliver chemotherapeutic agent, imatinib (I), (referred as S-MTN@IG-P) for near-infrared (NIR)-triggered drug delivery and enhanced chemo-photothermal therapy.The fabricated S-MTN@IG-P nanoplatform showed higher drug loading (~20%) and increased drug release (~60%) in response to light in acidic condition (pH 5.0). As prepared nanoplatform significantly converted NIR light into thermal energy (43.2°C) to produce reactive oxygen species (ROS). The pronounced cytotoxic effect was seen in both colon cancer cells (HCT-116 and HT-29) that was mediated through the chemotherapeutic effect of imatinib and the photothermal and ROS generation effects of graphene oxide. In vivo study also showed that S-MTN@IG-P could significantly accumulate into the tumor area and suppress the tumor growth under NIR irradiation without any biocompatibility issues.Cumulatively, the above results showed promising effects of S-MTN@IG-P for effective chemo-phototherapy of colon cancer.

    View details for DOI 10.1007/s11095-020-02900-1

    View details for Web of Science ID 000560362600001

    View details for PubMedID 32749542

  • Western diet-induced increase in colonic bile acids compromises epithelial barrier in nonalcoholic steatohepatitis FASEB JOURNAL Gupta, B., Liu, Y., Chopyk, D. M., Rai, R. P., Desai, C., Kumar, P., Farris, A. B., Nusrat, A., Parkos, C. A., Anania, F. A., Raeman, R. 2020; 34 (5): 7089-7102


    There is compelling evidence implicating intestinal permeability in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain poorly understood. Here we examined the role of bile acids (BA) in western diet (WD)-induced loss of colonic epithelial barrier (CEB) function in mice with a genetic impairment in intestinal epithelial barrier function, junctional adhesion molecule A knockout mice, F11r-/- . WD-fed knockout mice developed severe NASH, which was associated with increased BA concentration in the cecum and loss of CEB function. Analysis of cecal BA composition revealed selective increases in primary unconjugated BAs in the WD-fed mice, which correlated with increased abundance of microbial taxa linked to BA metabolism. In vitro permeability assays revealed that chenodeoxycholic acid (CDCA), which was elevated in the cecum of WD-fed mice, increased paracellular permeability, while the BA-binding resin sevelamer hydrochloride protected against CDCA-induced loss of barrier function. Sequestration of intestinal BAs by in vivo delivery of sevelamer to WD-fed knockout mice attenuated colonic mucosal inflammation and improved CEB. Sevelamer also reduced hepatic inflammation and fibrosis, and improved metabolic derangements associated with NASH. Collectively, these findings highlight a hitherto unappreciated role for BAs in WD-induced impairment of the intestinal epithelial barrier in NASH.

    View details for DOI 10.1096/fj.201902687R

    View details for Web of Science ID 000531325500073

    View details for PubMedID 32275114

    View details for PubMedCentralID PMC7831197

  • Phytosterol-loaded CD44 receptor-targeted PEGylated nano-hybrid phyto-liposomes for synergistic chemotherapy EXPERT OPINION ON DRUG DELIVERY Gautam, M., Thapa, R., Gupta, B., Soe, Z., Ou, W., Poudel, K., Jin, S., Choi, H., Yong, C., Kim, J. 2020; 17 (3): 423-434


    Background: Phytosterols significantly reduce the risk of cancer by directly inhibiting tumor growth, inducing apoptosis, and inhibiting tumor metastasis. Stigmasterol (STS), a phytosterol, exhibits anticancer effects against various cancers, including breast cancer. Chemotherapeutics, including doxorubicin (DOX), might act synergistically with phytosterol against the proliferation and metastasis of breast cancer. Although such compounds can show potential anticancer activity, their combined effect with suitable formulation has not investigated yet.Methods: Hyaluronic acid (HA)-modified PEGylated DOX-STS loaded phyto-liposome was fabricated via a thin-film hydration method. The prepared phyto-liposome was optimized with regards to its physicochemical and other properties. Further, in vitro and in vivo study was carried out in breast cancer cells expressing a different level of CD44 receptors.Results: The particle size of prepared HA-DOX-STS-lipo was 173.9 ± 2.4 nm, and showed pH-depended DOX release, favoring the effective tumor targetability. The in vitro anticancer activity of HA-DOX-STS-lipo was significantly enhanced in MDA-MB-231, CD44-overexpressing cells relative to MCF-7 cells demonstrating HA-mediated targeting effect. HA-DOX-STS-lipo accumulated more and increased antitumor efficacy in the MDA-MB-231 xenograft tumor model expressing high levels of CD44, suggesting the potential of carrier system toward CD44-overexpressing tumors.

    View details for DOI 10.1080/17425247.2020.1727442

    View details for Web of Science ID 000513779500001

    View details for PubMedID 32028805

  • Multifaceted NIR-responsive polymer-peptide-enveloped drug-loaded copper sulfide nanoplatform for chemo-phototherapy against highly tumorigenic prostate cancer NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE Poudel, K., Thapa, R., Gautam, M., Ou, W., Soe, Z., Gupta, B., Ruttala, H., Hanh Nguyen Thuy, Phung Cao Dai, Jeong, J., Ku, S., Choi, H., Yong, C., Kim, J. 2019; 21: 102042


    Targeted, biocompatible, and synergistic "all in one" systems should be designed to combat the heterogeneity of cancer. In this study, we constructed a dual function nanosystem, copper sulfide nanoplatform loaded with the chemotherapeutic drug docetaxel wrapped by a conjugated polymer-peptide for targeted chemo-phototherapy. The nanoconstruct has been successfully designed with a size of 186.1 ± 5.2 nm, a polydispersity index of 0.18 ± 0.01, and zeta potential of -16.4 ± 0.1 mV. The enhanced uptake and near-infrared-responsive behavior of the nanosystem resulted in efficient drug release, photothermal ablation, effective cytotoxic activity, and potentiated reactive oxygen species generation. The induction of apoptotic markers, enhanced accumulation in the tumor site, and maximum tumor growth inhibition were seen during in vivo studies compared to non-targeted nanoformulations and free drug. Cumulatively, our results indicate that, with low systemic toxicity and better biocompatibility, this nanoconstruct could provide a promising strategy for treating prostate cancer.

    View details for DOI 10.1016/j.nano.2019.102042

    View details for Web of Science ID 000503261200006

    View details for PubMedID 31247311

  • Aerosol technique-based carbon-encapsulated hollow mesoporous silica nanoparticles for synergistic chemo-photothermal therapy ACTA BIOMATERIALIA Gautam, M., Thapa, R., Poudel, B., Gupta, B., Ruttala, H., Hanh Thuy Nguyen, Soe, Z., Ou, W., Poudel, K., Choi, H., Ku, S., Yong, C., Kim, J. 2019; 88: 448-461


    Near-infrared (NIR)-responsive drug delivery systems have enhanced tumor ablative efficiency through permeation and retention effects. Graphene oxide (GO) has shown great potential both in photothermal therapy and in drug delivery. Thus, in this study, we designed an ambient spark-generated GO, wrapped on topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSN-NH2-TPT-CGO), to function as an efficient platform for pH-dependent sustained release of TPT. HMSN-NH2-TPT-CGO also exhibited a combined chemo-photothermal effect within a single carrier system. This developed system was stable with a uniform particle size (∼190 nm) and was demonstrated to possess a sufficient heat-absorbing capacity to induce tumor cell ablation. We performed the ablation of tumor cells both in vitro and in vivo in combination with photothermal therapy and chemotherapy using the spark-generated functional GO and HMSN. The prepared nanocarriers demonstrated high cellular uptake, apoptosis, and G0/G1 cell cycle arrest. In vivo study using the MDA-MB-231 xenograft model revealed the ultraefficient tumor ablative performance of HMSN-NH2-TPT-CGO compared with that of free TPT, with no toxic effect on vital organs. Altogether, the optimized nanocarriers presented a significant potential to act as a vehicle for cancer treatment. STATEMENT OF SIGNIFICANCE: This is the first study that uses spark-generated graphene oxide nanoflakes to cover the topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSNs) to treat breast cancer. Dense silica was used as a hard template to prepare the HMSNs attributing to a high drug payload. The concentration of Na2CO3 was precisely controlled to minimize the silica etching time within 70 min. The use of the nanographene flakes served a dual purpose, first, by acting as a capping agent to prevent the premature release of drug and, second, by serving as a nano heater that significantly ablates the tumor cells. The prepared nanocarriers (NCs) exhibited effective and enhanced in vitro and in vivo apoptosis, as well as significant tumor growth inhibition even after 15 days of treatment time, with no toxic effect to the vital organs. The NCs enhanced in vitro tumor cell killing effects and served as an effective carrier for in vivo tumor regression, thereby highlighting the enormous potential of this system for breast cancer therapy.

    View details for DOI 10.1016/j.actbio.2019.02.029

    View details for Web of Science ID 000463688900035

    View details for PubMedID 30818051

  • Tailored Black Phosphorus for Erythrocyte Membrane Nanocloaking with Interleukin-1 alpha siRNA and Paclitaxel for Targeted, Durable, and Mild Combination Cancer Therapy THERANOSTICS Ou, W., Byeon, J., Soe, Z., Kim, B., Thapa, R., Gupta, B., Poudel, B., Ku, S., Yong, C., Kim, J. 2019; 9 (23): 6780-6796


    Several therapeutic nanosystems have been engineered to remedy the shortcomings of cancer monotherapies, including immunotherapy (stimulating the host immune system to eradicate cancer), to improve therapeutic efficacy with minimizing off-target effects and tumor-induced immunosuppression. Light-activated components in nanosystems confer additional phototherapeutic effects as combinatorial modalities; however, systemic and thermal toxicities with unfavorable accumulation and excretion of nanoystem components now hamper their practical applications. Thus, there remains a need for optimal multifunctional nanosystems to enhance targeted, durable, and mild combination therapies for efficient cancer treatment without notable side effects. Methods: A nanosystem constructed with a base core (poly-L-histidine [H]-grafted black phosphorus [BP]) and a shell (erythrocyte membrane [EM]) is developed to offer a mild photoresponsive (near-infrared) activity with erythrocyte mimicry. In-flight electrostatic tailoring to extract uniform BP nanoparticles maintains a hydrodynamic size of <200 nm (enabling enhanced permeability and retention) after EM cloaking and enhances their biocompatibility. Results: Ephrin-A2 receptor-specific peptide (YSA, targeting cancer cells), interleukin-1α silencing small interfering RNA (ILsi, restricting regulatory T cell trafficking), and paclitaxel (X, inducing durable chemotherapeutics) are incorporated within the base core@shell constructs to create BP-H-ILsi-X@EM-YSA architectures, which provide a more intelligent nanosystem for combination cancer therapies. Conclusion: The in-flight tailoring of BP particles provides a promising base core for fabricating <200 nm EM-mimicking multifunctional nanosystems, which could be beneficial for constructing smarter nanoarchitectures to use in combination cancer therapies.

    View details for DOI 10.7150/thno.37123

    View details for Web of Science ID 000487830500004

    View details for PubMedID 31660068

    View details for PubMedCentralID PMC6815959

  • Hyaluronic acid-capped compact silica-supported mesoporous titania nanoparticles for ligand-directed delivery of doxorubicin ACTA BIOMATERIALIA Gupta, B., Poudel, B., Ruttala, H., Regmi, S., Pathak, S., Gautam, M., Jin, S., Jeong, J., Choi, H., Ku, S., Yong, C., Kim, J. 2018; 80: 364–77


    Mesoporous titania nanoparticles (MTN), owing to their high surface area to volume ratio and tunable pore sizes, appear capable of delivering sizable amounts of drug payloads, and hence, show considerable promise as drug delivery candidates in cancer therapy. We designed silica-supported MTN (MTNst) coated with hyaluronic acid (HA) to effectively deliver doxorubicin (DOX) for breast cancer therapy. The HA coating served a dual purpose of stabilizing the payload in the carriers as well as actively targeting the nanodevices to CD44 receptors. The so-formed HA-coated MTNst carrying DOX (HA/DOX-MTNst) had spheroid particles with a considerable drug-loading capacity and showed significantly superior in vitro cytotoxicity against MDA-MB-231 cells as compared to free DOX. HA/DOX-MTNst markedly improved the cellular uptake of DOX in an apparently CD44 receptor-dependent manner, and increased the number of apoptotic cells as compared to free DOX. These nanoplatforms accumulated in large quantities in the tumors of MDA-MB-231 xenograft tumor-bearing mice, where they significantly enhanced the inhibition of tumor growth compared to that observed with free DOX with no signs of acute toxicity. Based on these excellent results, we deduced that HA/DOX-MTNst could be successfully used for targeted breast cancer therapy. STATEMENT OF SIGNIFICANCE: This is the first study to use silica-supported mesoporous titania nanoparticles (MTNst) for doxorubicin (DOX) delivery to treat breast cancer, which exhibited effective and enhanced in vitro and in vivo apoptosis and tumor growth inhibition. Solid silica was used to support the mesoporous TiO2 resulting in MTNst, which efficiently incorporated a high DOX payload. The hyaluronic acid (HA) coating over the MTNst surface served a dual purpose of first, stabilizing DOX inside the MTNst (capping agent), and second, directing the nanoplatform device to CD44 receptors that are highly expressed in MDA-MB-231 cells (targeting ligand). The NPs exhibited highly efficacious in vitro tumor-cell killing and excellent in vivo tumor regression, highlighting the enormous promise of this system for breast cancer therapy.

    View details for DOI 10.1016/j.actbio.2018.09.006

    View details for Web of Science ID 000449133400030

    View details for PubMedID 30201431

  • In situ fabrication of mesoporous silica-coated silver-gold hollow nanoshell for remotely controllable chemo-photothermal therapy via phase-change molecule as gatekeepers INTERNATIONAL JOURNAL OF PHARMACEUTICS Poudel, B., Soe, Z., Ruttala, H., Gupta, B., Ramasamy, T., Thapa, R., Gautam, M., Ou, W., Hanh Thuy Nguyen, Jeong, J., Jin, S., Choi, H., Yong, C., Kim, J. 2018; 548 (1): 92-103


    This study reports a new strategy for in situ fabrication of plasmonic hollow silver-gold nanoshell (with resonance tuned to NIR region) encased in the hollow mesoporous silica as an efficient platform to efficiently and precisely regulate the release of 5-fluorouracil (anticancer drug) for prostate cancer therapy and photothermal therapy. The mesopores were capped with thermosensitive phase-change material lauric acid, which allowed for remote, precise, and spatiotemporal control of drug release via external heating or photothermal heating of plasmonic silver-gold nanoshell via NIR laser irradiation. The system was nanometric, monodispersed, and showed negative surface charge. The nanocarrier showed better pH stability and thermodynamic stability compared to dense silica-coated gold nanoshells. The drug release could be triggered remotely by applying low powered continuous wave NIR laser (λ = 808 nm). The nanocarrier showed improved internalization by cancer cells, which was further enhanced by laser irradiation. High powered laser directly killed the cancer cells via photothermal effect in the region irradiated. Thus, this system fabricated by novel synthetic strategy provided efficient chemo- and phototherapy.

    View details for DOI 10.1016/j.ijpharm.2018.06.056

    View details for Web of Science ID 000440552100010

    View details for PubMedID 29959089

  • Polyamino Acid Layer-by-Layer (LbL) Constructed Silica-Supported Mesoporous Titania Nanocarriers for Stimuli-Responsive Delivery of microRNA 708 and Paclitaxel for Combined Chemotherapy ACS APPLIED MATERIALS & INTERFACES Gupta, B., Ruttala, H., Poudel, B., Pathak, S., Regmi, S., Gautam, M., Poudel, K., Sung, M., Ou, W., Jin, S., Jeong, J., Ku, S., Choi, H., Yong, C., Kim, J. 2018; 10 (29): 24392–405


    Cellular Fas-associated protein with death domain-like interleukin-1β-converting enzyme-inhibitory protein (c-FLIP), often strongly expressed in numerous cancers, plays a pivotal role in thwarting apoptosis and inducing chemotherapy resistance in cancer. An integrated approach combining chemotherapy with suppression of c-FLIP levels could prove paramount in the treatment of cancers with c-FLIP overexpression. In this study, we utilized a polymeric layer-by-layer (LbL) assembly of silica-supported mesoporous titania nanoparticles (MTNst) to co-deliver paclitaxel (PTX) and microRNA 708 (miR708) for simultaneous chemotherapy and c-FLIP suppression in colorectal carcinoma. The resulting LbL miR708/PTX-MTNst showed dose-dependent cytotoxicity in HCT-116 and DLD-1 colorectal carcinoma cell lines, which was remarkably superior to that of free PTX or LbL PTX-MTNst. LbL miR708/PTX-MTNst strongly inhibited c-FLIP expression and resulted in increased expression of proapoptotic proteins. In DLD-1 xenograft tumor-bearing mice, the nanoparticles accumulated in the tumor, resulting in remarkable tumor regression, with the PTX and miR708-loaded nanoparticles showing significantly greater inhibitory effects than the free PTX or PTX-loaded nanoparticles. Immunohistochemical analyses of the tumors further confirmed the remarkable apoptotic and antiproliferative effects of the nanoparticles, whereas organ histology reinforced the biocompatibility of the system. Therefore, the LbL miR708/PTX-MTNst system, owing to its ability to deliver both chemotherapeutic drug and inhibitory miRNA to the tumor site, shows great potential to treat colorectal carcinoma in clinical settings.

    View details for DOI 10.1021/acsami.8b06642

    View details for Web of Science ID 000440511900009

    View details for PubMedID 29978708

  • Polymeric microsphere-facilitated site-specific delivery of quercetin prevents senescence of pancreatic islets in vivo and improves transplantation outcomes in mouse model of diabetes ACTA BIOMATERIALIA Pathak, S., Regmi, S., Nguyen, T., Gupta, B., Gautam, M., Yong, C., Kim, J., Son, Y., Kim, J., Park, M., Bae, Y., Park, S., Jeong, D., Yook, S., Jeong, J. 2018; 75: 287–99


    Attenuation of senescence progression may be attractive way to preserve the functionality of pancreatic islets (PI) after transplantation. In this study, we developed a model for in vitro induction of premature senescence in rat PI and showed the effectiveness of quercetin (QU) to prevent the senescence. To provide targeted-delivery of QU to the PI after transplantation, we prepared the hybrid clusters (HC) of islet single cells (ISC) and QU-loaded polymeric microspheres (QU; ∼7.55 ng HC-1). Long-term culture of the HC revealed reduced levels of reactive oxygen species and decreased expression of senescence-associated beta galactosidase, Rb, p53, p16, and p21 compared to that of the control islets. Transplantation of HC into subcutaneous space of the immune-deficient mice produced better glycemic control compared to the control islets or the ICC-transplanted mice. SA-β-Gal staining of the in vivo transplanted HC sample showed lower intensity compared to that of the control islets or the islet cell clusters. Thus, in situ delivery of therapeutic agent may be a promising approach to improve therapeutic outcomes in cell therapy.In this study, we aimed to improve outcomes in islet transplantation using in situ delivery of quercetin to pancreatic islets, using polymeric microspheres. We prepared prolonged release-type microspheres and constructed hybrid clusters of pancreatic islets and the microspheres using hanging drop method. The presence of quercetin in the cellular microenvironment attenuated the progression of senescence in the pancreatic islets in a long-term in vitro culture. Moreover, transplantation of the hybrid clusters in the diabetic mice produced better glycemic control compared to that of the control islets. In addition, quercetin delayed the progression of senescence in the pancreatic islets after in vivo transplantation. Thus, local delivery of antioxidants like quercetin may be an attractive way to improve outcomes in cell therapy.

    View details for DOI 10.1016/j.actbio.2018.06.006

    View details for Web of Science ID 000440125600024

    View details for PubMedID 29883808

  • Paclitaxel and Erlotinib-co-loaded Solid Lipid Core Nanocapsules: Assessment of Physicochemical Characteristics and Cytotoxicity in Non-small Cell Lung Cancer PHARMACEUTICAL RESEARCH Gupta, B., Poudel, B., Regmi, S., Pathak, S., Ruttala, H., Gautam, M., An, G., Jeong, J., Choi, H., Yong, C., Kim, J. 2018; 35 (5): 96


    Lung cancer is the leading cause of cancer-related deaths. The aim of this study was to design solid lipid core nanocapsules (SLCN) comprising a solid lipid core and a PEGylated polymeric corona for paclitaxel (PTX) and erlotinib (ERL) co-delivery to non-small cell lung cancer (NSCLC), and evaluate their physicochemical characteristics and in vitro activity in NCI-H23 cells.PTX/ERL-SLCN were prepared by nanoprecipitation and sonication and physicochemically characterized by dynamic light scattering, transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy. In vitro release profiles at pH 7.4 and pH 5.0 were studied and analyzed. In vitro cytotoxicity and cellular uptake and apoptosis assays were performed in NCI-H23 cells.PTX/ERL-SLCN exhibited appropriately-sized spherical particles with a high payload. Both PTX and ERL showed pH-dependent and sustained release in vitro profiles. PTX/ERL-SLCN demonstrated concentration- and time-dependent uptake by NCI-H23 cells and caused dose-dependent cytotoxicity in the cells, which was remarkably greater than that of not only the free individual drugs but also the free drug cocktail. Moreover, well-defined early and late apoptosis were observed with clearly visible signs of apoptotic nuclei.PTX/ERL-SLCN could be employed as an optimal approach for combination chemotherapy of NSCLC.

    View details for DOI 10.1007/s11095-017-2337-6

    View details for Web of Science ID 000428687800002

    View details for PubMedID 29536182

  • PEGylated polyaminoacid-capped mesoporous silica nanoparticles for mitochondria-targeted delivery of celastrol in solid tumors COLLOIDS AND SURFACES B-BIOINTERFACES Choi, J., Gupta, B., Ramasamy, T., Jeong, J., Jin, S., Choi, H., Yong, C., Kim, J. 2018; 165: 56-66


    The major goal of cancer chemotherapy is to maximize the therapeutic efficacy of anticancer drugs, while minimizing their associated side effects. Celastrol (CST), which is extracted from the traditional Chinese medicinal plant Tripterygium wilfordii, has been reported to exhibit significant anticancer effects in various in vitro and in vivo cancer models. Nanoparticulate drug delivery systems could be employed to preserve and enhance the pharmacological effects of CST in cancer cells. Among these, mesoporous silica nanoparticles (MSNs) are one of the most promising drug delivery systems. MSNs possess the capability of passive accumulation within solid tumors, and could efficiently transport anticancer drugs to such tumors in a site-specific manner. In this study, PEGylated polyaminoacid-capped CST-loaded MSN (CMSN-PEG) showed controlled in vitro drug release behavior, and exhibited high in vitro cytotoxicity in different cancer cells. Compared to treatment with free CST, treatment with CMSN-PEG resulted in the increased expression of the apoptosis protein HIF-1α and proteins corresponding to mitochondrial apoptosis pathway. Importantly, CMSN-PEG remarkably reduced tumor burden with no toxicity to healthy cells in the SCC7 tumor-bearing xenograft model. Our results clearly demonstrate a promising potential of CMSN-PEG for the treatment of solid tumors.

    View details for DOI 10.1016/j.colsurfb.2018.02.015

    View details for Web of Science ID 000432506000007

    View details for PubMedID 29453086

  • PEGylated thermosensitive lipid-coated hollow gold nanoshells for effective combinational chemo-photothermal therapy of pancreatic cancer COLLOIDS AND SURFACES B-BIOINTERFACES Poudel, B., Gupta, B., Ramasamy, T., Thapa, R., Pathak, S., Oh, K., Jeong, J., Choi, H., Yong, C., Kim, J. 2017; 160: 73–83


    Pancreatic cancer has extremely poor prognosis with an 85% mortality rate that results from aggressive and asymptomatic growth, high metastatic potential, and rapid development of resistance to already ineffective chemotherapy. In this study, plasmonic hollow gold nanoshells (GNS) coated with PEGylated thermosensitive lipids were prepared as an efficient platform to ratiometrically co-deliver two drugs, bortezomib and gemcitabine (GNS-L/GB), for combinational chemotherapy and photothermal therapy of pancreatic cancer. Bortezomib was loaded within the lipid bilayers, while gemcitabine was loaded into the hydrophilic interior of the porous GNS via an ammonium sulfate-driven pH gradient method. Physicochemical characterizations and biological studies of GNS-L/GB were performed, with the latter using cytotoxicity assays, cellular uptake and apoptosis assays, live/dead assays, and western blot analysis of pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). The nanoshells showed remotely controllable drug release when exposed to near-infrared laser for site-specific delivery. GNS-L/GB showed synergistic cytotoxicity and improved internalization by cancer cells. High-powered near-infrared continuous wave laser (λ=808nm) effectively killed cancer cells via the photothermal effect of GNS-L/GB, irrespective of cell type in a power density-, time-, and GNS dose-dependent manner. These results suggest that this method can provide a novel approach to achieve synergistic combinational chemotherapy and photothermal therapy, even with resistant pancreatic cancer.

    View details for DOI 10.1016/j.colsurfb.2017.09.010

    View details for Web of Science ID 000418978500009

    View details for PubMedID 28917152

  • Engineered islet cell clusters transplanted into subcutaneous space are superior to pancreatic islets in diabetes FASEB JOURNAL Pathak, S., Regmi, S., Gupta, B., Tung Thanh Pham, Yong, C., Kim, J., Yook, S., Kim, J., Park, M., Bae, Y., Jeong, J. 2017; 31 (11): 5111–21


    An alternative route for pancreatic islet transplantation is the subcutaneous space; however, inadequate vascularization in the subcutaneous space limits the availability of oxygen and nutrients to the subcutaneously transplanted islets, which leads to the development of a necrotic core in the islets, thereby causing islet dysfunction. Thus, we aimed to prevent the early apoptosis of pancreatic islets after transplantation into subcutaneous space by preparing islet clusters of appropriate size. We prepared fully functional islet cell clusters (ICCs) by using the hanging-drop technique. We optimized the size of ICCs on the basis of viability and functionality after culture in an hypoxic environment. We transplanted ICCs into the subcutaneous space of diabetic mice and evaluated the viability of the islets at the transplantation site. In an hypoxic environment, ICCs exhibited improved viability and functionality compared with control islets. ICCs, upon transplantation into the hypoxic subcutaneous space of diabetic mice, showed better glycemic control compared with control islets. Live/dead imaging of the islets after retrieval from the transplanted area revealed significantly reduced apoptosis in ICCs. Transplantation of ICCs may be an attractive strategy to prevent islet cell apoptosis that results from nonimmune-mediated physiologic stress at the transplantation site.-Pathak, S., Regmi, S., Gupta, B., Pham, T. T., Yong, C. S., Kim, J. O., Yook, S., Kim, J.-R., Park, M. H., Bae, Y. K., Jeong, J.-H. Engineered islet cell clusters transplanted into subcutaneous space are superior to pancreatic islets in diabetes.

    View details for DOI 10.1096/fj.201700490R

    View details for Web of Science ID 000413398500038

    View details for PubMedID 28754712

  • Multiple polysaccharide-drug complex-loaded liposomes: A unique strategy in drug loading and cancer targeting CARBOHYDRATE POLYMERS Ruttala, H., Ramasamy, T., Gupta, B., Choi, H., Yong, C., Kim, J. 2017; 173: 57-66


    In the present study, a unique strategy was developed to develop nanocarriers containing multiple therapeutics with controlled release characteristics. In this study, we demonstrated the synthesis of dextran sulfate-doxorubicin (DS-DOX) and alginate-cisplatin (AL-CIS) polymer-drug complexes to produce a transferrin ligand-conjugated liposome. The targeted nanoparticles (TL-DDAC) were nano-sized and spherical. The targeted liposome exhibited a specific receptor-mediated endocytic uptake in cancer cells. The enhanced cellular uptake of TL-DDAC resulted in a significantly better anticancer effect in resistant and sensitive breast cancer cells compared to that of the free drugs. Specifically, DOX and CIS at a molar ratio of 1:1 exhibited better therapeutic performance compared to that of other combinations. The combination of an anthracycline-based topoisomerase II inhibitor (DOX) and a platinum compound (CIS) resulted in significantly higher cell apoptosis (early and late) in both types of cancer cells. In conclusion, treatment with DS-DOX and AL-CIS based combination liposomes modified with transferrin (TL-DDAC) was an effective cancer treatment strategy. Further investigation in clinically relevant animal models is warranted to prove the therapeutic efficacy of this unique strategy.

    View details for DOI 10.1016/j.carbpol.2017.05.062

    View details for Web of Science ID 000406182800007

    View details for PubMedID 28732901

  • Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice DRUG DELIVERY Pathak, S., Regmi, S., Gupta, B., Poudel, B. K., Tung Thanh Pham, Yong, C., Kim, J., Kim, J., Park, M., Bae, Y., Yook, S., Ahn, C., Jeong, J. 2017; 24 (1): 1350–59


    Immune rejection after transplantation is common, which leads to prompt failure of the graft. Therefore, to prolong the survival time of the graft, immunosuppressive therapy is the norm. Here, we report a robust immune protection protocol using FK506-loaded microspheres (FK506M) in injectable hydrogel. Pancreatic islets were codelivered with the FK506M into the subcutaneous space of streptozocin-induced diabetic mice. The islets codelivered with 10 mg/kg FK506M maintained normal blood glucose levels during the study period (survival rate: 60%). However, transplantation of islets and FK506M at different sites hardly controlled the blood glucose level (survival rate: 20%). Immunohistochemical analysis revealed an intact morphology of the islets transplanted with FK506M. In addition, minimal number of immune cells invaded inside the gel of the islet-FK506M group. The single injection of FK506M into the local microenvironment effectively inhibited immune rejection and prolonged the survival time of transplanted islets in a xenograft model.

    View details for DOI 10.1080/10717544.2017.1377317

    View details for Web of Science ID 000410914100002

    View details for PubMedID 28911248

  • Smart chemistry-based nanosized drug delivery systems for systemic applications: A comprehensive review JOURNAL OF CONTROLLED RELEASE Ramasamy, T., Ruttala, H., Gupta, B., Poudel, B., Choi, H., Yong, C., Kim, J. 2017; 258: 226-253


    This review focuses on the smart chemistry that has been utilized in developing polymer-based drug delivery systems over the past 10years. We provide a comprehensive overview of the different functional moieties and reducible linkages exploited in these systems, and outline their design, synthesis, and application from a therapeutic efficacy viewpoint. Furthermore, we highlight the next generation nanomedicine strategies based on this novel chemistry.

    View details for DOI 10.1016/j.jconrel.2017.04.043

    View details for Web of Science ID 000403886400021

    View details for PubMedID 28472638

  • Folate receptor-targeted hybrid lipid-core nanocapsules for sequential delivery of doxorubicin and tanespimycin COLLOIDS AND SURFACES B-BIOINTERFACES Gupta, B., Pathak, S., Poudel, B., Regmi, S., Ruttala, H., Gautam, M., Lee, J., Jeong, J., Choi, H., Yong, C., Kim, J. 2017; 155: 83–92


    When exposed to cancer cells, cytotoxic drugs such as doxorubicin (DOX) can lead to the induction of heat shock protein 90 (Hsp90), a molecular chaperone associated with a number of cancer-related client proteins, and result in cell survival. Co-administration of DOX with tanespimycin (TNP), an Hsp90 inhibitor, can sensitize the cancer cells to the cytotoxic effects of DOX. The effect of such a combination has been found to depend on the schedule of administration. Sequential administration of DOX and TNP has been linked to highly synergistic combination effects. Therefore, we aimed to develop folate-receptor targeted hybrid lipid-core nanocapsules comprising a hybrid lipid core lodging TNP and a polymeric corona lodging DOX (F-DTN). These nanocarriers were capable of delivering DOX and TNP sequentially, which was well demonstrated by an in vitro release study. The in vitro release profiles displayed pH-dependent and sustained release features. F-DTN exhibited excellent morphological characteristics with highly monodispersed particles. In vitro tests with F-DTN in MCF-7 cell line demonstrated exceptional cytotoxicity, with high cellular uptake and apoptosis. These findings were appreciably more assertive than tests with free individual drugs (DOX, TNP), free drug combination (DOX/TNP), or non-folate receptor-targeted hybrid lipid-core nanocapsules (DTN). In vivo pharmacokinetic study revealed noticeable enhancement of bioavailability and plasma circulation time of the drugs when encapsulated in the carrier system. Therefore, hybrid lipid-core nanocapsules have the potential to be utilized for application in folate receptor-targeted combination chemotherapy.

    View details for DOI 10.1016/j.colsurfb.2017.04.010

    View details for Web of Science ID 000403738000010

    View details for PubMedID 28410515

  • Preparation and Optimization of Immediate Release/Sustained Release Bilayered Tablets of Loxoprofen Using Box-Behnken Design AAPS PHARMSCITECH Tak, J., Gupta, B., Thapa, R., Woo, K., Kim, S., Go, T., Choi, Y., Choi, J., Jeong, J., Choi, H., Yong, C., Kim, J. 2017; 18 (4): 1125-1134


    The aim of our current study was to characterize and optimize loxoprofen immediate release (IR)/sustained release (SR) tablet utilizing a three-factor, three-level Box-Behnken design (BBD) combined with a desirability function. The independent factors included ratio of drug in the IR layer to total drug (X 1), ratio of HPMC to drug in the SR layer (X 2), and ratio of Eudragit RL PO to drug in the SR layer (X 3). The dependent variables assessed were % drug released in distilled water at 30 min (Y 1), % drug released in pH 1.2 at 2 h (Y 2), and % drug released in pH 6.8 at 12 h (Y 3). The responses were fitted to suitable models and statistical validation was performed using analysis of variance. In addition, response surface graphs and contour plots were constructed to determine the effects of different factor level combinations on the responses. The optimized loxoprofen IR/SR tablets were successfully prepared with the determined amounts of ingredients that showed close agreement in the predicted and experimental values of tablet characterization and drug dissolution profile. Therefore, BBD can be utilized for successful optimization of loxoprofen IR/SR tablet, which can be regarded as a suitable substitute for the current marketed formulations.

    View details for DOI 10.1208/s12249-016-0580-5

    View details for Web of Science ID 000404548700018

    View details for PubMedID 27401334

  • A three-dimensional assemblage of gingiva-derived mesenchymal stem cells and NO-releasing microspheres for improved differentiation INTERNATIONAL JOURNAL OF PHARMACEUTICS Regmi, S., Cao, J., Pathak, S., Gupta, B., Poudel, B., Pham Thanh Tung, Yook, S., Park, J., Yong, C., Kim, J., Yoo, J., Jeong, J. 2017; 520 (1-2): 163–72


    Stem cell therapy is an attractive approach to bone tissue regeneration. Nitric oxide (NO) has been reported to facilitate osteogenic differentiation of stem cells. To enhance osteogenic differentiation of gingiva-derived mesenchymal stem cells (GMSCs), we designed a method for in situ delivery of exogenous NO to these cells. A NO donor, polyethylenimine/NONOate, was incorporated into poly(lactic-co-glycolic acid) microspheres to deliver NO to the cells for an extended period of time under in vitro culture conditions. A hybrid aggregate of GMSCs and NO-releasing microspheres was prepared by the hanging drop technique. Confocal microscopy revealed homogeneous arrangement of the stem cells and microspheres in heterospheroids. Western blot analysis and live-dead imaging showed no significant change in cell viability. Importantly, the in situ delivery of NO within the heterospheroids enhanced osteogenic differentiation indicated by a 1.2-fold increase in alkaline phosphatase activity and an approximately 10% increase in alizarin red staining. In addition, a low dose of NO promoted proliferation of the GMSCs in this 3D system. Thus, delivery of the NO-releasing microsphers to induce differentiation of stem cells within this three dimensional system may be one of possible strategies to direct differentiation of a stem cell-based therapeutic agent toward a specific lineage.

    View details for DOI 10.1016/j.ijpharm.2017.02.014

    View details for Web of Science ID 000396948400018

    View details for PubMedID 28185957

  • Development of Bioactive PEGylated Nanostructured Platforms for Sequential Delivery of Doxorubicin and Imatinib to Overcome Drug Resistance in Metastatic Tumors ACS APPLIED MATERIALS & INTERFACES Gupta, B., Ramasamy, T., Poudel, B., Pathak, S., Regmi, S., Choi, J., Son, Y., Thapa, R., Jeong, J., Kim, J., Choi, H., Yong, C., Kim, J. 2017; 9 (11): 9280–90


    Metastasis of cancers accounts for almost all cancer-related deaths. In this study, we report a PEGylated nanostructured platform for coadministration of doxorubicin (DOX) and imatinib (IMT) intended to effectively inhibit metastatic tumors. The DOX and IMT coloaded nanostructured system (DOX/IMT-N) is characterized by an excellent encapsulation potential for both drugs and shows sequential and sustained drug release in vitro. DOX/IMT-N significantly inhibited the in vitro proliferation of MDA-MB-231 and SK-MEL-28 cells. The inhibitory effect on in vitro proliferation of the cells was significantly greater than the effect of free DOX, DOX/IMT cocktail, or the nanostructured system housing DOX only (DOX-N). DOX/IMT-N remarkably enhanced cellular drug uptake, resulting in enhanced apoptosis, caused by significant increases in the expression levels of apoptotic marker proteins. Intravenous administration of DOX/IMT-N to MBA-MB-231 xenograft tumor-bearing mice resulted in significantly improved inhibition of tumor progression compared to that with DOX, DOX/IMT, or DOX-N. Therefore, the nanostructured DOX/IMT-N system could potentially aid in overcoming drug resistance in metastatic tumors and improve the effectiveness of metastatic tumor therapeutics.

    View details for DOI 10.1021/acsami.6b09163

    View details for Web of Science ID 000397478100012

    View details for PubMedID 28240860

  • Preclinical and Clinical Studies Demonstrate That the Proprietary Herbal Extract DA-5512 Effectively Stimulates Hair Growth and Promotes Hair Health EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE Yu, J., Gupta, B., Park, H., Son, M., Jun, J., Yong, C., Kim, J., Kim, J. 2017; 2017: 4395638


    The proprietary DA-5512 formulation comprises six herbal extracts from traditional oriental plants historically associated with therapeutic and other applications related to hair. Here, we investigated the effects of DA-5512 on the proliferation of human dermal papilla cells (hDPCs) in vitro and on hair growth in C57BL/6 mice and conducted a clinical study to evaluate the efficacy and safety of DA-5512. DA-5512 significantly enhanced the viability of hDPCs in a dose-dependent manner (p < 0.05), and 100 ppm of DA-5512 and 1 μM minoxidil (MXD) significantly increased the number of Ki-67-positive cells, compared with the control group (p < 0.05). MXD (3%) and DA-5512 (1%, 5%) significantly stimulated hair growth and increased the number and length of hair follicles (HFs) versus the controls (each p < 0.05). The groups treated with DA-5512 exhibited hair growth comparable to that induced by MXD. In clinical study, we detected a statistically significant increase in the efficacy of DA-5512 after 16 weeks compared with the groups treated with placebo or 3% MXD (p < 0.05). In conclusion, DA-5512 might promote hair growth and enhance hair health and can therefore be considered an effective option for treating hair loss.

    View details for DOI 10.1155/2017/4395638

    View details for Web of Science ID 000400511800001

    View details for PubMedID 28539964

    View details for PubMedCentralID PMC5429933

  • Development of polymeric irinotecan nanoparticles using a novel lactone preservation strategy INTERNATIONAL JOURNAL OF PHARMACEUTICS Poudel, B., Gupta, B., Ramasamy, T., Thapa, R., Youn, Y., Choi, H., Yong, C., Kim, J. 2016; 512 (1): 75-86


    Irinotecan (IRT) is an important part of the first- and second-line regimen for metastatic colorectal and some other cancers. However, IRT suffers the constraints of pH-dependent conversion of active lactone form to inactive carboxylate form, burst release owing to its aqueous solubility, short half-life and dose-dependent side effects. In this study, we developed polymeric nanoparticles (NPs) that not only deliver IRT to tumor sites, but also overcome its drawbacks by preserving active lactone conformation, prolonging the plasma circulation time, and by providing sustained release. IRT complex was rendered hydrophobic by ion-pairing with anions (docusate sodium, sodium lauryl sulfate, and sodium tripolyphosphate), and loaded in PEG-PLGA NPs via water/oil/water double emulsification method. The NPs were spherical, ∼60nm, monodispersed, and had shell-core morphology. They retained >80% lactone form for more than 1 month of storage and exhibited sustained release characteristics. In addition, sub -100nm size of NPs offered elevated cellular internalization. Owing to the presence of hydrophilic PEG outer layer and drug-loaded hydrophobic PLGA core, NPs conferred excellent plasma stability and prolonged the retention time of IRT by more than 10-fold as compared to free IRT. Therefore, this system could provide an excellent platform for efficient and sustained delivery of IRT and similar labile drugs to the tumor site, while maintaining their chemical integrity.

    View details for DOI 10.1016/j.ijpharm.2016.08.018

    View details for Web of Science ID 000384863700008

    View details for PubMedID 27558884

  • Hybrid Congregation of Islet Single Cells and Curcumin-Loaded Polymeric Microspheres as an Interventional Strategy to Overcome Apoptosis Associated with Pancreatic Islets Transplantation ACS APPLIED MATERIALS & INTERFACES Pathak, S., Regmi, S., Gupta, B., Poudel, B. K., Tung Thanh Pham, Kim, J., Park, P., Yong, C., Kim, J., Bae, Y., Kim, S., Jeong, J. 2016; 8 (39): 25702–13


    Hypoxic or near-anoxic conditions that occur in the core of transplanted islets induce necrosis and apoptosis during the early stages after transplantation, primarily due to loss of vascularization during the isolation process. Moreover, secretion of various cytokines from pancreatic islets is detrimental to the viability of islet cells in vitro. In this study, we aimed to protect pancreatic islet cells against apoptosis by establishing a method for in situ delivery of curcumin to the pancreatic islets. Self-assembled heterospheroids composed of pancreatic islet cells and curcumin-loaded polymeric microspheres were prepared by the three-dimensional cell culture technique. Release of curcumin in the microenvironment of pancreatic islets promoted survival of the islets. In hypoxic culture conditions, which mimic the in vivo conditions after transplantation, viability of the islets was significantly improved, as indicated by a decreased expression of pro-apoptotic protein and an increased expression of anti-apoptotic protein. Additionally, oxidative stress-induced cell death was suppressed. Thus, unlike co-transplantation of pancreatic islets and free microspheres, which provided a wide distribution of microspheres throughout the transplanted area, the heterospheroid transplantation resulted in colocalization of pancreatic islet cells and microspheres, thereby exerting beneficial effects on the cells.

    View details for DOI 10.1021/acsami.6b07897

    View details for Web of Science ID 000384951800009

    View details for PubMedID 27666317

  • Effects of Formulation Variables on the Particle Size and Drug Encapsulation of Imatinib-Loaded Solid Lipid Nanoparticles AAPS PHARMSCITECH Gupta, B., Poudel, B., Pathak, S., Tak, J., Lee, H., Jeong, J., Choi, H., Yong, C., Kim, J. 2016; 17 (3): 652–62


    Imatinib (IMT), an anticancer agent, inhibits receptor tyrosine kinases and is characterized by poor aqueous solubility, extensive first-pass metabolism, and rapid clearance. The aims of the current study are to prepare imatinib-loaded solid lipid nanoparticles (IMT-SLN) and study the effects of associated formulation variables on particle size and drug encapsulation on IMT-SLN using an experimental design. IMT-SLN was optimized by use of a "combo" approach involving Plackett-Burman design (PBD) and Box-Behnken design (BBD). PBD screening resulted in the determination of organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), and amount of Tween® 20 (Tw20) as three significant variables for particle size (S z), drug loading (DL), and encapsulation efficiency (EE) of IMT-SLN, which were used for optimization by BBD, yielding an optimized criteria of O/A = 0.04, D/L = 0.03, and Tw20 = 2.50% w/v. The optimized IMT-SLN exhibited monodispersed particles with a size range of 69.0 ± 0.9 nm, ζ-potential of -24.2 ± 1.2 mV, and DL and EE of 2.9 ± 0.1 and 97.6 ± 0.1% w/w, respectively. Results of in vitro release study showed a sustained release pattern, presumably by diffusion and erosion, with a higher release rate at pH 5.0, compared to pH 7.4. In conclusion, use of the combo experimental design approach enabled clear understanding of the effects of various formulation variables on IMT-SLN and aided in the preparation of a system which exhibited desirable physicochemical and release characteristics.

    View details for DOI 10.1208/s12249-015-0384-z

    View details for Web of Science ID 000378939800012

    View details for PubMedID 26304931

  • Preparation of High-Payload, Prolonged-Release Biodegradable Poly(lactic-co-glycolic acid)-Based Tacrolimus Microspheres Using the Single-Jet Electrospray Method CHEMICAL & PHARMACEUTICAL BULLETIN Pathak, S., Gupta, B., Poudel, B., Tuan Hiep Tran, Regmi, S., Tung Thanh Pham, Thapa, R., Kim, M., Yong, C., Kim, J., Jeong, J. 2016; 64 (2): 171–78


    Tacrolimus-loaded poly(lactic-co-glycolic acid) microspheres (TAC-PLGA-M) can be administered for the long-term survival of transplanted organs due to their immunosuppressive activity. The purpose of our study was to optimize the parameters of the electrospray method, and to prepare TAC-PLGA-M with a high payload and desirable release properties. TAC-PLGA-M were prepared using the electrospray method. In vitro characterization and evaluation were performed using scanning electron microscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy. Drug-loading efficiency was greater than 80% in all formulations with a maximum loading capacity of 16.81±0.37%. XRD and DSC studies suggested that the drug was incorporated in an amorphous state or was molecularly dispersed in the microspheres. The in vitro release study showed prolonged release patterns. TAC-PLGA-M with enhanced drug loading and prolonged-release patterns were successfully prepared using the electrospray method.

    View details for DOI 10.1248/cpb.c15-00799

    View details for Web of Science ID 000369124300012

    View details for PubMedID 26833445

  • Liquid crystalline nanoparticles encapsulating cisplatin and docetaxel combination for targeted therapy of breast cancer BIOMATERIALS SCIENCE Thapa, R., Choi, J., Gupta, B., Ramasamy, T., Poudel, B., Ku, S., Youn, Y., Choi, H., Yong, C., Kim, J. 2016; 4 (9): 1340-1350


    Cancer remains a leading cause of death. A combination of anticancer agents can effectively kill cancer through multiple pathways; however, improvements to their delivery are needed. Hence, docetaxel and cisplatin-loaded liquid crystalline nanoparticles with folic acid were prepared for effective and targeted anticancer therapy. Notably, hydroxypropyl-β-cyclodextrin/cisplatin complexes in 0.9% NaCl solution were used for the prevention of possible aquation of cisplatin, which would otherwise lead to severe adverse effects. The optimized nanoparticles exhibited small particle size, high drug loading capacity (>90%), and controlled drug release profiles. In vitro cell cytotoxicity assays demonstrated that the optimized nanoparticles were taken up by folate receptor-expressing cells to a greater extent than non-folate expressing cells, which is attributable to folate-specific endocytosis of the optimized nanoparticles. Enhanced expression of apoptotic markers (Bax, p21, and cleaved caspase-3) along with enhanced anti-migration effects in MDA-MB-231 cells following treatment suggests that the optimized nanoparticles provide an effective treatment for metastatic breast cancer. These results were further supported by in vivo findings obtained for a MDA-MB-231 tumor xenograft model. Altogether, the optimized nanoparticles may potentially be developed as an effective treatment modality for folate-targeted metastatic breast cancer treatment.

    View details for DOI 10.1039/c6bm00376a

    View details for Web of Science ID 000382116200007

    View details for PubMedID 27412822

  • Co-aggregation of curcumin loaded poly (lactic-co-glycolic acid) microspheres with pancreatic islet cells into heterospheroids; a potential strategy to deliver drugs and biological agents to the islets of langerhans Jeong, J., Pathak, S., Gupta, B., Regmi, S., Pham Thanh Tung, Yong, C., Kim, J., Jeong, J. WILEY-BLACKWELL. 2015: S107
  • Multilayer-Coated Liquid Crystalline Nanoparticles for Effective Sorafenib Delivery to Hepatocellular Carcinoma ACS APPLIED MATERIALS & INTERFACES Thapa, R., Choi, J., Poudel, B. K., Tran Tuan Hiep, Pathak, S., Gupta, B., Choi, H., Yong, C., Kim, J. 2015; 7 (36): 20360–68


    Hepatocellular carcinoma is one of the most common cancers in adults and develops due to activation of oncogenes and inactivation of tumor suppressor genes. Sorafenib (SF) is a U.S. Food and Drug Administration (FDA) approved drug for the treatment of hepatocellular carcinoma. However, its clinical use is limited by its poor aqueous solubility and undesirable side effects. Monoolein-based liquid crystalline nanoparticles (LCN) are self-assembled structures that have been determined as promising drug-delivery vehicles. Therefore, the main aim of this study was to prepare layer-by-layer (LbL) polymer-assembled SF-loaded LCNs (LbL-LCN/SF) for effective delivery of SF to hepatocellular carcinoma. Results revealed that LbL-LCN/SF presented optimum particle size (∼165 nm) and polydispersity index (PDI, ∼0.14) with appropriate polymer layer assembly confirmed by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Furthermore, LbL-LCN/SF effectively controlled burst release and exhibited pH-sensitive release of SF, thereby increasing drug release in the acidic microenvironment of tumor cells. Compared to free SF and bare LCN, the hemolytic activity of LbL-LCN/SF was significantly reduced (p<0.01). Interestingly, LbL-LCN/SF was more cytotoxic to HepG2 cells than the free drug was. Additionally, high cellular uptake and greater apoptotic effects of LbL-LCN/SF in HepG2 cells indicates superior antitumor effects. Therefore, LbL-LCN/SF is a potentially effective formulation for hepatocellular carcinoma.

    View details for DOI 10.1021/acsami.5b06203

    View details for Web of Science ID 000361501700058

    View details for PubMedID 26315487

  • Modulation of Pharmacokinetic and Cytotoxicity Profile of Imatinib Base by Employing Optimized Nanostructured Lipid Carriers PHARMACEUTICAL RESEARCH Gupta, B., Poudel, B., Tuan Hiep Tran, Pradhan, R., Cho, H., Jeong, J., Shin, B., Choi, H., Yong, C., Kim, J. 2015; 32 (9): 2912-2927


    To prepare, optimize and characterize imatinib-loaded nanostructured lipid carriers (IMT-NLC), and evaluate their pharmacokinetic and cytotoxicity characteristics.IMT-NLC was prepared by hot homogenization method, and optimized by an approach involving Plackett-Burman design (PBD) and central composite design (CCD). An in vivo pharmacokinetic study was conducted in rats after both oral and intravenous administration. The in vitro cytotoxicity was evaluated by MTT assay on NCI-H727 cell-lines.PBD screening, followed by optimization by CCD and desirability function, yielded an optimized condition of 0.054, 6% w/w, 2.5% w/w and 1.25% w/v for organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), amount of lecithin (Lec) and amount of Tween® 20 (Tw20) respectively. The optimized IMT-NLC exhibited a particle size (Sz) of 148.80 ± 1.37 nm, polydispersity index (PDI) 0.191 ± 0.017 of and ζ-potential of -23.0 ± 1.5 mV, with a drug loading (DL) of 5.48 ± 0.01% and encapsulation efficiency (EE) of 97.93 ± 0.03%. IMT-NLC displayed sustained IMT release in vitro, significantly enhanced in vivo bioavailability of IMT after intravenous and oral administration, and greater in vitro cytotoxicity on NCI-H727 cells, compared with free IMT.A combined DoE approach enabled accurate optimization and successful preparation of IMT-NLC with enhanced in vivo pharmacokinetic and in vitro cytotoxicity characteristics.

    View details for DOI 10.1007/s11095-015-1673-7

    View details for Web of Science ID 000359140800010

    View details for PubMedID 25939551